Ann Thorac Surg 2005;80:757-767
© 2005 The Society of Thoracic Surgeons
Review
Effect of Cardioplegic and Organ Preservation Solutions and Their Components on Coronary Endothelium-Derived Relaxing Factors
Qin Yang, MD, PhD
a
,
Guo-Wei He, MD, PhD, DSc
a
,
b
,
c
,
d
,
*
a Department of Surgery, Oregon Health & Science University, Portland, Oregon
b Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
c Providence Heart Institute, Albert Starr Academic Center, Portland, Oregon
d Wuhan Heart Institute, The Central Hospital of Wuhan, Wuhan, China
Abbreviations and Acronyms Ca2+
= calcium; cAMP = cyclic 3'5'-adenosine monophosphate; cGMP = cyclic 3'5'-guanosine monophosphate; COX = cyclooxygenase; EDHF = endothelium-derived hyperpolarizing factor; EDRF = endothelium-derived relaxing factor; EET = epoxyeicosatrienoic acid; 5-HT = 5-hydroxytryptamine; HTK = histidine-tryptophan-ketoglutarate; ICAM = intercellular adhesion molecule; K+
= potassium; KATP
= ATP-sensitive K+ channel; KCa
= calcium-activated K+ channels; Kv = voltage-gated K+ channels; ligand for ICAM-1 = leukocyte molecule CD18; Mg2+
= magnesium; Na+
= sodium; NF-
B = nuclear factor -B; NHE = sodium-hydrogen ion exchange;
L-NNA =
N
G-nitro-L-arginine; NO = nitric oxide; NOS = nitric oxide synthase; PGI2
= prostacyclin; ST = St. Thomas Hospital; UW = University of Wisconsin
* Address reprint requests to Prof He, Department of Surgery, The Chinese University of Hong Kong, Block B, 5A, Prince of Wales Hospital, Shatin, N.T., Hong Kong SAR, China (Email: gwhe{at}cuhk.edu.hk).
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Abstract
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Cardioplegic (and organ preservation) solutions were initially designed to protect the myocardium (cardiac myocytes) during cardiac operation (and heart transplantation). Because of differences between cardiac myocytes and vascular (endothelial and smooth muscle) cells in structure and function, the solutions may have an adverse effect on coronary vascular cells. However, such effect is often complicated by many other factors such as ischemia-reperfusion injury, temperature, and perfusion pressure or duration. To evaluate the effect of a solution on the coronary endothelial function, a number of points should be taken into consideration. First, the overall effect on endothelium should be identified. Second, the effect of the solution on the individual endothelium-derived relaxing factors (nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor) must be distinguished. Third, the effect of each major component of the solution should be investigated. Lastly, the effect of a variety of new additives in the solution may be studied. Based on available literature these issues are reviewed to provide information for further development of cardioplegic or organ preservation solutions.
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Introduction
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Ischemia-reperfusion injury is the major problem in open-heart operations, including heart transplantation. The goal of cardioplegia was to eliminate this injury. Cardioplegic (and organ preservation) solutions were initially designed to protect the myocardium (cardiac myocytes) from ischemia-reperfusion injury. Subsequently, researchers found that, despite their protective effect on cardiac myocytes, these solutions may impair coronary vascular endothelial cells. These opposite effects are due to the differences in structure and function between cardiac myocytes and coronary vascular (endothelial and smooth muscle) cells.
A number of issues should be taken into account in the investigations regarding the effect of cardioplegic/organ preservation solutions on the coronary endothelial function. First, in the whole heart, the overall effect of these solutions is a result of the combination of the effect on the cardiac myocytes and the effect on the coronary endothelium. Second, even in studies focused on endothelial function, the effect of the solutions has often been mixed with ischemia-reperfusion injury and other factors. The goal of this review is to discuss the effect of the solutions and their components on the endothelium to provide information for further development of protective solutions. In addition, this review emphasizes the effect of cardioplegic/organ preservation solutions on individual endothelial factors.
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Literature Selection Methods
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A comprehensive English literature search through PubMed was performed with closing date of June 28, 2004. Multiple keywords were used for searching as follows: [(endothelium OR endothelial function OR EDRF)] AND [(cardiac operation OR heart transplantation)] OR [(cardioplegia OR cardioplegic solution OR organ preservation solution OR hyperkalemia)] AND [(cardioplegic additives OR supplementation OR adjunct)]. The focus of the literature selection was original studies. Book chapters or references before 1970 were occasionally cited for historic or technical aspects.
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Cardioplegic and Organ Preservation Solutions
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Crystalloid Cardioplegic Solutions
The introduction of cardioplegia for myocardial protection was a breakthrough in cardiac operations. Melrose and colleagues [1] in 1955 proposed the concept of chemical heart arrest with the mixture of blood and 2.5% solution of potassium citrate with the concentrations of potassium varying from 9 to 245 mEq/L in experimental studies, and the method was soon used clinically by Effler in 1957 [2]. However, the extremely high potassium concentrations in the Melrose solution were later demonstrated to induce myocardial necrosis and then abandoned. Bretschneider [3] reported to use low-sodium, mildly hyperkalemic (7 mEq/L), calcium-free procaine solution in Germany 1975, and Gay and Ebert [4] found that potassium crystalloid cardioplegia at a potassium concentration of 24 mEq/L increased recovery after ischemia. The effectiveness of moderately hyperkalemic potassium cardioplegia was then supported and was widely demonstrated by excellent clinical results in the 1970s. One of the widely used cardioplegic solutions was St. Thomas Hospital (ST) solution [5]. During the 1980s and early 1990s, hundred of studies of cardioplegia were published.
Due to its superb operating conditions and its effectiveness in myocardial preservation, cold cardioplegic arrest became the most commonly used method until blood cardioplegia became popular. During this period, a number of crystalloid cardioplegic solutions were developed, including histidine-tryptophan-ketoglutarate (HTK) solution [6]. Although the composition varies in different solutions, the pharmacologic principles involved in myocardial protection are similar [7, 8]. First, immediate arrest induced by K+, Mg2+, procaine, profound hypocalcemia, or a combination of these modalities lowers energy demand to avoid depletion of the high-energy phosphate pool and conserves the myocardial energy reserves that can be used during the period of ischemia to maintain ionic and metabolic homeostasis and, consequently, leads to the better tolerance to ischemia. Second, reduction of myocardial temperature during arrest or storage lowers metabolic rate during ischemia. Third, supplementation of glucose and amino acid (ie, glutamate or aspartate) enhances anaerobic or aerobic energy production (or both) with a buffer such as tris (hydroxymethyl) aminoethane, bicarbonate, phosphate, and histidine and optimizes the small energy output of anaerobic glycolysis during ischemia. Fourth, membrane stabilization provided by exogenous additives (ie, steroids, procaine, oxygen radical scavengers, Ca2+ antagonists), hypocalcemia, or enrichment of Mg2+ may counteract the myocardial injury during ischemia and reperfusion. Lastly, addition of an osmotic agent such as mannitol and adjustment of infusion pressure limit myocardial edema and prevent the occurrence of "no-flow phenomenon" [7, 8].
Blood Cardioplegia
Cold oxygenated blood with potassium as the arresting agent was described in the 1970s [9–11]. The presence of red cells and plasma proteins as well as other blood components provides a strong capacity for oxygen carrying, buffering, and antioxidation [11]. The most commonly used method is mixing the crystalloid cardioplegia with blood in a ratio of 1:4 [8, 11]. The final delivery concentrations of potassium remain at 20 to 25 mEq/L for the initial prompt arrest of the heart and 8 to 10 mEq/L for the subsequent delivery of the solution [8]. The final concentration of Mg2+ and procaine is less than that in crystalloid cardioplegic solutions such as ST. For example, the concentration of Mg2+ is 5 to 6 mEq/L in cold blood cardioplegia and 10 to 12 mEq/L in warm blood cardioplegia in the Buckberg blood cardioplegic solution [8]. Since the 1980s, blood cardioplegia has become the choice of myocardial protection in most cardiac units, although crystalloid cardioplegia is still used today because of either the preference of the surgeon or economic concerns.
Organ Preservation Solutions Including Crystalloid Cardioplegic Solutions Used for Heart Preservation
Preservation of the heart with organ preservation solutions has been demonstrated as a useful strategy in heart transplantation. These solutions protect the heart by controlling the risk factors involved in ischemic-reperfusion injury with similar principles of cardioplegic solutions, including reduction of oxygen demand, cellular swelling, extracellular edema, and Ca2+ overload [12]. In fact, commonly in cardiac operations one solution serves as both a cardioplegic and heart preservation solution. The composition of various crystalloid cardioplegic or heart preservation solutions are listed in Table 1.
University of Wisconsin solution
As an intracellular type of solution developed in 1980s, University of Wisconsin (UW) solution was initially developed for pancreas transplantation [13]. The effectiveness of this solution is proved in heart and lung preservation [14, 15]. However, although UW solution markedly extends preservation time for abdominal organs to tolerate 24 to 48 hours of cold ischemia, the safe time limit for cardiac preservation is only 4 to 6 hours [16].
St. Thomas Hospital solution
This crystalloid cardioplegic solution is an extracellular type of solution [5]. The subsequent discovery of the efficacy of St. Thomas Hospital (ST) solution in heart storage promoted its application in the field of heart preservation for transplantation [17, 18]. St. Thomas Hospital solution was widely used for cardioplegia in the 1970s and the 1980s until blood cardioplegia became popular. This solution is still used as crystalloid cardioplegia in some hospitals and also used as a cardioplegic additive for blood cardioplegia. Composition of ST solution varies between its two forms—the original ST solution and ST solution No. 2 (Plegisol). The composition of the ST solution used in our clinical and experimental studies is listed in Table 1.
Histidine-Tryptophan-Ketoglutarate solution
Similar to ST solution, HTK solution was initially developed for cardioplegia. Use of HTK solution was expanded to preservation of the liver, kidney, and pancreas as well as the heart and lung [19–23]. The protective effect of HTK solution is based on the high buffering capacity provided by histidine and its low electrolyte content, thus restricting tissue acidosis induced by ischemia [24].
Celsior solution
Celsior solution was developed for heart preservation not only as a storage medium but also as a perfusion fluid during initial donor-heart arrest, poststorage graft reimplantation, and early reperfusion [25]. Celsior formulation prevents cell swelling (by mannitol and lactobionate), oxygen-derived free radical injury (by reduced glutathione, histidine, and mannitol), and contracture by enhancement of energy production (glutamate) and limitation of calcium overload (high magnesium content, slight degree of acidosis) [25].
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Overall Effect of Cardioplegic and Organ Preservation Solutions on Coronary Endothelial Function
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Coronary circulation plays the key role in myocardial perfusion. Injury to the coronary circulation may change the coronary resistance and therefore affect the coronary flow. The reduction of coronary flow may damage myocardial perfusion. During cardiac arrest or heart preservation, the coronary vascular endothelium is immersed in the solution. Although the preservation effect of crystalloid cardioplegic or organ preservation solutions on the endothelial function has been reported [26–28], numerous studies provided evidence for endothelial damage after exposure to these solutions. Histologic examination and cell culture approach also revealed that crystalloid hyperkalemic cardioplegic solutions impair the vascular endothelium and reduce the ability of coronary endothelial cells to replicate [29, 30].
Factors Involved in the Effect of Cardioplegic and Organ Preservation Solutions
As mentioned before, the so-called effect of solutions on coronary endothelium is often mixed with the effects due to other factors combined with the cardioplegia procedure. That is, damage (or protection) to the endothelium may result from not only the solution per se, but also from other components of the procedure. Theoretically, these factors may include the following aspects:
- 1 Direct action of the solutions due to their intrinsic characteristics (the components of the solution)
- 2 Adjuncts to the cardioplegic procedure such as hypothermia or the infusion pressure or duration acting both as independent factors and through their interaction with cardioplegic solutions
- 3 The effect of ischemia-reperfusion injury
- 4 Other factors involved in isolated working heart models or in vivo models when these models are used to study endothelial function.
In these studies, the coronary flow is often used as the index of endothelial function but the flow is largely influenced by perfusion pressure [31, 32], contractility of the myocardium, and the function of the coronary smooth muscle, among other factors.
Due to the influence of these factors, studies suggested that crystalloid-perfused isolated heart is an inappropriate model to interpret the interaction between coronary flow reserve and ischemic injury [33]; use of vascular bed preparation was recommended in the assessment of vascular function [34].
Taken together, the "true" effect of the solutions on the endothelium should be carefully distinguished from other factors in order to identify the possible damaging effect due to the intrinsic characteristics of the solution.
Hyperkalemia on Endothelium-Regulated Coronary Flow or Endothelium-Dependent Relaxation
In Langendorff preparation of the rat heart [35] and an in vivo porcine model of cardiopulmonary bypass [36–38], cold hyperkalemic (25 or 40 mmol/L K+) cardioplegia reduced vasodilatory response to 5-hydroxytryptamine [35], adenosine phosphate, calcium ionophore A23187 [36–38], bradykinin, and the 
-agonist BHT-920 [38]. However, ischemia-reperfusion injury was another factor in these studies. The effect of the time of cold ischemic storage with cardioplegic solution was demonstrated [39, 40].
Comparison Between Crystalloid and Blood Cardioplegia
Compared with crystalloid cardioplegia, blood cardioplegia preserves the coronary endothelium [38, 40, 41] and prevents endothelial cells from deformity [40]. The impact of the ischemic period was also confirmed [40, 41]. However, with prolonged ischemic intervals, the preservative effect of intermittent antegrade warm blood cardioplegia was lost [40].
Effect of University of Wisconsin, Histidine-Tryptophan-Ketoglutarate, and Celsior Solutions
Numerous studies regarding the effect of heart preservation solutions on the endothelial function have been published. These experimental studies were performed in either hearts or coronary arteries of rat or piglet, aorta of rabbits, endothelial cells of bovine aorta or human saphenous or umbilical veins, but rarely in the coronary arteries of large mammals or humans. The results are largely conflicting because of the variety of experimental methods including the differences of the models, preservation duration and solution temperature, and the index for endothelial function. The results associated with UW and HTK solutions were well summarized in a recent review by Parolari and colleagues [42] and will not be repeated in this review. It has been reported that loss of endothelium-dependent vasodilatation and nitric oxide (NO) release on bradykinin stimulation after myocardial protection with UW solution in neonatal piglet heart [43].
Fewer studies have been conducted on the effect of Celsior solution. Kevelaitis and associates [44] reported protective effect of reduced glutathione on endothelial function of coronary arteries subjected to prolonged cold storage. Use of Celsior solution for induction of cardioplegia and storage better preserved endothelium-dependent G-protein-mediated relaxation compared with the other arrest and preservation strategies using blood and crystalloid solutions in heart transplantation [45]. Further, a comparison of UW and Celsior solutions revealed that total ischemic time correlated with impaired endothelial function in the Celsior but not in the UW group [46]. Again, in most of these studies, the effect of the solution was combined with other factors.
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Possible Mechanisms Underlying the Damage of Cardioplegia and Organ Preservation on Endothelial Function
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Possible mechanisms underlying the damage of cardioplegia and organ preservation on endothelial function include hyperkalemic components of the solutions (to be discussed in the next section), hypothermia and mechanical damage (perfusion pressure and duration; see details in a previous review [42]), and ischemia-reperfusion injury.
Oxidative stress-induced endothelial cell activation is the key component of the detrimental effect of ischemia-reperfusion. With expression of a set of proinflammatory, procoagulant, and vasoactive genes, a series of protein production steps in endothelial cells is promoted that causes intravascular microthrombosis, reduced blood flow, and activation of inflammatory cells. Among those proteins, the production of E-selectin, P-selectin, and intercellular adhesion molecules (ICAMs) lead to recruitment of neutrophils, which have been recognized as the principal effector cells of ischemia-reperfusion injury [47]. Leukocyte-endothelium adherence has indeed been observed after cardioplegic arrest and reperfusion [37].
Recently, the cellular mechanism underlying endothelial activation has been revealed with the study of nuclear factor -B (NF-B). Oxidative stress activates the tyrosine phosphorylation of IB, an inhibitor of NF-B that binds to NF-B in the cytoplasm; such phosphorylation dissociates IB from NF-B. The translocation of functional NF-B to the nucleus with binding to the target genes results in transcriptional activation of those genes [48]. In patients undergoing cardiopulmonary bypass with cardioplegic arrest, NF-B increased dramatically after reperfusion compared with before cardioplegia [49]. Therefore, targeting on the signaling pathway of endothelial cell activation may ameliorate cardioplegic arrest and reperfusion-induced endothelium impairment. Better recovery of coronary vascular response to serotonin and bradykinin in porcine coronary vessels and to acetylcholine in the neonatal lamb heart [51] was obtained by adding deferoxamine or manganese superoxide dismutase to the cardioplegic solution to reduce the oxygen-derived free radicals [50] or with leukocyte molecule CD18 (ligand for ICAM-1) antibody before cardioplegic arrest [51]. Moreover, transfection of NF-B decoy oligonucleotides into isolated heart blocked ICAM-1 upregulation and inhibited increase in neutrophil adhesion [52].
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Endothelial-Derived Relaxing Factors
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Endothelium has multiple functions, including regulation of vascular tone, prevention of platelet aggregation, antiproliferation, and so on [53]. This article reviews the effect of cardioplegic and organ preservation solutions on the endothelial function related to regulation of vascular tone—the endothelium-dependent relaxation. Endothelium-dependent relaxation is known to be mediated by three different endothelium-derived relaxing factors (EDRFs): nitric oxide (NO), prostacyclin (PGI2), and an unidentified endothelium-derived hyperpolarizing factor (EDHF).
Prostacyclin
Prostacyclin is the first defined relaxing factor derived from endothelium. Earlier in 1970s, Moncada, Vane, and others proposed that PGI2, a product of arachidonic acid metabolism of endothelium, has relaxant effect on vascular smooth muscle [54, 55]. When activated by stimuli, the enzyme phospholipase A2 in endothelial cells converts membrane phospholipids to arachidonic acid that is subsequently metabolized to PGI2, thromboxane A2, and several other prostaglandins (PGE2, PGF2, PGD2) through the action of cyclooxygenase (COX). When activated by sheer stress, hypoxia, or receptor-operated mechanisms, endothelial cells produce 10 to 20 times more PGI2 than the smooth muscle cells [55, 56]. Prostacyclin causes vasorelaxation in most arteries including the coronary bed [56–58], mediated by the rise of cyclic 3', 5'-adenosine monophosphate (cAMP) [59] that leads to the extrusion of Ca2+ from the cytosol [60] and the decreased sensitivity of the contractile apparatus to Ca2+ [61]. The relaxation may involve a Ca2+-independent mechanism [62] and membrane hyperpolarization of smooth muscle cell through potassium (K+) channels including ATP-sensitive K+ (KATP) channels [63, 64], calcium-activated K+ (KCa) channels [65], and voltage-gated K+ (Kv) channels [66, 67].
Nitric Oxide
In 1980, Furchgott and Zawadzki postulated that in rabbit aortic arteries, on stimulation of acetylcholine, endothelial cells release another vasodilator substance distinguished from PGI2 [68]. The existence of the EDRF was demonstrated by bioassay techniques and layered preparations [69, 70] and was subsequently identified as NO [71, 72]. Nitric oxide is synthesized from amino acid L-arginine by nitric oxide synthase (NOS). At least two major NOS isoforms exist. One isoform is expressed constitutively in neurons and vasculature that is involved in cell communication and is activated by an increase in intracellular calcium. The other isoenzyme exists in macrophages to participate in host defense and is not normally found in endothelial cells or vascular smooth muscle unless induced by cytokines [73]. As a mixed-function monooxygenase using NADPH, NOS oxidizes L-arginine to form NO and citrulline [74]. In the vascular system, the endothelium-derived NO diffuses from endothelial cell and acts on the underlying smooth muscle cell layer. The subsequent upregulation of cyclic 3', 5'-guanosine monophosphate (cGMP) in smooth muscle results in the activation of cGMP-dependent protein kinase that leads to vasorelaxation [75, 76]. Several types of K+ channels are involved in NO-mediated hyperpolarization—KATP and KCa channels through cGMP-dependent manner [77–79], KCa channels by direct activation [80], and the cGMP-independent stimulation of Na+-K+-ATPase [81].
Endothelium-Derived Hyperpolarizing Factor
Since Bolton and associates demonstrated that a muscarinic agonist elicited endothelium-dependent hyperpolarization of vascular smooth muscle cells [82], the hyperpolarizing phenomenon has been confirmed in various blood vessels, including coronary arteries [83, 84]. Further studies revealed the existence of a novel vasorelaxant agent termed endothelium-derived hyperpolarizing factor (EDHF) [83–86].
Certain investigators suggested that the so-called EDHF is merely an electrical signal conducted from the endothelial cell to the underlying smooth muscle cell through myoendothelial gap junctions, the intercellular connection between the layer of endothelium and smooth muscle [87–93]. Failure in detecting bioassayable hyperpolarizing substances may support this hypothesis [94]. Contrary to this viewpoint, others [95–97] and we [98] have found evidence that this factor is bioassayable and therefore is a transferable chemical(s). Several substances have been suggested to be EDHF, including epoxyeicosatrienoic acid (EET) [96, 99], anandamide [100], K+ [101], H2O2 [102], citrulline, NH3, and ATP [103]. The EDHF evokes hyperpolarization/relaxation of the smooth muscle by opening KCa channels, resulting in the closure of voltage-dependent Ca2+ channels and the reduction of intracellular free Ca2+ [84, 95–98, 104, 105]. The mechanisms of these three factors are shown in Figure 1.
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Fig 1. Diagram describing the pathways of endothelium-dependent vasorelaxation. Under sheer stress or the stimulation of agonists, [Ca2+]i rise in endothelial cells that leads to the release of prostacyclin (PGI2
), nitric oxide (NO), and endothelium-derived hyperpolarizing factor (EDHF). These three endothelium-derived relaxing factors decrease the [Ca2+]i in smooth muscle cells through different mechanisms and ultimately relax the smooth muscle. (BKCa
= large conductance calcium-activated potassium channel; cAMP = cyclic 3', 5'-adenosine monophosphate; cGMP = cyclic 3', 5'-guanosine monophosphate; EET = epoxyeicosatrienoic acid; IKCa
= intermediate conductance calcium-activated potassium channel; KATP
= ATP-sensitive potassium channel; Kir = inward rectifier potassium channel; R = receptor; SKCa
= small conductance calcium-activated potassium channel.)
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Influence of Cardioplegia and Organ Preservation Solutions on Individual Endothelium-Derived Relaxing Factors
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Prostacyclin
The increase of PGI2 release during myocardial ischemia with or without cardioplegic arrest has been demonstrated [106, 107]. Gene expression of COX-1 and PGI2 synthase were not altered after cardioplegia, but COX-1 protein level was significantly reduced accompanied with increased expression of COX-2 [108]. However, the combined effect of ischemia-reperfusion was not excluded. How long this increase would be maintained under hypoxic conditions is unknown.
Nitric Oxide
Studies have suggested impaired NO-related endothelial function during cardiopulmonary operations. By measuring the end products of NO—nitrite and nitrate—Gohra and coworkers demonstrated that NO release decreased significantly at approximately 70 minutes of crystalloid cardioplegic arrest in human coronary vasculature and was further reduced after reperfusion [109]. Similarly, the inability of the endothelium to release NO associated with reduced endothelium-dependent vasodilatation after infusion with UW solution [43] or loss of NO production after cardioplegia-reperfusion associated with decreased protein level of constitutive NO synthase [108] was demonstrated. The NO loss after cold (4°C) ischemic storage with crystalloid cardioplegia was recovered by chronic oral administration of L-arginine, the physiologic substrate of NO [110]. However, the combined ischemia-reperfusion injury was probably the main cause of the NO-related endothelial dysfunction in these and other studies [111, 112].
We have demonstrated that when the effect of ischemia-reperfusion is excluded, the NO-related, endothelium-dependent vasorelaxation after exposure to oxygenated crystalloid hyperkalemic cardioplegia to acetylcholine or substance P is well preserved in either porcine epicardial coronary arteries [113] or neonatal rabbit aorta [114]. Although in these studies, the indomethacin-resistant relaxation was actually mediated by both NO and EDHF, the unchanged endothelium-dependent response and the susceptibility of EDHF to cardioplegic solution [115–117] provided convincing evidence for the minimal impact of hyperkalemic cardioplegic solution on the NO-related function after exposure for a certain period (1 or 2 hours).
Endothelium-Derived Hyperpolarizing Factor
We conducted a series of experiments to investigate the effect of cardioplegic solution and organ preservation solutions on EDHF-mediated function. With exclusion of the effect of ischemia-reperfusion and elimination of the effect of PGI2 and NO, we have demonstrated that hyperkalemia [115, 116] as well as ST [117] and UW solutions [118] impair EDHF-related function either in porcine or human coronary arteries [115, 116]. The mechanism is due to the opposite effect of EDHF and hyperkalemia. Hyperkalemia depolarizes whereas EDHF hyperpolarizes the smooth muscle membrane. The persistent depolarizing effect of hyperkalemia even after washout of cardioplegic solutions restricts the hyperpolarizing effect of EDHF [105, 116, 118]. Use of potassium-channel openers as hyperpolarizing cardioplegia may overcome this shortage of hyperkalemic cardioplegia [119].
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Influence of Different Components in Cardioplegic and Organ Preservation Solutions on Endothelial Function
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Potassium
Potassium is the key component in cardioplegic or organ preservation solutions, as mentioned above. The concentration of K+ varies in different solutions. In UW solution, [K+] is as high as 125 mmol/L compared with only 20 mmol/L in ST and 10 mmol/L in HTK solution, respectively. The importance of K+ concentration with regard to coronary endothelial impairment has been revealed: K+ at 30 mmol/L but not at 20 mmol/L abolished endothelial-dependent, 5-hydroxytryptamine-induced vasodilatation [120].
In contrast, studies from others [26] and us have demonstrated that hyperkalemia per se does not significantly alter the endothelium-dependent relaxation as a whole to acetylcholine or substance P in porcine coronary arteries (to K+ 50 mmol/L) [113] and neonatal rabbit aorta (to K+ 100 mmol/L) [114]. These contradictory results should stimulate further investigation into the effect of hyperkalemia on individual relaxing factors derived from endothelial cells. As of now, little direct evidence exists to show that the reduction of the production of NO is due to hyperkalemia. Rather, reduced NO production is most likely due to the combined ischemia-reperfusion injury. When the capability of the endothelium to release NO is preserved or specific NO inhibitors are not present, the endothelium is tolerant to hyperkalemia as far as the endothelium-dependent relaxation is concerned, as shown above [26, 113, 114].
However, in contrast to NO, susceptibility of EDHF to high concentration of K+ has been demonstrated in accumulating studies. When the effect of PGI2 and NO is inhibited by indomethacin and N
G-nitro-L-arginine (L-NNA), the endothelium-dependent relaxation or hyperpolarization (mediated by EDHF) to a number of EDRF stimuli is impaired by incubation with K+ ranging from 20 to 125 mmol/L in porcine and human coronary arteries [105, 115, 116]. Realizing that L-NNA cannot abolish the production of NO, we further added oxyhemoglobin, a scavenger of NO, to abolish the effect of residual NO and demonstrated again the detrimental effect of hyperkalemia on EDHF-mediated relaxation and hyperpolarization in porcine coronary microarteries [121].
The mechanism of the reduced EDHF-mediated relaxation in hyperkalemic solutions is twofold. First, hyperkalemia depolarizes the coronary smooth muscle membrane and the prolonged depolarization increases the difficulty for subsequent hyperpolarization. Second, EDHF hyperpolarizes the vascular smooth muscle cell by opening K+ channels, the function of which may be blocked by K+ that inhibits K+ channels [105, 116].
Magnesium
The introduction of Mg2+ into cardioplegia helps to achieve immediate heart arrest during cardiac operations, and the enrichment of Mg2+ may counteract the unfavorable effect of hypocalcemia on sarcolemmal membrane by preventing calcium influx, thus obtaining better membrane stabilization [7]. In addition to the protective effect on myocardium [122, 123], Mg2+ has been proven to be a potent vasodilator through both endothelium-dependent and -independent mechanisms [124, 125]. The fact that Mg2+ infusion improves methacholine-induced vasorelaxation demonstrated the importance of endothelium in the effect of Mg2+ in human forearm vessels [126]. Pretreatment with the NOS inhibitor L-NAME (Nw-Nitro-L-arginine methyl ester) reduces Mg2+-mediated vasodilatation, and NO donor sodium nitroprusside or a cGMP analog, 3-guanosine monophosphate, restores the response to Mg2+, indicating the role of the NO-cGMP pathway in the action of Mg2+ [124, 125]. Moreover, the involvement of the COX system marked with the production of PGI2 has also been suggested in Mg2+-induced relaxation [125, 127]. Tofukuji and associates reported that hyper-Mg2+ cardioplegia (25 mmol/L Mg2+) is superior to hyper-K+ cardioplegia in terms of preserving ß-adrenoceptor-mediated and endothelium-dependent regulation of the coronary microcirculation in pigs undergoing cardiopulmonary bypass [128]. Further, Pearson and colleagues observed the inhibitory effect of hypomagnesemia on endothelium-dependent vasodilatation induced by acetylcholine or adenosine diphosphate; they proposed that such impairment of endothelial function is due to the decreased release of NO [129]. In addition, a recent study from our laboratory demonstrated that in porcine coronary arteries, Mg2+ preserves the EDHF-mediated relaxation and hyperpolarization and restores the EDHF function impaired by hyperkalemia [121].
Procaine
Similar to Mg2+, the local anesthetic procaine is added to cardioplegia to induce asystole and obtain membrane stabilization [7]. Procaine is recognized as a vasodilator [130, 131]. At a concentration of 1 mmol/L, procaine relaxes vascular smooth muscle not only in an endothelium-independent manner but also in an endothelium-dependent manner that is closely related to NO but not PGI2 [131]. We further showed that procaine does not affect EDHF function in coronary circulation [132] despite the fact that it depolarizes the membrane of vascular smooth muscle cells by reducing K+ conductance [133].
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Effect of Different Additives to Cardioplegic or Organ Preservation Solutions on Endothelial Function
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The additives that are intended to protect endothelial function may be categorized as follows:
- 1 Nitric oxide substrates or donors. The benefit of supplementation of NO precursor L-arginine or NO donors such as nitroglycerin in cardioplegia on postischemic ventricular performance and endothelial function has been well established; thus such supplementation is considered an effective replacement therapy in cardiac operation [134–136].
- 2 Prostacyclin analogs. Prostacyclin analogs such as iloprost and OP-41483, added to crystalloid cardioplegia, provide better preservation of cardiac function after ischemic arrest [137, 138].
- 3 Endothelium-derived hyperpolarizing factor analogs. Addition of epoxyeicosatrienoic acid11,12 (EET11,12), the possible analog of EDHF, to hyperkalemic solution may partially restore the bradykinin-induced, EDHF-mediated endothelial function in porcine coronary arteries [139]. Further, the benefit of EET11,12-supplementation in ST solution was shown under moderate hypothermia [140].
- 4 Potassium channel openers (KCOs). When added to hyperkalemic cardioplegia, aprikalim (a known adenosine triphosphate-sensitive KCO) reduces the Na+-Ca2+ exchange outward current elevated by hyperkalemia and thus may attenuate the [Ca2+]i elevation, leading to improved contractile function after cardioplegia in the ventricular myocyte [141]. In addition, supplementation with aprikalim in traditional hyperkalemic solutions preserves EDHF-mediated coronary relaxation, indicating its protective effect on endothelial function [142]. Other KCOs such as KRN4884 have been demonstrated to have a preconditioning effect on the EDHF-mediated relaxation and may be beneficial if added to cardioplegic solutions [143].
- 5 Scavengers of oxygen-derived free radicals. Supplementation of crystalloid cardioplegic solutions with free radical scavengers, such as ascorbate and deferoxamine, reduces postreperfusion myocardial injury [144] and preserves the endothelium-dependent vasodilatation in coronary microvessels [50].
- 6 Sodium-hydrogen ion exchange (NHE) inhibitors. The cardioprotective effect of NHE inhibitors is not only observed with perioperative administration to patients undergoing bypass operation [145], but also demonstrated when added into blood cardioplegia [146]. The decreased accumulation of intracellular Na+ and subsequently decreased Ca2+ overload contribute to the reduced postischemic infarct size and tissue edema due to the supplementation of the selective NHE type 1 isoform inhibitor, cariporide. In isolated postischemic left anterior descending coronary artery rings, maximum relaxation in response to acetylcholine was significantly greater in the cariporide group than in the vehicle group, indicating the preservation effect of cariporide on endothelium [146].
- 7 Other substances. Adenosine has been shown to partially attenuate the microcirculatory injury by cardioplegia [147] but the effect is controversial [148]. Adding phosphodiesterase III-inhibitor (E-1020) to Bretschneider’s HTK cardioplegic solution has been shown to improve myocardial functional recovery [149]. The finding that 17ß-estradiol prevented intracellular Ca2+ loading or hypercontracture of ventricular cardiomyocytes in high K+ exposure [150], together with its direct favorable effects on vascular endothelial function [151], raises the possibility of 17ß-estradiol acting as a cardioprotective adjunct in hyperkalemic cardioplegia. The effect of prevention of Ca2+ overloading by Ca2+ antagonists highlights the cardiovascular protective effect of Ca2+ antagonist-supplemented cardioplegic solutions [152, 153]. In addition to these strategies, solutions enriched with metabolic substrates (ie, glutamate, aspartate, fumarate, etc) have been used clinically for a long time for better myocardial protection [154]. However, little is known regarding the consequence of such enrichment on endothelial performance.
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Conclusion
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In summary, due to the differences between the cardiac myocytes and vascular (endothelial and smooth muscle) cells in structure and function, cardioplegic or organ preservation solutions primarily designed to protect the myocardium may have detrimental effects on coronary vascular endothelial cells, as demonstrated over the last few decades. One must be aware that under either experimental or clinical settings, the reported effects of the solutions on coronary endothelium are often mixed, with many other factors contributing to the outcome, such as ischemia-reperfusion injury, temperature, and perfusion pressure and duration.
In evaluating a clinically used solution and in developing a new solution, these factors should be carefully distinguished from the effect of the solution. The key component of the cardioplegic and heart preservation solutions that causes cardiac arrest—high concentrations of potassium ion (hyperkalemia)—is the major component that has been studied regarding endothelial function. Despite numerous studies that reported "impaired endothelial function or endothelium-dependent relaxation by hyperkalemia," most of these studies had combined effects due to ischemia-reperfusion injury or other factors. Little evidence exists to show that hyperkalemia changes NO-related endothelial function. The impairment of the NO pathway is mainly due to ischemia-reperfusion injury. In fact, without ischemia-reperfusion, the coronary-endothelial NO pathway is resistant to the moderately increased potassium concentrations used for cardioplegia (about 20 mEq/L). This fact explains the excellent clinical results by using either crystalloid or blood cardioplegia. However, the second endothelium-dependent relaxation pathway that is usually a "back-up" of the NO pathway—the EDHF pathway—is significantly altered (damaged) by hyperkalemia even at the moderately high concentration of potassium. This is because hyperkalemia inhibits K+ channels in the endothelium and smooth muscle that are related to either the release of EDHF from the endothelium or the target of the action of EDHF. Magnesium has a protective effect on this pathway because it hyperpolarizes the coronary smooth muscle membrane and therefore has "synergetic" effect with EDHF. When combined with ischemia-reperfusion and other factors that significantly impair the NO pathway, the effect of hyperkalemia on the EDHF pathway becomes an important issue in the protection of coronary endothelium.
A variety of new additives designed to protect these two major endothelium-dependent pathways may further improve the protection of the coronary endothelium from other factors such as ischemia-reperfusion injury. All these issues should be taken into account in the development of new cardioplegic and heart preservation solutions in the future in order to provide "perfect" cardiac protection.
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Acknowledgments
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This review was fully supported by grants from the Research Grants Council of the Hong Kong Special Administrative Region (Project No. CUHK4127/01 M & CUHK4383/03 M), China and the Providence St. Vincent Medical Foundation, Portland, OR.
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References
|
|---|
- Melrose DG, Dreyer B, Bentall HH, Barker JB. Elective cardiac arrest Lancet 1955;2:21-22.
- Effler DB, Knight HF, Groves LK, Kolff WJ. Elective cardiac arrest for open heart surgery Surg Gynecol Obstet 1957;105:407-416.[Medline]
- Bretschneider HJ, Hubner G, Knoll D, Lohr B, Nordbeck H, Spieckermann PG. Myocardial resistance and tolerance to ischemiaphysiological and biochemical basis. J Thorac Cardiovasc Surg 1975;16:241-260.
- Gay WA, Ebert PA. Functional, metabolic, and morphologic effects of potassium-induced cardioplegia Surgery 1973;74:284-290.[Medline]
- Hearse DJ, Stewart DA, Braimbridge MV. Cellular protection during myocardial ischemiathe development and characterization of a procedure for the induction of reversible ischemic arrest. Circulation 1976;54:193-202.[Abstract/Free Full Text]
- Gebhard MM, Preusse CJ, Schnabel PA, Bretschneider HJ. Different effects of cardioplegic solution HTK during single or intermittent administration Thorac Cardiovasc Surg 1984;32:271-276.[Medline]
- Vinten-Johansen J, Hammon JW. Myocardial protection during cardiac surgeryIn: Gravlee GP, Davis RF, Utley JR, editors. Cardiopulmonary Bypass. Principles and Practice. Baltimore, MD: Williams & Wilkins; 1993. pp. 155-206.
- Allen BS, Buckberg GD. Myocardial management in arterial revascularizationIn: He G-W, editor. Arterial Grafts for Coronary Artery Bypass Surgery. Singapore: Springer; 1999. pp. 83-105.
- Follette DM, Mulder DG, Maloney JV, Buckberg GD. Advantages of blood cardioplegia over continuous coronary perfusion or intermittent ischemiaexperimental and clinical study. J Thorac Cardiovas Surg 1978;76:604-619.[Medline]
- Laks H, Barner HB, Kaiser G. Cold blood cardioplegia J Thorac Cardiovasc Surg 1979;77:319-322.[Abstract]
- Barner HB. Blood cardioplegiaa review and comparison with crystalloid cardioplegia. Ann Thorac Surg 1991;52:1354-1367.[Abstract]
- Jahania MS, Sanchez JA, Narayan P, Lasley RD, Mentzer Jr RM. Heart preservation for transplantationprinciples and strategies. Ann Thorac Surg 1999;68:1983-1987.[Abstract/Free Full Text]
- Wahlberg JA, Southard JH, Belzer FO. Development of a cold storage solution for pancreas preservation Cryobiology 1986;23:477-482.[Medline]
- Swanson DK, Pasaoglu I, Berkoff HA, Southard JA, Hegge JO. Improved heart preservation with UW preservation solution J Heart Transplant 1988;7:456-467.[Medline]
- Rinaldi M, Martinelli L, Volpato G, et al. University of Wisconsin solution provides better lung preservation in human lung transplantation Transplant Proc 1995;27:2869-2871.[Medline]
- Stringham JC, Southard JH, Hegge J, Triemstra L, Fields BL, Belzer FO. Limitations of heart preservation by cold storage Transplantation 1992;53:287-294.[Medline]
- Wheeldon D, Sharples L, Wallwork J, English T. Donor heart preservation survey J Heart Lung Transplant 1992;11:986-993.[Medline]
- Demertzis S, Wippermann J, Schaper J, et al. University of Wisconsin versus St. Thomas’ Hospital solution for human donor heart preservation Ann Thorac Surg 1993;55:1131-1137.[Abstract]
- Gubernatis G, Dietl KH, Kemnitz J, et al. Extended cold preservation time (20 hours 20 minutes) of a human liver graft by using cardioplegic HTK solution Transplant Proc 1991;23:2408-2409.[Medline]
- Gschwend JE, de Petriconi R, Maier S, Kleinschmidt K, Hautmann RE. Continuous in situ cold perfusion with histidine tryptophan ketoglutarate solution in nephron sparing surgery for renal tumors J Urol 1995;154:1307-1311.[Medline]
- Brandhorst H, Hering BJ, Brandhorst D, et al. Comparison of histidine-tryptophane-ketoglutarate (HTK) and University of Wisconsin (UW) solution for pancreas perfusion before islet isolation, culture and transplantation Transplant Proc 1995;27:3175-3176.[Medline]
- Reichenspurner H, Russ C, Uberfuhr P, et al. Myocardial preservation using HTK solution for heart transplantation. A multicenter study Eur J Cardiothorac Surg 1993;7:414-419.[Abstract]
- Couraud L, Baudet E, Velly JF, Roques X, Martigne C, Gallon P, The Bordeaux Lung and Heart-Lung Transplant Group Lung and heart-lung transplantation for end-stage lung disease Eur J Cardiothorac Surg 1990;4:318-322.[Abstract]
- Gu K, Kin S, Saitoh Y, et al. HTK solution is more effective than UW solution for cardiac preservation Transplant Proc 1996;28:1906-1907.[Medline]
- Menasche P, Termignon JL, Pradier F, et al. Experimental evaluation of Celsior, a new heart preservation solution Eur J Cardiothorac Surg 1994;8:207-213.[Abstract]
- Evora PR, Pearson PJ, Schaff HV. Crystalloid cardioplegia and hypothermia do not impair endothelium-dependent relaxation or damage vascular smooth muscle of epicardial coronary arteries J Thorac Cardiovasc Surg 1992;104:1365-1374.[Abstract]
- Ekin ST, Pearson PJ, Evora PR, Schaff HV. One-hour exposure to University of Wisconsin solution does not impair endothelium-dependent relaxation or damage vascular smooth muscle of epicardial coronary arteries J Heart Lung Transplant 1993;12:624-633.[Medline]
- Sorajja P, Cable DG, Schaff HV. Hypothermic storage with University of Wisconsin solution preserves endothelial and vascular smooth-muscle function Circulation 1997;96(Suppl):II-297-II-303.
- Follet DM, Buckberg GD, Mulder DG, Fonkalsrud EW. Deleterious effects of crystalloid hyperkalemic cardioplegic solutions on arterial endothelial cells Surg Forum 1980;31:253.
- Nilsson FN, Miller VM, Johnson CM, Tazelaar H, McGregor CG. Cardioplegia alters porcine coronary endothelial cell growth and responses to aggregating platelets J Vasc Res 1993;30:43-52.[Medline]
- Katayama O, Amrani M, Ledingham S, et al. Effect of cardioplegia infusion pressure on coronary artery endothelium and cardiac mechanical function Eur J Cardiothorac Surg 1997;11:751-762.[Abstract]
- Cartier R, Pellerin M, Hollmann C, Pelletier LC. Effects of pressure and duration of hyperkalemic infusions on endothelial function Ann Thorac Surg 1993;55:700-705.[Abstract]
- Deng Q, Scicli AG, Lawton C, Silverman NA. Coronary flow reserve after ischemia and reperfusion of the isolated heart. Divergent results with crystalloid versus blood perfusion J Thorac Cardiovasc Surg 1995;109:466-472.[Abstract/Free Full Text]
- Saldanha C, Hearse DJ. Cardioplegia and vascular injury. Dissociation of the effects of ischemia from those of the cardioplegic solution J Thorac Cardiovasc Surg 1994;108:279-290.[Abstract/Free Full Text]
- Saldanha C, Hearse DJ. Coronary vascular responsiveness to 5-hydroxytryptamine before and after infusion of hyperkalemic crystalloid cardioplegic solution in the rat heart. Possible evidence of endothelial damage J Thorac Cardiovasc Surg 1989;98:783-787.[Abstract]
- Sellke FW, Shafique T, Schoen FJ, Weintraub RM. Impaired endothelium-dependent coronary microvascular relaxation after cold potassium cardioplegia and reperfusion J Thorac Cardiovasc Surg 1993;105:52-58.[Abstract]
- Sellke FW, Friedman M, Dai HB, et al. Mechanisms causing coronary microvascular dysfunction following crystalloid cardioplegia and reperfusion Cardiovasc Res 1993;27:1925-1932.[Abstract/Free Full Text]
- Nilsson FN, Miller VM, Vanhoutte PM, McGregor CG. Methods of cardiac preservation alter the function of the endothelium in porcine coronary arteries J Thorac Cardiovasc Surg 1991;102:923-930.[Abstract]
- Budrikis A, Liao Q, Bolys R, Westerlaken B, Steen S. Effects of cardioplegic flushing, storage, and reperfusion on coronary circulation in the pig Ann Thorac Surg 1999;67:1345-1349.[Abstract/Free Full Text]
- Curro D, Bombardieri G, Barilaro C, et al. Time dependence of endothelium-mediated vasodilation by intermittent antegrade warm blood cardioplegia Ann Thorac Surg 1997;64:1354-1359.[Abstract/Free Full Text]
- Harjula A, Mattila S, Mattila I, et al. Coronary endothelial damage after crystalloid cardioplegia J Cardiovasc Surg 1984;25:147-152.[Medline]
- Parolari A, Rubini P, Cannata A, et al. Endothelial damage during myocardial preservation and storage Ann Thorac Surg 2002;73:682-690.[Abstract/Free Full Text]
- Pearl JM, Laks H, Drinkwater DC, et al. Loss of endothelium-dependent vasodilatation and nitric oxide release after myocardial protection with University of Wisconsin solution J Thorac Cardiovasc Surg 1994;107:257-264.[Abstract/Free Full Text]
- Kevelaitis E, Nyborg NC, Menasche P. Protective effect of reduced glutathione on endothelial function of coronary arteries subjected to prolonged cold storage Transplantation 1997;64:660-663.[Medline]
- Perrault LP, Nickner C, Desjardins N, Dumont E, Thai P, Carrier M. Improved preservation of coronary endothelial function with Celsior compared with blood and crystalloid solutions in heart transplantation J Heart Lung Transplant 2001;20:549-558.[Medline]
- Wildhirt SM, Weis M, Schulze C, et al. Effects of Celsior and University of Wisconsin preservation solutions on hemodynamics and endothelial function after cardiac transplantation in humansa single-center, prospective, randomized trial. Transpl Int 2000;13(Suppl 1):S203-S211.
- Winn RK, Ramamoorthy C, Vedder NB, Sharar SR, Harlan JM. Leukocyte-endothelial cell interactions in ischemia-reperfusion injury Ann N Y Acad Sci 1997;832:311-321.[Medline]
- Boyle Jr EM, Canty Jr TG, Morgan EN, Yun W, Pohlman TH, Verrier ED. Treating myocardial ischemia-reperfusion injury by targeting endothelial cell transcription Ann Thorac Surg 1999;68:1949-1953.[Abstract/Free Full Text]
- Valen G, Paulsson G, Vaage J. Induction of inflammatory mediators during reperfusion of the human heart Ann Thorac Surg 2001;71:226-232.[Abstract/Free Full Text]
- Sellke FW, Shafique T, Ely DL, Weintraub RM. Coronary endothelial injury after cardiopulmonary bypass and ischemic cardioplegia is mediated by oxygen-derived free radicals Circulation 1993;88:II395-II400.
- Kawata H, Aoki M, Hickey PR, Mayer Jr JE. Effect of antibody to leukocyte adhesion molecule CD18 on recovery of neonatal lamb hearts after 2 hours of cold ischemia Circulation 1992;86:II364-II370.
- Kupatt C, Habazettl H, Goedecke A, et al. Tumor necrosis factor-alpha contributes to ischemia- and reperfusion-induced endothelial activation in isolated hearts Circ Res 1999;84:392-400.[Abstract/Free Full Text]
- Flavahan NA, Vanhoutte PM. Endothelial cell signaling and endothelial dysfunction Am J Hypertens 1995;8:28S-41S.[Medline]
- Moncada S, Gryglewski R, Bunting S, Vane JR. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation Nature 1976;263:663-665.[Medline]
- Eldor A, Falcone DJ, Hajjar DP, Minick CR, Weksler BB. Recovery of prostacyclin production by de-endothelialized rabbit aorta. Critical role of neointimal smooth muscle cells J Clin Invest 1981;67:735-741.
- Bunting S, Gryglewski R, Moncada S, Vane JR. Arterial walls generate from prostaglandin endoperoxides a substance (prostaglandin X) which relaxes strips of mesenteric and coeliac arteries and inhibits platelet aggregation Prostaglandins 1976;12:897-913.[Medline]
- Malomvolgyi B, Hadhazy P, Magyar K. Relaxation by prostacyclin (PGI2) of human, dog and rabbit femoral artery stripsinterspecies difference. Biomed Biochim Acta 1988;47:S125-S128.[Medline]
- Shirahase H, Usui H, Manabe K, Kurahashi K, Fujiwara M. Vasorelaxing effects of prostaglandin I2 on the canine basilar and coronary arteries J Pharmacol Exp Ther 1989;248:769-773.[Abstract/Free Full Text]
- Miller OV, Aiken JW, Hemker DP, Shebuski RJ, Gorman RR. Prostacyclin stimulation of dog arterial cyclic AMP levels Prostaglandins 1979;18:915-925.[Medline]
- Raeymaekers L, Eggermont JA, Wuytack F, Casteels R. Effects of cyclic nucleotide dependent protein kinases on the endoplasmic reticulum Ca2+ pump of bovine pulmonary artery Cell Calcium 1990;11:261-268.[Medline]
- Morgan JP, Morgan KG. Alteration of cytoplasmic ionized calcium levels in smooth muscle by vasodilators in the ferret J Physiol 1984;357:539-551.[Abstract/Free Full Text]
- Brophy CM, Whitney EG, Lamb S, Beall A. Cellular mechanisms of cyclic nucleotide-induced vasorelaxation J Vasc Surg 1997;25:390-397.[Medline]
- Murphy ME, Brayden JE. Apamin-sensitive K+ channels mediate an endothelium-dependent hyperpolarization in rabbit mesenteric arteries J Physiol 1995;489:723-734.[Abstract/Free Full Text]
- Corriu C, Feletou M, Canet E, Vanhoutte PM. Inhibitors of the cytochrome P450-mono-oxygenase and endothelium-dependent hyperpolarizations in the guinea-pig isolated carotid artery Br J Pharmacol 1996;117:607-610.[Medline]
- Schubert R, Serebryakov VN, Mewes H, Hopp HH. Iloprost dilates rat small arteriesrole of K(ATP)- and K(Ca)-channel activation by cAMP-dependent protein kinase. Am J Physiol 1997;272:H1147-H1156.
- Li PL, Zou AP, Campbell WB. Regulation of potassium channels in coronary arterial smooth muscle by endothelium-derived vasodilators Hypertension 1997;29:262-267.[Abstract/Free Full Text]
- Dong H, Waldron GJ, Cole WC, Triggle CR. Roles of calcium-activated and voltage-gated delayed rectifier potassium channels in endothelium-dependent vasorelaxation of the rabbit middle cerebral artery Br J Pharmacol 1998;123:821-832.[Medline]
- Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine Nature 1980;288:373-376.[Medline]
- Griffith TM, Edwards DH, Lewis MJ, Newby AC, Henderson AH. The nature of endothelium-derived vascular relaxant factor Nature 1984;308:645-647.[Medline]
- Rubanyi GM, Lorenz RR, Vanhoutte PM. Bioassay of endothelium-derived relaxing factor(s)inactivation by catecholamines. Am J Physiol 1985;249:H95-H101.
- Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide Proc Natl Acad Sci U S A 1987;84:9265-9269.[Abstract/Free Full Text]
- Palmer RM, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor Nature 1987;327:524-526.[Medline]
- Nijhawan N, Warltier DC. Regulation of the cardiovascular systemIn: Priebe HJ, Skarvan K, editors. Cardiovascular Physiology. London, England: BMJ Publishing Group; 2000. pp. 213-239.
- Leone AM, Palmer RM, Knowles RG, Francis PL, Ashton DS, Moncada S. Constitutive and inducible nitric oxide synthases incorporate molecular oxygen into both nitric oxide and citrulline J Biol Chem 1991;266:23790-23795.[Abstract/Free Full Text]
- Holzmann S. Endothelium-induced relaxation by acetylcholine associated with larger rises in cyclic GMP in coronary arterial strips J Cyclic Nucleotide Res 1982;8:409-419.[Medline]
- Rapoport RM, Draznin MB, Murad F. Endothelium-dependent relaxation in rat aorta may be mediated through cyclic GMP-dependent protein phosphorylation Nature 1983;306:174-176.[Medline]
- Murphy ME, Brayden JE. Nitric oxide hyperpolarizes rabbit mesenteric arteries via ATP-sensitive potassium channels J Physiol 1995;486:47-58.[Abstract/Free Full Text]
- Robertson BE, Schubert R, Hescheler J, Nelson MT. cGMP-dependent protein kinase activates Ca-activated K channels in cerebral artery smooth muscle cells Am J Physiol 1993;265:C299-C303.
- Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase Proc Natl Acad Sci U S A 1994;91:7583-7587.[Abstract/Free Full Text]
- Bolotina VM, Najibi S, Palacino JJ, Pagano PJ, Cohen RA. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle Nature 1994;368:850-853.[Medline]
- Gupta S, McArthur C, Grady C, Ruderman NB. Stimulation of vascular Na+-K+-ATPase activity by nitric oxidea cGMP-independent effect. Am J Physiol 1994;266:H2146-H2151.
- Bolton TB, Lang RJ, Takewaki T. Mechanisms of action of noradrenaline and carbachol on smooth muscle of guinea-pig anterior mesenteric artery J Physiol 1984;351:549-572.[Abstract/Free Full Text]
- Feletou M, Vanhoutte PM. Endothelium-dependent hyperpolarization of canine coronary smooth muscle Br J Pharmacol 1988;93:515-524.[Medline]
- Chen G, Suzuki H, Weston AH. Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels Br J Pharmacol 1988;98:1165-1174.
- Nagao T, Vanhoutte PM. Characterization of endothelium-dependent relaxations resistant to nitro-L-arginine in the porcine coronary artery Br J Pharmacol 1992;107:1102-1107.[Medline]
- Ge ZD, Zhang XH, Fung PC, He G-W. Endothelium-dependent hyperpolarization and relaxation resistance to N
G-nitro-L-arginine and indomethacin in coronary circulation Cardiovasc Res 2000;46:547-556.[Abstract/Free Full Text]
- Beny J. Electrical coupling between smooth muscle cells and endothelial cells in pig coronary arteries Pflugers Arch 1997;433:364-367.[Medline]
- Yamamoto Y, Imaeda K, Suzuki H. Endothelium-dependent hyperpolarization and intercellular electrical coupling in guinea-pig mesenteric arterioles J Physiol 1999;514:505-513.[Abstract/Free Full Text]
- Edwards G, Feletou M, Gardener MJ, Thollon C, Vanhoutte PM, Weston AH. Role of gap junctions in the responses to EDHF in rat and guinea-pig small arteries Br J Pharmacol 1999;128:1788-1794.[Medline]
- Christ GJ, Spray DC, el-Sabban M, Moore LK, Brink PR. Gap junctions in vascular tissues. Evaluating the role of intercellular communication in the modulation of vasomotor tone Circ Res 1996;79:631-646.[Abstract/Free Full Text]
- Kumar NM, Gilula NB. The gap junction communication channel Cell 1996;84:381-388.[Medline]
- Busse R, Fichtner H, Luckhoff A, Kohlhardt M. Hyperpolarization and increased free calcium in acetylcholine-stimulated endothelial cells Am J Physiol 1988;255:H965-H969.
- Emerson GG, Segal SS. Endothelial cell pathway for conduction of hyperpolarization and vasodilation along hamster feed artery Circ Res 2000;86:94-100.[Abstract/Free Full Text]
- Kauser K, Rubanyi GM. Bradykinin-induced, N
omega-nitro-L-arginine-insensitive endothelium-dependent relaxation of porcine coronary arteries is not mediated by bioassayable relaxing substances J Cardiovasc Pharmacol 1992;20(Suppl 12):S101-S104.
- Popp R, Bauersachs J, Hecker M, Fleming I, Busse R. A transferable, beta-naphthoflavone-inducible, hyperpolarizing factor is synthesized by native and cultured porcine coronary endothelial cells J Physiol 1996;497:699-709.[Abstract/Free Full Text]
- Mombouli JV, Bissiriou I, Agboton VD, Vanhoutte PM. Bioassay of endothelium-derived hyperpolarizing factor Biochem Biophys Res Commun 1996;221:484-488.[Medline]
- Gebremedhin D, Harder DR, Pratt PF, Campbell WB. Bioassay of an endothelium-derived hyperpolarizing factor from bovine coronary arteriesrole of a cytochrome P450 metabolite. J Vasc Res 1998;35:274-284.[Medline]
- Yang Q, Ge Z-D, Yang C-Q, Huang Y, He G-W. Bioassay of endothelium-derived hyperpolarizing factor with abolishment of nitric oxide and the role of gap junctions in the porcine coronary circulation Drug Dev Res 2003;58:99-110.
- Gauthier KM, Deeter C, Krishna UM, et al. 14,15-Epoxyeicosa-5(Z)-enoic acida selective epoxyeicosatrienoic acid antagonist that inhibits endothelium-dependent hyperpolarization and relaxation in coronary arteries. Circ Res 2002;90:1028-1036.[Abstract/Free Full Text]
- Randall MD, Kendall DA. Involvement of a cannabinoid in endothelium-derived hyperpolarizing factor-mediated coronary vasorelaxation Eur J Pharmacol 1997;335:205-209.[Medline]
- Edwards G, Dora KA, Gardener MJ, Garland CJ, Weston AH. K+ is an endothelium-derived hyperpolarizing factor in rat arteries Nature 1998;396:269-272.[Medline]
- Matoba T, Shimokawa H, Nakashima M, et al. Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in mice J Clin Invest 2000;106:1521-1530.[Medline]
- Vanhoutte PM. Vascular biology. Old-timer makes a comeback Nature 1998;396:213215–6.[Medline]
- Garland CJ, Plane F, Kemp BK, Cocks TM. Endothelium-dependent hyperpolarizationa role in the control of vascular tone. Trends Pharmacol Sci 1995;16:23-30.[Medline]
- He G-W, Yang CQ, Graier WF, Yang JA. Hyperkalemia alters EDHF-mediated hyperpolarization and relaxation in coronary arteries Am J Physiol 1996;271:H760-H767.
- Wennmalm A, Pham-Huu-Chanh, Junstad S. Hypoxia causes prostaglandin release from perfused rabbit hearts Acta Physiol Scand 1974;91:133-135.[Medline]
- Nomura F, Matsuda H, Hirose H, et al. Assessment of prostacyclin and thromboxane A2 release during reperfusion after global ischemia induced by crystalloid cardioplegia—comparison between warm and cold ischemia Eur Surg Res 1988;20:110-119.[Medline]
- Metais C, Li J, Simons M, Sellke FW. Serotonin-induced coronary contraction increases after blood cardioplegia-reperfusionrole of COX-2 expression. Circulation 1999;100(Suppl):II328-II334.
- Gohra H, Fujimura Y, Hamano K, et al. Nitric oxide release from coronary vasculature before, during, and following cardioplegic arrest World J Surg 1999;23:1249-1253.[Medline]
- Nakamura K, Schmidt I, Gray CC, et al. The effect of chronic L-arginine administration on vascular recovery following cold cardioplegic arrest in rats Eur J Cardiothorac Surg 2002;21:753-759.[Abstract/Free Full Text]
- Dignan RJ, Dyke CM, Abd-Elfattah AS, et al. Coronary artery endothelial cell and smooth muscle dysfunction after global myocardial ischemia Ann Thorac Surg 1992;53:311-317.[Abstract]
- Engelman DT, Watanabe M, Engelman RM, et al. Constitutive nitric oxide release is impaired after ischemia and reperfusion J Thorac Cardiovasc Surg 1995;110:1047-1053.[Abstract/Free Full Text]
- He G-W, Yang CQ, Wilson GJ, Rebeyka IM. Tolerance of epicardial coronary endothelium and smooth muscle to hyperkalemia Ann Thorac Surg 1994;57:682-688.[Abstract]
- He G-W, Yang CQ, Rebeyka IM, Wilson GJ. Effects of hyperkalemia on neonatal endothelium and smooth muscle J Heart Lung Transplant 1995;14:92-101.[Medline]
- He G-W. Hyperkalemia exposure impairs EDHF-mediated endothelial function in the human coronary artery Ann Thorac Surg 1997;63:84-87.[Abstract/Free Full Text]
- He G-W, Yang CQ, Yang JA. Depolarizing cardiac arrest and endothelium-derived hyperpolarizing factor-mediated hyperpolarization and relaxation in coronary arteriesthe effect and mechanism. J Thorac Cardiovasc Surg 1997;113:932-941.[Abstract/Free Full Text]
- Ge ZD, He G-W. Altered endothelium-derived hyperpolarizing factor-mediated endothelial function in coronary microarteries by St Thomas’ Hospital solution J Thorac Cardiovasc Surg 1999;118:173-180.[Abstract/Free Full Text]
- Ge ZD, He G-W. Comparison of University of Wisconsin and St Thomas’ Hospital solutions on endothelium-derived hyperpolarizing factor-mediated function in coronary micro-arteries Transplantation 2000;70:22-31.[Medline]
- He G-W, Yang CQ. Superiority of hyperpolarizing to depolarizing cardioplegia in protection of coronary endothelial function J Thorac Cardiovasc Surg 1997;114:643-650.[Abstract/Free Full Text]
- Mankad PS, Chester AH, Yacoub MH. Role of potassium concentration in cardioplegic solutions in mediating endothelial damage Ann Thorac Surg 1991;51:89-93.[Abstract]
- Yang Q, Liu YC, Zou W, Yim AP, He G-W. Protective effect of magnesium on the endothelial function mediated by endothelium-derived hyperpolarizing factor in coronary arteries during cardioplegic arrest in a porcine model J Thorac Cardiovasc Surg 2002;124:361-370.[Abstract/Free Full Text]
- Hearse DJ, Stewart DA, Braimbridge MV. Myocardial protection during ischemia cardiac arrestthe importance of magnesium in cardioplegic infusates. J Thorac Cardiovasc Surg 1978;75:877-885.[Abstract]
- Shakerinia T, Ali IM, Sullivan JA. Magnesium in cardioplegiais it necessary?. Can J Surg 1996;39:397-400.[Medline]
- Yang ZW, Gebrewold A, Nowakowski M, Altura BT, Altura BM. Mg2+-induced endothelium-dependent relaxation of blood vessels and blood pressure loweringrole of NO. Am J Physiol 2000;278:R628-R639.
- Longo M, Jain V, Vedernikov YP, Facchinetti F, Saade GR, Garfield RE. Endothelium dependence and gestational regulation of inhibition of vascular tone by magnesium sulfate in rat aorta Am J Obstet Gynecol 2001;184:971-978.[Medline]
- Haenni A, Johansson K, Lind L, Lithell H. Magnesium infusion improves endothelium-dependent vasodilation in the human forearm Am J Hypertens 2002;15:5-10.
- Laurant P, Berthelot A. Influence of endothelium in the in vitro vasorelaxant effect of magnesium on aortic basal tension in DOCA-salt hypertensive rat Magnes Res 1992;5:255-260.[Medline]
- Tofukuji M, Stamler A, Li J, et al. Effects of magnesium cardioplegia on regulation of the porcine coronary circulation J Surg Res 1997;69:233-239.[Medline]
- Pearson PJ, Evora PR, Seccombe JF, Schaff HV. Hypomagnesemia inhibits nitric oxide release from coronary endotheliumprotective role of magnesium infusion after cardiac operations. Ann Thorac Surg 1998;65:967-972.[Abstract/Free Full Text]
- Ahn HY, Karaki H. Inhibitory effects of procaine on contraction and movement in vascular and intestinal smooth muscles Br J Pharmacol 1988;94:789-796.[Medline]
- Huang Y, Lau CW, Chan FL, Yao XQ. Contribution of nitric oxide and K+ channel activation to vasorelaxation of isolated rat aorta induced by procaine Eur J Pharmacol 1999;367:231-237.[Medline]
- Yang Q, Liu YC, Zou W, Yim AP, He G-W. Procaine in cardioplegiathe effect on EDHF-mediated function in porcine coronary arteries. J Card Surg 2002;17:470-475.[Medline]
- Itoh T, Kuriyama H, Suzuki H. Excitation-contraction coupling in smooth muscle cells of the guinea-pig mesenteric artery J Physiol 1981;321:513-535.[Abstract/Free Full Text]
- Sato H, Zhao ZQ, McGee DS, Williams MW, Hammon Jr JW, Vinten-Johansen J. Supplemental L-arginine during cardioplegic arrest and reperfusion avoids regional postischemic injury J Thorac Cardiovasc Surg 1995;110:302-314.[Abstract/Free Full Text]
- Lefer AM. Attenuation of myocardial ischemia-reperfusion injury with nitric oxide replacement therapy Ann Thorac Surg 1995;60:847-851.[Abstract/Free Full Text]
- McKeown PP, McClelland JS, Bone DK, et al. Nitroglycerin as an adjunct to hypothermic hyperkalemic cardioplegia Circulation 1983;68:II107-II111.
- Feng J, Wu G, Tang S, Chahine R, Lamontagne D. Beneficial effects of iloprost cardioplegia in ischemic arrest in isolated working rat heart Prostaglandins Leukot Essent Fatty Acids 1996;54:279-283.[Medline]
- Nomura F, Matsuda H, Shirakura R, et al. Experimental evaluation of myocardial protective effect of prostacyclin analog (OP-41483) as an adjunct to cardioplegic solution J Thorac Cardiovasc Surg 1991;101:860-865.[Abstract]
- Zou W, Yang Q, Yim AP, He G-W. Epoxyeicosatrienoic acids (EET11,12) may partially restore endothelium-derived hyperpolarizing factor-mediated function in coronary microarteries Ann Thorac Surg 2001;72:1970-1976.[Abstract/Free Full Text]
- Yang Q, Zhang R-Z, Yim AP, He G-W. Effect of 11,12-epoxyeicosatrienoic acid as an additive to St. Thomas’ cardioplegia and University of Wisconsin solutions on endothelium-derived hyperpolarizing factor-mediated function in coronary microarteriesinfluence of temperature and time. Ann Thorac Surg 2003;76:1623-1630.[Abstract/Free Full Text]
- Li HY, Wu S, He G-W, Wong TM. Aprikalim reduces the Na+-Ca2+ exchange outward current enhanced by hyperkalemia in rat ventricular myocytes Ann Thorac Surg 2002;73:1253-1260.[Abstract/Free Full Text]
- He G-W. Potassium-channel opener in cardioplegia may restore coronary endothelial function Ann Thorac Surg 1998;66:1318-1322.[Abstract/Free Full Text]
- Ren Z, Yang Q, Floten HS, Furnary AP, Yim AP, He G-W. ATP-sensitive potassium channel openers may mimic the effects of hypoxic preconditioning on the coronary artery Ann Thorac Surg 2001;71:642-647.[Abstract/Free Full Text]
- Chambers DJ, Astras G, Takahashi A, Manning AS, Braimbridge MV, Hearse DJ. Free radicals and cardioplegiaorganic anti-oxidants as additives to the St Thomas’ Hospital cardioplegic solution. Cardiovasc Res 1989;23:351-358.[Medline]
- Theroux P, Chaitman BR, Danchin N, et al. Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators Circulation 2000;102:3032-3038.[Abstract/Free Full Text]
- Muraki S, Morris CD, Budde JM, Zhao ZQ, Guyton RA, Vinten-Johansen J. Blood cardioplegia supplementation with the sodium-hydrogen ion exchange inhibitor cariporide to attenuate infarct size and coronary artery endothelial dysfunction after severe regional ischemia in a canine model J Thorac Cardiovasc Surg 2003;125:155-164.[Abstract/Free Full Text]
- Keller MW, Geddes L, Spotnitz W, Kaul S, Duling BR. Microcirculatory dysfunction following perfusion with hyperkalemic, hypothermic, cardioplegic solutions and blood reperfusion. Effects of adenosine Circulation 1991;84:2485-2494.[Abstract/Free Full Text]
- Sellke FW, Friedman M, Wang SY, Piana RN, Dai HB, Johnson RG. Adenosine and AICA-riboside fail to enhance microvascular endothelial preservation Ann Thorac Surg 1994;58:200-206.[Abstract]
- Wang Y, Sunamori M, Suzuki A. Effect of phosphodiesterase III-inhibitor (E-1020) adjunct to Bretschneider’s HTK cardioplegic solution on myocardial preservation in rabbit heart Thorac Cardiovasc Surg 1996;44:167-172.[Medline]
- Jovanovic S, Jovanovic A, Shen WK, Terzic A. Protective action of 17ß-estradiol in cardiac cellsimplications for hyperkalemic cardioplegia. Ann Thorac Surg 1998;66:1658-1661.[Abstract/Free Full Text]
- Rubanyi GM, Johns A, Kauser K. Effect of estrogen on endothelial function and angiogenesis Vascul Pharmacol 2002;38:89-98.[Medline]
- Standeven JW, Jellinek M, Menz LJ, Kolata RJ, Barner HB. Cold blood potassium diltiazem cardioplegia J Thorac Cardiovasc Surg 1984;87:201-212.[Abstract]
- Trubel W, Zwoelfer W, Moritz A, Laczkovics A, Haider W. Cardioprotection by nifedipine cardioplegia during coronary artery surgery Eur J Anaesthesiol 1994;11:101-106.[Medline]
- Rosenkranz ER. Substrate enhancement of cardioplegic solutionexperimental studies and clinical evaluation. Ann Thorac Surg 1995;60:797-800.[Abstract/Free Full Text]
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Abstract
Introduction
