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Ann Thorac Surg 1999;67:878-888
© 1999 The Society of Thoracic Surgeons
a Cardiac Surgical Research Laboratory, Baker Medical Research Institute and Alfred Hospital, Prahran, Australia
c Department of Cardiac Surgery, Austin and Repatriation Medical Centre, Heidelberg, Australia
d Department of Pharmacology, University of Melbourne, Melbourne, Victoria, Australia
b Department of Cardiothoracic Surgery, University of Hong Kong, Grantham Hospital, Hong Kong, China
Address reprint requests to Dr Rosenfeldt, Baker Medical Research Institute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008 Australia
e-mail: frank.rosenfeldt{at}baker.edu.au
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Abstract |
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 Top Abstract IntroductionIn vitro pharmacology of...Pharmacology of the internal...Pharmacology of other arterial...Guidelines for the use...Pharmacology of the saphenous...Pharmacologic relaxation of the...ConclusionsReferences |
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Introduction |
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TopAbstractIntroductionIn vitro pharmacology of...Pharmacology of the internal...Pharmacology of other arterial...Guidelines for the use...Pharmacology of the saphenous...Pharmacologic relaxation of the...ConclusionsReferences |
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Pharmacologists then began to study these questions using their standard preparation, the isolated vessel ring in the organ bath [3]. This methodology enabled concentration–relaxation response curves for each vasodilator to be obtained, agents to be compared with each other, and combinations of vasodilator drugs to be tested. Surgeons joined in the study of graft pharmacology by measuring the effects of vasodilators on blood flow through the IMA before it was attached to the heart [4].
In recent years, with the increasing use of new arterial grafts such as the gastroepiploic, inferior epigastric, and radial arteries, the problem of graft spasm has become more obvious. Thus it has become essential for surgeons to understand the causes of spasm of vascular grafts and to use the optimal vasodilator in the most appropriate way to counteract spasm.
In this review we summarize the current state of knowledge of the pharmacology of vascular grafts and describe the practical application of this knowledge.
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In vitro pharmacology of blood vessels |
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TopAbstractIntroductionIn vitro pharmacology of...Pharmacology of the internal...Pharmacology of other arterial...Guidelines for the use...Pharmacology of the saphenous...Pharmacologic relaxation of the...ConclusionsReferences |
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Normalization technique for setting resting tension
The preferred response when measuring blood vessel reactivity is to stretch the vessel radially to its optimal length for development of active force and measure changes in isometric tension. The amount of passive force (stretch) applied to a segment of artery or vein in an organ bath should be relevant for the amount of muscle present and its geometry.
That is why we have developed techniques to determine the passive length–tension relationship for each vessel segment, cut to a precise length. This normalization procedure attempts to set the passive distension to correspond with that caused by transmural pressure experienced in vivo. Clearly this will vary from arterial pressure for arterial grafts to the lower hydrostatic pressure in veins.
Segments of human arteries or veins collected from patients undergoing CABG procedures are taken to the laboratory. Rings are cut from these vessels and mounted on wires in organ baths for isometric force measurement. Many investigators set the resting tension (force per unit length) at 2 to 4 g regardless of the type or size of the blood vessel being studied. However, a more physiologic approach is to set the vessel at an optimal point according to its own length–tension curve, which will allow for differences in length of vessel segment and smooth muscle geometry. This concept was initially applied to isolated resistance arteries [5]. The principle is to establish individual length–tension exponential curves for each vessel by relating the isometric tension, obtained from a strain gauge, with the corresponding diameter and circumferential length determined by a micrometer. This technology was successfully transferred to large blood vessels [3, 6] and has been continuously used in our studies and adopted by others for studying CABG pharmacology [7, 8].
Concentration–response relationship
Isolated tissue experiments allow the drug concentration in the bathing solution to come into equilibrium throughout the tissue. This may take considerable time for thick-walled arteries, especially if the drug is not lipophilic. Metabolism of the test drug and stability in Krebs solution at 37°C are important considerations. Access is also an issue. In the operating room, drugs such as papaverine are usually applied topically to the adventitial surface alone, whereas in the organ bath, drugs access the smooth muscle through both the adventitia and the lumen. Endogenous vasoactive constrictor stimuli such as serotonin (5-HT), thromboxane A2 (TXA2), or endothelin 1 (ET-1) may access the IMA in vivo only through the endothelial surface with little access to the outer medial smooth muscle by way of the vasa vasorum.
The two parameters that are obtained from organ bath studies of greatest predictive value are (1) potency, ie, sensitivity of the vessel to a drug, and (2) range of the maximum response of the drug at high concentration. The sensitivity to each drug is given by the EC50, which is the effective concentration that reduces the contraction by 50%. This value can vary considerably with the nature of the agent used to precontract the vessel and the amount of contraction that a chosen concentration of constrictor will develop. The latter concept reflects functional antagonism—how effectively the dilator agent can relax a vessel precontracted by a particular constrictor.
Vasoconstrictor agents
If the mechanism of contraction involves activating a specific receptor, eg, an 
-adrenoceptor, then a selective -adrenoceptor antagonist will be highly effective because the locus of the interaction is identical. In the case of a functional antagonist such as nifedipine, it will relax K+-contracted vessels at a lower concentration than required if a receptor-operating constrictor such as norepinephrine (NE) had been used to precontract the vessel, even if the level of contraction from the K+ and NE was similar.
Raised extracellular K+ causes closure of the hyperpolarizing K+ channels on smooth muscle, allowing the voltage-operated Ca2+ channels (VOCC) to open and intracellular [Ca2+] to rise, resulting in contraction. Therefore, a VOCC antagonist such as nifedipine would readily relax a tissue precontracted by K+. Conversely the contraction caused by NE is only partly caused by depolarization of the tissue through VOCC and partly caused by calcium release from intracellular sources. Thus, this latter mechanism would be more resistant to nifedipine.
Vasodilator agents
These are usually studied by establishing concentration–relaxation curves after precontracting the vessel. The relaxation is expressed as a percentage of the precontraction force. In relaxation studies, particular attention is paid to the following: (1) The level of precontraction force should be chosen in the range of 50% to 80% of the maximum achievable by that agent. This is easily determined as the EC50 to EC80 concentration from the constrictor concentration–response curve. (2) The precontraction force should be stable for the period needed for completing the cumulative concentration–relaxation curve. A time control often is necessary to demonstrate the stability of the precontraction [9, 10]. Unless this is done, the investigator may falsely ascribe relaxation to the added drug rather than spontaneous, time-dependent dissipation of contraction.
The effective concentration causing 50% of the maximal response (contraction or relaxation) is used to describe the sensitivity of the vessel to an agent. This is often calculated by the formula 
, where E is response, M is maximal contraction (or relaxation), A is concentration, K is EC50 concentration, and p is the slope parameter [6].
Endothelium in arterial and venous grafts
The role of the endothelium in maintaining vascular tone and preventing platelet aggregation has been extensively studied. Studies of endothelial function of CABGs have shown that arterial endothelium has more ability to produce nitric oxide (NO) than venous endothelium [11]. Among the arterial grafts, the gastroepiploic artery (GEA) has been demonstrated to have similar endothelium-dependent relaxation to the inferior epigastric artery (IEA) [12]. Non–receptor-mediated endothelium-dependent relaxation is less in the IEA than in the IMA, and this may be an early sign of arteriosclerosis in the IEA [13]. In the human IMA, as in other vessels, endothelium plays a modulatory role in contractility [14]. Endothelium-derived hyperpolarizing factor (EDHF) also plays a role in arterial grafts [9].
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Pharmacology of the internal mammary artery |
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Constrictor stimuli
Vasoconstriction may be evoked by various stimuli such as mechanical trauma, nerve stimulation, and vasoconstrictor substances. Endothelin is one of several endothelium-derived contracting factors (EDCF) and is the most potent vasoconstrictor known [17]. Thromboxane A2 is also considered as one of the EDCFs [18] but it is also derived from platelets. These two vasoconstrictors are very potent in arterial grafts. Elevated plasma levels of ET [19] or TXA2 [20] have been found during cardiopulmonary bypass. Therefore, these two vasoconstrictors are prime candidates as spasmogenic agents for arterial grafts during CABG surgery. Other possible spasmogenic agents are prostaglandin F2 (PGF2), 5-HT (which is derived from platelets), circulating sympathomimetic substances (NE and epinephrine), angiotensin II, and vasopressin.
Adrenoceptors
ß-Adrenoceptors. The clinical importance of studying ß-adrenoceptors in the IMA is first to determine whether administered sympathomimetic agents can stimulate ß-adrenoceptors to mediate relaxation, and second, whether ß-adrenoceptor antagonists can block active relaxation and thus evoke vasospasm in the IMA as has been reported for the coronary artery. Although - and ß-adrenoceptors have been demonstrated by autoradiography on smooth muscle and endothelium in the human IMA [21], ß-adrenoceptor-mediated relaxation is minimal in the human IMA. We found that isoproterenol induced only a maximum response of 24% relaxation in the human IMA compared with 89% in the canine coronary artery [22]. Therefore it is inferred that in the human IMA, ß-adrenoceptor agonists will not induce a significant relaxation and that the use of ß-adrenoceptor antagonists should not evoke IMA vasospasm.
-adrenoceptors
-Adrenoceptors (AR) are composed of two subtypes, 1 and 2. Both may mediate contraction in vascular smooth muscle. The predominance of subtypes of ARs varies from one blood vessel to another. In the IMA, the nonselective 1- and 2-AR agonist NE and the selective 1-AR agonists methoxamine and phenylephrine cause contraction [23]. The IMA has been shown to be an 1-AR predominant vessel with little 2-AR function [24, 25]. Therefore, circulating catecholamines may contract the artery mainly through an 1-AR mechanism.
2-Adrenoceptors are located on endothelial cells of some arteries and mediate smooth muscle relaxation through the endothelium-dependent relaxing factor (NO) mechanism [26]. However, in the IMA, although there is evidence that when the 2-AR is blocked the contraction induced by electrical stimulation is enhanced, this effect is not significant in the contraction induced by NE [25]. Therefore, 2-ARs located in the IMA endothelium may not be functionally important.
Endothelin receptors
Endothelin induces strong contraction in the IMA [27, 28]. Both ETA and ETB receptor subtypes mediate contraction and have been found in the IMA smooth muscle [29].
Thromboxane A2 receptors
The TXA2 receptor is one of the most important receptors in the IMA, judged by the powerful contraction induced by the synthetic and stable analog U46619, which acts through TXA2 receptors [23].
Other receptors
Serotonin receptors, PGF2 (FP) receptors [30], and dopaminergic receptors [31] have all been demonstrated in the IMA. The agonists for those receptors may also be spasmogenic agents for the IMA.
Vasodilators
Factors influencing the action of dilators
Nature of the Constriction. The response to some dilator agents depends on the nature of the vasoconstriction, that is, whether it is mediated through receptors or depolarizing agents. This is particularly important in the case of calcium antagonists.
Timing
The effect of a vasodilator may depend on whether it is given before or after a vasoconstrictor. Some dilator agents are ineffective if applied before the constrictor stimulus but will be effective if applied to an already contracted vessel. This is especially important for glyceryl trinitrate (GTN) in the human IMA [23, 32]. Here, GTN may effectively reverse an already established contraction, but it has little efficacy to prevent contraction if used before the contraction is initiated, whether by potassium ion or TXA2, -AR agonists, or ET [32]. The cause of this difference, depending on the order of administration, is probably related to the short burst of cyclic guanosine 5'-monophosphate (cGMP) generated by GTN [23] or rapid tolerance [10], which causes the GTN effect to wear off before the vasoconstrictor develops its full effect.
Tolerance
When used repeatedly, some vasodilators may have a diminishing effect, ie, tolerance occurs. Tolerance is a well-recognized phenomenon for some nitrates that require a metabolic step to generate NO before stimulating cGMP and relaxing the vessel [10]. This can be a disadvantage in clinical use.
Concentration of vasodilator
The plasma concentration of a vasodilator is also a key point in its efficacy. Vasodilators may completely reverse the vasoconstriction in vitro at high concentrations, but these concentrations may not be achievable in vivo after systemic administration of the vasodilator. For example, nifedipine at a concentration more than 10 µmol/L completely depresses the contraction induced by ET in the human IMA, but this concentration is far higher than the plasma concentration achievable clinically.
Onset of the effect
The onset of activity after dosing is particularly important in surgery in which a rapid onset is desirable. In regard to the onset of the effect for each vasodilator, nitrates are the fastest, calcium antagonists are intermediate, and papaverine the slowest [3].
The above discussion is focused on the IMA. Although the effect of vasodilators on other arterial conduits (IEA, GEA, and radial artery) is less well studied, the results from the limited studies are in accordance with the above observations [7, 8, 13, 33–35]. Taken together, we may conclude that there is no perfect vasodilator for dilating IMA or other arterial grafts. Consequently, a combination of vasodilators may offer a better effect.
Specific dilators
Calcium Antagonists. When the IMA is contracted by a depolarizing agent such as K+, nifedipine or other calcium-channel antagonists are very effective in either preventing or reducing the contraction [23]. This is because of the fact that calcium antagonists contract blood vessels through a specific mechanism. Calcium antagonists reduce Ca2+ influx by blocking VOCCs, which is the major mechanism of the constricting action of depolarizing agents such as K+ (Fig 1). However, in the case of contraction mediated by membrane receptors, such as TXA2 receptors, -ARs, or ET receptors, calcium antagonists such as nifedipine are less effective [23]. In addition nifedipine has a limited effect in preventing or reducing -AR-mediated contraction [36]. Therefore, although calcium antagonists such as nifedipine are very effective under some circumstances (contraction mediated by depolarizing agents such as K+), one cannot say these vasodilators are satisfactory as sole agents for use during IMA surgical procedures, because they may be less effective in situations when the contraction is mediated by specific receptors that raise intracellular calcium. This mechanism is resistant to blockade by L-type calcium-channel antagonists.
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Papaverine
This is a nonspecific vasodilator substance, which relaxes blood vessels through multiple mechanisms. It is a phosphodiesterase inhibitor, so it may raise cGMP level in smooth muscle cells [37]. Papaverine-induced relaxation is also caused by other actions such as decreased calcium influx [38] or inhibition of the release of calcium from intracellular stores [39]. At high concentrations it usually relaxes vessels (such as the human IMA) regardless of the nature of the contraction. However, papaverine is not recommended for systemic use at these high concentrations. Although this vasodilator may be used topically with good results, its solution is highly acidic at concentrations used during surgery (pH 4.4 at 2.5 mmol/L and pH 4.8 at 0.03 mmol/L as measured in our laboratory). Papaverine hydrochloride is relatively unstable in nonacidic solutions and a white precipitate sometimes forms when papaverine is added to plasmalyte solution (pH approximately 7.4). Acidic solutions have been shown to damage the endothelium [40]. This problem may be overcome by mixing papaverine with blood to a final concentration of 1 mmol/L (pH 7.4) or with albumin [41].
Combination vasodilator—glyceryl trinitrate–verapamil solution
In human IMA, calcium-entry blockers are very potent in inhibiting potassium-induced contractions, but less potent when applied to prevent contraction caused by TXA2 [23]. However, GTN is a potent vasodilator against TXA2 or -AR agonists [10, 23]. Glyceryl trinitrate is very effective in reversing contraction of the human IMA, but less effective in preventing contraction (spasm) [10, 23]. Calcium-entry blocking drugs act selectively on the voltage-dependent calcium channel, whereas GTN acts by releasing NO in the muscle cell, which stimulates guanylate cyclase to raise cGMP. This in turn leads to Ca2+ removal from the cell (Fig 1). Thus on theoretical grounds the combination of verapamil and GTN with different mechanisms of action should be more effective in preventing or reversing spasm than either agent given alone.
Therefore, a combined vasodilator solution (GTN and verapamil, GV solution) has been developed to relax grafts during CABG. The formula for GV solution is verapamil, 5 mg; GTN, 2.5 mg; 8.4% NaHCO3, 0.2 mL; heparin, 500 U (0.5 mL of 1,000 U/mL); Ringer’s lactate solution, 300 mL. In this solution, the concentrations of verapamil and GTN were each 30 µmol/L (-4.5 log mol/L). This concentration of each agent given separately causes full relaxation of human IMA in vitro. The addition of NaHCO3 is necessary to bring the pH from about 4.8 to 7.4. The solution can be used both topically and intraluminally.
Other vasodilators
The effect of other vasodilators, such as TXA2 antagonists (GR32191B) [30], the phosphodiesterase inhibitor milrinone [42, 43], and the potassium-channel opener aprikalim [44], have also been studied. These new vasodilators may prove to have therapeutic value in CABG.
Anatomic factors
Thus far we have considered the IMA as a uniform conduit, such that the structure and the pharmacologic reactivity of a segment of the IMA is the same regardless of its location along the length of the vessel. We now go on to show that the IMA is not uniform from its proximal to its distal extent, which has important implications for the surgeon.
Segmental differences in contractility along the length of the internal mammary artery
Anatomic studies [45] have suggested that the IMA is an elastic (passive) conduit at most portions along its length, except in the proximal and very distal sections, where it is elastomuscular. The very proximal section of the superior epigastric artery and musculophrenic artery, which are the continuation of the bifurcation of the distal end of the IMA, are muscular with few elastic lamellae. Although superior long-term patency rate of the IMA graft has led to its extensive use, and most patients are rendered asymptomatic, there is evidence that blood flow through arterial grafts in some patients in whom IMA grafts were used is inadequate for maximal exercise [46]. In some cases in the postoperative period, inadequate graft flow may cause left ventricular failure manifested by a low output state [47]. In some cases this may be caused by technical problems at the coronary anastomosis, but in others this is not so. Low cardiac output tends to occur early in the patient’s course, and this situation may be worsened by high-dose vasopressor therapy that could further reduce arterial graft flow [47, 48].
There are two questions to be answered. First, is the pharmacologic reactivity of the human IMA different in its various sections? Second, is the human IMA a nonreactive passive conduit in the part used for most of the graft, that is, the mid and the proximal section? This may be important in a situation of flow limitation because any contraction may further reduce the IMA flow to a critical level. An in vitro study was designed to answer these questions [47]. The study demonstrated that the reactivity of the human IMA is variable along its full length and the distal section of this artery has the highest reactivity. This was demonstrated by the fact that the distal section was more responsive to two receptor agonists, NE and ET, and more sensitive to the TXA2 mimetic U46619. The EC50 was as much as 100-fold lower for these agents in the distal section than in the mid section. Physiologically, this may be important because the distal end of the IMA, and possibly the proximal portion as well, regulates blood flow in this artery, which allows it to shut down when vital organs of the body need better perfusion. The mid and proximal sections of the IMA are also not simply passive conduits. He [48] found that the mid section of the IMA contracted somewhat to all four vasoconstrictors tested, which suggests that even this part of the IMA is a reactive conduit despite the fact that there are fewer smooth muscle cells in the mid section than in the other sections.
Vasospasm is usually more readily encountered in the smaller and more reactive distal segment rather than in the mid and the proximal section of the IMA. In a marginal situation such as postoperative low output, the flow limitation may be critical and require pharmacologic therapy. Furthermore, in the most reactive section of the artery, the distal 3 to 4 cm proximal to the bifurcation, the pharmacologic reactivity is inversely correlated to its diameter, ie, the smaller the diameter, the more reactive the artery [48–50]. In other words, the more distal the section, the greater the tendency to develop spasm because of the more marked reactivity to vasoconstrictor agents. Therefore, to avoid spasm, we believe that as much of the distal IMA as possible should be trimmed off.
Greater contractility of internal mammary artery bifurcation
Under certain circumstances, such as when both the left anterior descending artery and the diagonal branch require grafts, the distal bifurcation of the IMA may be used for Y-grafting. Despite the popular use of this part of the IMA, a recent report has revealed that the patency rate for the bifurcation of the IMA is poor [51]. A recent study [49] has shown that at the bifurcation of the IMA, the contractility is greater than that at the distal section of the main IMA. This is because (1) the standardized contraction force of the bifurcation to ET and NE is higher; and (2) the bifurcation is more sensitive to TXA2. This may contribute to the poor long-term patency of the small-diameter IMA bifurcation grafts.
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Pharmacology of other arterial grafts |
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He and Yang [55, 56] compared the contractility of the GEA, the IMA, and the IEA and found that among arterial grafts the GEA has the highest contractility. They classified arterial grafts into three types (type I, somatic arteries; type II, visceral arteries; type III, limb arteries). Types II and III are prone to spasm [55, 56]. On the other hand, if the contraction force is normalized as a percentage of K+-induced contraction, there is no difference between these two vessels, which suggests that the spasmogenic agents for these two vessels may be similar. It is important to measure contractility in this context as 
T/ri, where the increase in active tension (T) is related to the normalized internal radius (ri). This absolute measure can then be used to compare contractile responses of different arteries.
Relaxation
Relaxation of the GEA to SNP [7] or to endothelium-dependent vasodilators [12] appears to be similar to the IMA.
Inferior epigastric artery
Vasoconstrictors
Mügge and coworkers [57] have suggested that compared with the IMA, the IEA contracts less in response to histamine, but relaxes more in response to endothelium-dependent vasodilators. Another study [58] has shown different contractile responses to TXA2 and NE between the IEA and the IMA. However, He and coworkers [13] have demonstrated that the maximal contraction force and the EC50 value in response to ET, NE, K+, and U46619 in IEA is similar to that of IMA. There was no difference between the IEA and the IMA for these four vasoconstrictors, either in the maximal contraction or EC50. This suggests that the contractile response of the IEA is basically similar to that of the IMA [13].
Relaxation
The non–receptor-mediated endothelium-dependent relaxation (induced by calcium ionophore A23187) in the IEA is less than in the IMA, although the receptor-mediated endothelium-dependent relaxation induced by acetylcholine is similar. This impaired non–receptor-mediated endothelium-dependent relaxation may indicate that decreased endothelium-dependent relaxation is an early sign of arteriosclerosis in the IEA [13]. Similarly, a recent report also found that endothelium-dependent relaxation is reduced in this artery compared with the IMA [35].
Radial artery
In the 1970s spasm of the radial artery graft and a low patency rate led to the abandonment of this arterial graft at an early stage of its usage [59]. With improved understanding of the characteristics of this vessel and the development of techniques for preventing and treating the spasm (using local papaverine and systemic diltiazem intraoperatively and postoperatively), use of this arterial graft has been recently revived [33]. Contraction to KCl in the radial artery is stronger than in the IMA or the GEA [8]. The radial artery is more reactive than the IMA to angiotensin II and ET-1, but the endothelial function of the radial artery is similar to the IMA [60]. Regarding relaxation, all three arteries (radial artery, GEA, and IMA) relax equally well to an endothelium-dependent agent, acetylcholine, and the endothelium-independent agent GTN [60, 61]. The radial artery studied in vitro was found to relax fully either to GV solution or to papaverine, but the relaxation to GV solution was more rapid in onset and of longer duration than for papaverine [61]. Recently in our clinical practice we have used GV solution on the radial artery to dilate it during harvesting and preparation and have found it to be satisfactory.
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Guidelines for the use of vasodilators for arterial grafts during CABG |
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1-adrenergic mechanism. 1-adrenergic constrictor mechanism. |
Pharmacology of the saphenous vein |
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The occlusion rate of SV grafts in the first year is between 15% and 26% [64]. By 10 years, one third of vein grafts are occluded, and of those patent, half show marked arteriosclerotic changes [65]. Although the mechanism of occlusion of vein grafts is not fully understood, there is good evidence to suggest that the use of high-pressure distention to reverse spasm during harvesting is a contributing factor. The immediate effects of excessive distention pressure are loss of the endothelium and damage to the media [66, 67]. The delayed effects are enhanced uptake of lipid by the vein wall [68] and reduced patency. In an important study of vein grafts to the carotid arteries in pigs, Angelini and associates [69] found that compared with undistended grafts, veins distended to 600 mm Hg had reduced patency up to 6 weeks. The use of vasodilator agents during vein harvesting may reduce the need for high-pressure distention and thereby improve long-term patency. Historically the vasodilator used in the human SV has been that used most commonly in the human IMA, namely papaverine. However, because it is not certain that papaverine is the ideal venodilator and there are concerns about the effects of concentrated papaverine on venous endothelium, it is important to consider alternative agents.
What causes spasm of the saphenous vein?
To make a rational choice of agents to prevent or reverse spasm in venous grafts, it is desirable to know the cause and mechanism of venospasm. Surprisingly, despite many studies, the cause of spasm of a vein during harvesting is not well understood. The most likely cause is the response of smooth muscle to mechanical stimulation during handling and dissection. From the pharmacologic point of view, there are a number of substances that are known to be potent venoconstrictors: 5-HT and PGs from platelets, ET-1 from the endothelium, and the circulating constrictors, angiotensin II, catecholamines, and vasopressin. Although these substances may not be implicated in the genesis of venous spasm during surgery, nevertheless they are useful tools for generating venous contraction in the laboratory so that dilators of the vein can be studied.
Method of studying reactivity of saphenous vein
The same organ bath techniques developed for use in the IMA [3] can be used to study contraction and relaxation of veins [70]. Human SV segments are removed from patients undergoing CABG procedures. A discarded, undistended, 1- to 2-cm segment of vein or a large branch not required for grafting is collected. The vein is stretched to an equivalent transmural pressure of 20 mm Hg, which corresponds to the in vivo pressure in the standing position. The vein is then relaxed to a circumference equal to 90% of that corresponding to a pressure of 20 mm Hg, and held at this degree of stretch for the remainder of the experiment. This level of passive stretch (resting force) is considered optimal for the development of the active force in veins [70].
Constrictors
Before testing vasodilators it is necessary to contract the vein segments. In a study by He and associates [70] the reactivity of the SV was tested to a variety of vasoconstrictors: the TXA2 analog U46619, 5-HT, NE, phenylephrine, and potassium. The most powerful constrictor was U46619. Potassium also produced a powerful contraction. The concentration of each vasoconstrictor required to give 50% to 80% of maximum response (EC50 to EC80) was determined, and these concentrations were then applied to new rings to develop a stable submaximal contraction from which cumulative concentration–relaxation curves were obtained.
Dilators
Glyceryl trinitrate caused nearly full relaxation of veins precontracted by potassium or U46619. Verapamil caused full relaxation (100%) in potassium-contracted veins but less relaxation (75%) in U46619-contracted rings [70]. The sensitivity to verapamil was similar for these two constrictor agents. Verapamil was more potent than papaverine. Papaverine also caused full (100%) relaxation in rings precontracted by K+ and U46619. The EC50 values were similar to those obtained using GTN and calcium antagonists. In potassium-contracted rings, the sensitivity to papaverine was less than to GTN. Sodium nitroprusside was found in a later study to be a less powerful dilator than the other three agents [71]. Nicorandil, a novel dilator with blocking activity for both potassium and calcium channels, had low potency in SV [71].
The onset and offset of relaxation for GTN and verapamil individually and in combination was tested. The mixture of GTN (10 µmol/L) and verapamil (10 µmol/L) combined the rapid onset (less than 2 minutes) of GTN with the prolonged duration (more than 2 hours) of verapamil. Papaverine, at least in canine tissue, had a slower onset than GTN [3].
Endothelial-dependent relaxation
There is much interest in the role of basal or stimulated NO release from endothelium in relaxing vascular smooth muscle. Drugs such as acetylcholine, bradykinin, or substance P release NO from the endothelium, which then acts to relax the vessel. However, therapeutically, giving NO donor drugs such as GTN or SNP will have the same effect, ie, to raise cGMP in the smooth muscle and relax the vessel without requiring endothelial receptor stimulation. In the SV the endothelium may be damaged or lost during harvesting and thus endothelial-dependent vasodilation may be impaired.
A possible future therapeutic target for venodilation is the NO synthase enzyme in the endothelium, in which either giving the substrate L-arginine or inducing more enzyme could enhance NO production. At present in the perioperative setting, NO donor drugs seem of most benefit.
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Pharmacologic relaxation of the saphenous vein during harvesting |
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An alternative method of introducing the dilator solution into the vein before it is exposed is to cannulate the vein at the ankle and inject solution so that it can act on each vein segment before it is exposed. Additional solution can be sprayed on the surface of the vein as it is progressively exposed [70, 73]. Thus the vein is exposed internally and externally to the optimal concentration of vasodilator. This technique has been used in many thousands of patients in our units.
Benefit of pharmacologic relaxation
Haudenschild and coworkers [2] found good preservation of the endothelium and the entire venous wall in dogs during preparation and harvesting using a subcutaneous injection of papaverine combined with low-pressure perfusion with tissue culture medium containing papaverine. Catinella and associates [74] found that the use of heparinized electrolyte solution containing papaverine for bathing and distending the vein during harvesting for CABG improved early postoperative graft patency. A prospective randomized clinical study has shown that the use of GV solution during harvesting of the SV reduced the distension pressure necessary to reverse spasm, improved the energy status of the vein wall, and was superior to topical papaverine in preserving the endothelium (Fig 2) [75].
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For many years papaverine has been the most commonly used topical agent for relaxing blood vessels, including the SV [76]. There are several concerns about the use of papaverine in the lumen of the SV. Roberts and coworkers [41] found that flushing the human SV with a solution of papaverine (0.36 mg/mL) caused depletion of the platelet-inhibitory substance prostacyclin and also caused ultrastructural damage. By contrast, if a balanced electrolyte solution was used to flush the vein, these effects were much less. Another concern with papaverine solution used intraluminally is its acidity. As mentioned previously, undiluted papaverine solution is highly acidic at concentrations used during cardiac surgery (pH 4.4 at 2.5 mmol/L and pH 4.8 at 0.03 mmol/L as measured in our laboratory). Acidic solutions have been shown to damage the endothelium [40] and hence are best avoided for intraluminal use. This problem can be countered by mixing papaverine with blood (1 mg/mL) or albumin [76]. In our experience, when the blood–papaverine mixture was used topically on the vein during harvesting, the blood obscured the operative field. In our own comparative clinical study, topical papaverine in Ringer’s lactate solution was less protective than intraluminal GV solution [75]. The GV solution reduced the pressure necessary to distend the vein adequately and reduced the loss of endothelium during preparation of the vein graft (Fig 2). Whether the benefit of reduced distention pressure and reduced endothelial damage translates into improved long-term graft patency has not yet been determined in man.
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TopAbstractIntroductionIn vitro pharmacology of...Pharmacology of the internal...Pharmacology of other arterial...Guidelines for the use...Pharmacology of the saphenous...Pharmacologic relaxation of the...ConclusionsReferences |
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In the organ bath it can be shown that there are many dilators of arterial and venous grafts that vary in potency, rapidity of onset, and duration of action. Using these findings to make a rational choice of type of dilator and optimal concentration for clinical use requires consideration of many additional factors, including the systemic effects of the agent if it enters the circulation, the effect of the agent and its vehicle on the endothelium, convenience of preparation, and cost. We have summarized these considerations in Table 2.
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References |
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TopAbstractIntroductionIn vitro pharmacology of...Pharmacology of the internal...Pharmacology of other arterial...Guidelines for the use...Pharmacology of the saphenous...Pharmacologic relaxation of the...ConclusionsReferences |
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