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Ann Thorac Surg 1995;60:1275-1281
© 1995 The Society of Thoracic Surgeons
Department of Surgery, University of Connecticut School of Medicine, Farmington, Connecticut, and Baystate Medical Center, Springfield, Massachusetts
Accepted for publication June 13, 1995.
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Methods. Normothermic regional ischemia was induced in the open-chest working pig heart for 30 minutes followed by 90 minutes of reperfusion. A preischemic 10-minute intravenous infusion of 4 mg • kg-1 • min-1 of L-arginine (n = 12) was compared with 12 control pigs. Nitric oxide release was measured from the coronary sinus using an amperometric probe. Left ventricular function, malonaldehyde, creatine kinase, myocardial oxygen extraction, and the soluble adhesion molecules (intracellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1) were measured.
Results. Nitric oxide release was significantly reduced from baseline throughout ischemia/reperfusion only in the control group. Systolic and diastolic function, and myocardial oxygen extraction were also significantly decreased during early reperfusion in the control compared with the L-arginine group. Peak creatine kinase release was not significantly different between groups. The incidence of ventricular fibrillation, malonaldehyde release, and soluble intracellular adhesion molecule-1, endothelial leukocyte adhesion molecule-1, and vascular cell adhesion molecule-1 were each significantly decreased during reperfusion in the L-arginine group.
Conclusions. L-Arginine reduced lipid peroxidation, plasma levels of soluble adhesion molecules, myocardial stunning, and arrhythmias. These results support an excessive endothelial injury/inflammatory response after regional ischemia/reperfusion that can be ameliorated through augmented nitric oxide.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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In the vascular system, NO has been shown to be an endogenous inhibitor of leukocyte chemotaxis, adherence, and activation [5]. In addition, NO may inactivate superoxide free radicals generated by leukocytes [6]. The present study was designed to assess the role of endothelial function/activation after regional ischemia and reperfusion in L-arginine–supplemented in situ blood-perfused porcine hearts using continuous measurements of myocardial function and coronary sinus NO release. To further delineate the effects of L-arginine on myocardial energetics and cellular necrosis, malonaldehyde release, an indirect marker of free radical-mediated lipid peroxidation, myocardial oxygen extraction, and creatine kinase release were measured during ischemia and reperfusion. In addition, the soluble endothelial ``proadhesive'' molecules vascular cell adhesion molecule-1 (sVCAM-1), endothelial leukocyte adhesion molecule-1 (sE-selectin), and intercellular adhesion molecule-1 (sICAM-1) were each quantified from coronary sinus blood.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Surgical Preparation
Yorkshire pigs of either sex weighing 20 to 25 kg were tranquilized with ketamine (50 mg/kg), anesthetized with sodium pentobarbital (25 mg/kg), and placed on a mechanical ventilator. The electrocardiogram was continuously recorded. Cannulas were placed in the femoral vein and artery. The chest was then opened with a median sternotomy and the pericardium was suspended in a pericardial cradle. The azygous and hemiazygos veins were ligated, and the inferior vena cava was snared with 3-mm-wide tape (Umbilical Tape; Ethicon, Inc, Somerville, NJ).
Heparin sodium (250 U/kg) was then administered systematically. Sonometric dimension crystals (diameter, 6 mm), which were made of 3 MHz piezoelectric crystals (Triton Technologies, Inc, San Diego, CA) were placed at the endocardial surface across the anteroposterior minor axis, septal-free wall minor axis, and base–apex major axis of the left ventricle. The anteroposterior crystals were placed adjacent to the anterior and posterior descending coronary arteries. The septal-free crystals were located one-half of the distance from the apex to the base. The base crystal was placed into the left ventricle adjacent to the origin of the left circumflex coronary artery and the apex crystal was placed into the left ventricular apex. Techniques for crystal placement have been previously described in detail by Freeman [7]. A pair of sonometric dimension crystals (diameter, 2.5 mm), which were made of 5 MHz piezoelectric crystals (Triton Technologies) were placed 1 cm apart in the left anterior descending coronary artery (LAD) distribution epicardium of the left ventricle. A 5F micromanometer-tipped catheter (Millar Instruments, Inc, Houston, TX) was inserted through the left ventricular apex for pressure measurements. A catheter was then placed into the coronary sinus. This catheter drained coronary sinus blood past an in-line NO probe and into a 37°C chamber that was connected via a roller pump to the femoral vein catheter. The experimental preparation is illustrated in Figure 1
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Experimental Protocol
Baseline measurements were made during steady-state contractions after instrumentation and stabilization. Control animals (CON; n = 12) then received an intravenous infusion of lactated Ringer's solution for 10 minutes. Treated animals (ARG; n = 12) received an intravenous infusion of L-arginine (4 mg • kg-1 • min-1) (Sigma Chemical, St. Louis, MO) for 10 minutes. The LAD was then ligated for 30 minutes just proximal to the origin of the first diagonal branch. The hearts were then reperfused for 90 minutes.
In 6 ARG pigs and 6 CON pigs, functional data was obtained before ischemia (baseline), after 15 and 30 minutes of ischemia, and after 10, 20, 30, 60, and 90 minutes of reperfusion. Nitric oxide release was measured continuously throughout the experimental protocol. Three-milliliter blood samples were taken from the coronary sinus for creatine kinase and malonaldehyde measurements at baseline, after 30 minutes of ischemia, and 3, 5, 15, 30, 60, and 90 minutes of reperfusion. Myocardial oxygen extraction was measured from simultaneously drawn coronary sinus and femoral artery blood samples at baseline, after 30 minutes of ischemia, and after 30 minutes of reperfusion. In a separate group of 6 ARG and 6 CON pigs, 3-mL blood samples were taken from the coronary sinus for soluble adhesion molecule measurements at baseline, after 30 minutes of ischemia, and at 3, 5, 15, 30, 60, and 90 minutes of reperfusion. All blood was immediately centrifuged at 1,000 g for 10 minutes and the plasma was stored in aliquots at -20°C for subsequent analysis.
Measurement of Myocardial Function
The hemodynamic variables continuously recorded were left ventricular pressure, left ventricular dimensions, and LAD regional segment length. These data were digitized and recorded in real-time with a 12-bit AD converter sampling at 200 Hz using the Cordat II Data Acquisition, Analysis, and Presentation System (Data Integrated Scientific Systems, Pinckney, MI; Triton Technologies, Inc, San Diego, CA). The digitized data was later analyzed using the CV AutoReport Cardiovascular Data Analysis Program (Scitelligence, Inc, Brighton, MI). Left ventricular volume (V) was modeled as two half-ellipsoids by the equation: V = 
/6 x ASL, where A, S, and L are the anteroposterior, septal-free, and base-apex dimensions [8]. The first derivative of left ventricular pressure was calculated as a polynomial approximation from the digital left ventricular pressure signal. End-diastolic volume was defined as the left ventricular volume at the first positive derivative of left ventricular pressure. Left ventricular stroke work (SW) was defined as the integral of left ventricular pressure, P, and volume, V, of the cardiac cycle by the equation SW = 
PdV. The linear regression analysis was performed on the stroke work–end-diastolic volume relationship, to generate the preload recruitable stroke work with slope, Mw, and x-axis intercept, V0. Similar data was generated from regional segment-length data by substituting end-diastolic LAD segment- length for end-diastolic left ventricular volume.
The ``stiffness'' coefficient (ß) was derived from exponential modeling of the end-diastolic pressure (EDP)–end-diastolic volume (EDV) relationship by the equation EDP = 
x e(ß x EDV). The stiffness coefficient is the inverse of compliance [9]. Similar data was generated from LAD regional segment–length data by substituting end-diastolic LAD segment–length for end-diastolic left ventricular volume.
To obtain pressure–volume relations, preload was reduced by transient occlusion of the inferior vena cava to produce a 30 mm Hg reduction in maximal left ventricular pressure. At each sampling time, data was recorded over a 10-second period with the respirator off at end-expiration. The animal was then allowed to equilibrate and caval occlusion data were again obtained. Three sets of occlusion data were obtained at each time point. Global and regional functional data were analyzed during each preload reduction.
Measurement of Nitric Oxide Release
Nitric oxide release was measured continuously from the coronary sinus using an amperometric sensor (ISO-NO, World Precision Instrument, Inc, Sarasota, FL). This probe measures the concentration of NO gas in aqueous solution [10]. Briefly, NO diffuses through a semipermeable membrane and is then oxidized at a working platinum electrode resulting in an electric current. This redox current is proportional to the concentration of NO at the membrane's outer surface. Electrode calibration was performed daily before each experiment. A calibration curve was obtained by measuring the current generated by the addition of liquid nitrite (NaNO2; Curtin Matheson Scientific, Inc, Wilmington, MA) to a solution containing KI, H2SO4, and K2SO4. This resulted in the immediate generation of NO by the equation: Comp: set equation2NaNO2 + 2KI + 2H2SO4 + 2K2SO4 
2NO + I2 + 2H2O + 3K2SO4 + Na2SO4.
Nitric oxide calibration was always linear (r 
0.99). After stabilization, the NO probe was placed into the coronary sinus catheter 10 cm from the point of blood drainage. As shown in Figure 1
, NO was measured from the coronary effluent as it flowed past the probe and was recirculated through the femoral vein. The concentration of NO was electronically digitized and recorded in real-time along with the hemodynamic measurements using the data acquisition system. At the conclusion of the experiment all hearts were weighed. Nitric oxide release was calculated in nanomole per gram wet weight.
Measurement of Malonaldehyde Formation, Myocardial Oxygen Extraction, and Creatine Kinase Release
Malonaldehyde was measured from 1.5 mL of plasma that was mixed with an equal volume of 20% trichloroacetic acid and 5.3 mmol/L sodium metabisulfite. Protein was precipitated on ice for 10 minutes, and the suspension centrifuged at 3,000 g for 10 minutes. Two milliliters of supernatant was derivatized with 2,4-dinitrophenylhydrazine and extracted with pentane. Malonaldehyde formation was then measured using high-performance liquid chromatography as previously described [11]. Myocardial oxygen extraction was determined by simultaneously sampling coronary venous and femoral arterial blood samples for oxygen content using a BGE IL 1400 blood gas analyzer (Instrumentation Laboratory, Lexington, MA). Myocardial oxygen extraction was calculated as arterial–venous oxygen content. Creatine kinase was quantified from 0.5 mL of plasma by the enzymatic assay method using a creatine kinase assay kit (Sigma Diagnostics, St. Louis, MO). The absorbance was read at 340 nm using a Beckman DU-8 spectrophotometer.
Measurement of Adhesion Molecules
Plasma (100 
) from the coronary sinus was assayed in duplicate for sVCAM-1, sE-selectin, and sICAM-1 by enzyme-linked immunosorbent assay. All assays were performed with commercially available kits (R&D Systems, Inc, Minneapolis, MN).
Statistical Analysis
All data are expressed as a mean ± standard error of the mean. Data was analyzed by a two-way analysis of variance for repeated measures followed by a multiple comparison Scheffé's test to determine differences between groups. The paired Student's t test was used for within-group comparisons with baseline values. Significance was considered at a p value of less than 0.05.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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. Preload recruitable stroke work was reduced after 30 minutes of ischemia and during the first 20 minutes of reperfusion in the LAD regional model. Global left ventricular preload recruitable stroke work was not significantly different between the groups. Diastolic function was similarly decreased in the CON hearts (Fig 2B). During reperfusion, the ``stiffness'' coefficient (ß) was significantly increased in CON hearts (indicating reduced diastolic function/ventricular compliance) in both the LAD regional and global left ventricular models. Diastolic function in the ARG hearts were not significantly different from baseline levels throughout the ischemia/reperfusion protocol. All diastolic and systolic functional abnormalities returned to near-baseline levels by 90 minutes reperfusion, with the exception of LAD regional ß, which remained significantly increased. Ventricular fibrillation occurred during ischemia in 50% of CON hearts versus 0% of the ARG hearts (p < 0.05). During reperfusion, ventricular fibrillation occurred in 83% of CON hearts versus 8% of the ARG hearts (p < 0.05). Electrical defibrillation was successful in all cases.
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. Nitric oxide release in the ARG group was not significantly different from baseline levels throughout the course of the experiment. In contrast, in the CON hearts, NO release was significantly decreased during ischemia, and continued to decline during reperfusion.
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. Malonaldehyde levels were significantly increased in the CON group at 3 and 5 minutes of reperfusion (162% baseline at 3 minutes) compared with the ARG group (108% baseline at 3 minutes). Malonaldehyde levels returned to baseline levels by 15 minutes of reperfusion. Myocardial oxygen extraction was significantly decreased in the CON compared with the ARG group at 30 minutes of ischemia (80% versus 119% baseline, respectively). Both groups returned to baseline values by 30 minutes of reperfusion. Peak creatine kinase release was not significantly different between groups at any time point.
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. The sVCAM-1 level began to rise after 3 minutes of reperfusion in both groups, and continued to rise thereafter. The sVCAM-1 level was significantly increased in the CON compared with the ARG group after 30 minutes of reperfusion. sE-selectin and sICAM-1 were similarly increased in the CON group but were unchanged from baseline in the ARG group. sE-selectin and sICAM-1 were both significantly increased in the CON compared with the ARG groups after 5 minutes of reperfusion but were not different after 60 minutes of reperfusion in the sICAM-1 group.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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It is well known that neutrophil-derived free radicals can exacerbate ischemia/reperfusion injury [14]. It has been suggested that NO synthesis can reduce oxidative stress, scavenge ambiently produced superoxide radicals [15], and terminate free-radical chain reactions within the lipid membrane [16], thereby reducing inflammatory mediators, adhesion molecule expression, and neutrophil–endothelial interactions [17]. The present study supports these findings by demonstrating in an in vivo system that NO supplementation reduced the release of malonaldehyde after ischemia/reperfusion. Lipid oxidation products, especially malonaldehyde, are a presumptive marker for lipid peroxidation, which is an indicator of free-radical production and oxidative stress. By binding and eliminating these toxic metabolites, NO may reduce lipid peroxidation and retard the damaging effects of reperfusion injury.
The adhesion of leukocytes to endothelial cells requires the expression of leukocyte-specific adhesion proteins on the surface of the vascular endothelium [18]. Upon up-regulation, these adhesion molecules are capable of attachment to activated polymorphonuclear neutrophils, allowing transendothelial migration and cytotoxic damage [19]. To assess whether decreased NO production during ischemia/reperfusion promotes endothelial–leukocyte interactions by increasing expression of these mediators, we measured three soluble adhesion molecules constitutively expressed on the vascular endothelium. We demonstrated that postischemic increases in each of these soluble adhesion molecules could be significantly ameliorated with L-arginine-induced NO supplementation. Elevations of sICAM-1, sE-selectin, and sVCAM-1 definitively indicate activation or damage to the vascular endothelium [20]. Although the biologic significance of these circulating soluble adhesion molecules is unclear, it has been reported that sE-selectin can up-regulate neutrophil integrin function, thereby acting as a physiologic proadhesive effector [21]. In addition, targeted reduction of adhesion molecule expression has been used to reduce ischemia/reperfusion injury. It has been demonstrated that a monoclonal antibody against ICAM-1 significantly attenuated the increase in polymorphonuclear neutrophil adherence to ischemic/reperfused coronary endothelium [5]. Regardless of the specific biologic roles for these soluble adhesion molecules, their up-regulation signifies an increased inflammatory endothelial response after ischemia/reperfusion injury.
Although coronary flows were not measured, coronary vasodilatation was probably not a major component of this protection. Previously, we have demonstrated in an isolated rat heart model that coronary flow is not significantly increased after L-arginine pretreatment [12]. Other investigators have demonstrated in dogs [4], cats [1], and rabbits [22] that arterial tone or coronary flows were not significantly changed after L-arginine administration. In addition, coronary collateral flow in pigs is very small.
Many of the proposed theories regarding the protective effects of NO suggest a free radical-mediated reperfusion phenomenon. However, we have demonstrated that significant functional improvement in regional systolic function and myocardial oxygen extraction were evident in the L-arginine-supplemented pigs even before reperfusion (after 30 minutes of ischemia). This may be evidence of a direct cytoprotective activity of NO. The functional impairment in control hearts was almost completely resolved after 90 minutes of reperfusion and there was no difference in creatine kinase release between the groups. Therefore, in this model, L-arginine pretreatment appears to have reduced myocardial stunning, rather than infarction. L-Arginine also afforded a profound antiarrhythmic protection in this study. This may be a consequence of reduced free radical generation/increased binding [23], increased cellular antioxidant (glutathione) levels in endothelial cells [24], or a direct, as yet uncharacterized, consequence of NO on cardiac musculature [25].
The systemic effects of L-arginine are probably not responsible for its cardioprotective activity. Arginine has been shown to result in the release of active hormones, including insulin, glucagon, growth hormone, and prolactin [1]. However the reported inability of D-arginine to provide cardioprotection [12] suggests that systemic hormonal effects are not operative.
In summary, supplemental L-arginine given before a regional ischemic insult, reduced free radical/neutrophil-mediated lipid peroxidation, plasma levels of soluble adhesion molecules, myocardial stunning, and reperfusion arrhythmias. These results support an excessive endothelial injury/inflammatory response after regional ischemia and reperfusion. Supplementation of the NO pathway provides dramatic antiinflammatory endothelial protection and may suggest novel cardioprotective strategies to ameliorate clinical ischemia/reperfusion injury.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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