Pharmacology of coronary artery bypass grafts

1999;67:878-888 Ann Thorac SurgFranklin L. Rosenfeldt, Guo-Wei He, Brian F. Buxton and James A. Angus

Pharmacology of coronary artery bypass grafts

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CURRENT REVIEW

Pharmacology of Coronary Artery Bypass GraftsFranklin L. Rosenfeldt, FRACS, Guo-Wei He, MD, PhD, Brian F. Buxton, FRACS, andJames A. Angus, PhDCardiac Surgical Research Laboratory, Baker Medical Research Institute and Alfred Hospital, Prahran, Cardiac Surgery, Austinand Repatriation Medical Centre, Heidelberg, Department of Pharmacology, University of Melbourne, Melbourne, Victoria,Australia, and Department of Cardiothoracic Surgery, University of Hong Kong, Grantham Hospital, Hong Kong, China

Spasm of arterial and venous graft conduits can occurboth during harvesting and after the graft is connected.Attempts to overcome spasm during harvesting by prob-ing or hydraulic distension can cause structural damageto the graft, which may impair short- and long-termpatency. After a coronary artery bypass graft is con-nected, spasm can cause major problems with myocardialperfusion. To select the best pharmacologic agent toprevent or reverse vasoconstriction in a graft requires anunderstanding of the reactivity of that particular type ofgraft to vasoconstrictor and vasodilator agents. The phar-

macologic reactivity of venous and arterial graft conduitshas been documented through extensive studies of iso-lated vessels in the organ bath and of in situ grafts in thebody. In this review we summarize the current state ofknowledge of the reactivity of arterial and venous graftsto vasoconstrictor and vasodilator agents and describethe practical application of this knowledge in the oper-ating room and in the postoperative period.

(Ann Thorac Surg 1999;67:878–88)© 1999 by The Society of Thoracic Surgeons

In the early days of coronary artery bypass graft (CABG)surgery, the saphenous vein (SV) was seen simply as

a passive conduit that was harvested and grafted intothe coronary circulation where arterial pressure kept itwell distended. If spasm of the vein occurred duringharvesting, this was overcome by vigorous hydraulicdistension using a syringe. With the advent of internalmammary artery (IMA) grafting, spasm was encoun-tered both during harvesting and after the graft hadbeen attached to the heart. George Green, the pioneerIMA graft surgeon, recommended injecting papaverineinto the IMA to overcome spasm [1]. Later, papaverinewas also applied to the saphenous vein [2]. In the earlydays of pharmacologic treatment of vascular grafts dur-ing CABG surgery it was not known whether papaverinewas the most effective vasodilator agent nor what was theappropriate concentration of papaverine for intraopera-tive use.

Pharmacologists then began to study these questionsusing their standard preparation, the isolated vessel ringin the organ bath [3]. This methodology enabled concen-tration–relaxation response curves for each vasodilator tobe obtained, agents to be compared with each other, andcombinations of vasodilator drugs to be tested. Surgeonsjoined in the study of graft pharmacology by measuringthe effects of vasodilators on blood flow through the IMAbefore it was attached to the heart [4].

In recent years, with the increasing use of new arterialgrafts such as the gastroepiploic, inferior epigastric, andradial arteries, the problem of graft spasm has becomemore obvious. Thus it has become essential for surgeonsto understand the causes of spasm of vascular grafts and

to use the optimal vasodilator in the most appropriateway to counteract spasm.

In this review we summarize the current state ofknowledge of the pharmacology of vascular grafts anddescribe the practical application of this knowledge.

In Vitro Pharmacology of Blood Vessels

Isolated blood vessel pharmacology allows the scientistto explore mechanisms of drug action and establishconcentration–response relationships for analysis of po-tency and range (efficacy) more readily than is possible inin vivo experiments. In vitro blood vessel assays provideinformation in a controlled environment without bloodflow and shear stress, extrinsic neural activity, or hor-monal influences. Therefore, although scientists gainquantitation and analytical power with an in vitroexperiment, they may lose predictive power in trans-lating their findings back to the integrated systems invivo. Therefore organ bath measurement of activity ofsegments of large arteries and veins can only predict whatcan happen in vivo, not what does happen (Table 1).

What Are the Causes of Vasospasm?Isolated tissue assays cannot identify the cause of in vivospasm. But these assays can determine what factors havethe potential to contract the tissue in vivo. The nextchallenge is to determine in the body what combinationof factors, including surgical trauma, locally releasedvasoconstrictors, neural factors, and circulating hor-mones interacting with passive distension from arterialpressure, are likely to present the vessel with abnormalconstrictor activity.

Address reprint requests to Dr Rosenfeldt, Baker Medical ResearchInstitute, PO Box 6492, St Kilda Road Central, Melbourne, Victoria 8008Australia; e-mail: [email protected].

© 1999 by The Society of Thoracic Surgeons 0003-4975/99/$20.00Published by Elsevier Science Inc PII S0003-4975(98)01299-5



Normalization Technique for Setting Resting TensionThe preferred response when measuring blood vesselreactivity is to stretch the vessel radially to its optimallength for development of active force and measurechanges in isometric tension. The amount of passiveforce (stretch) applied to a segment of artery or vein in anorgan bath should be relevant for the amount of musclepresent and its geometry.

That is why we have developed techniques to deter-mine the passive length–tension relationship for eachvessel segment, cut to a precise length. This normaliza-tion procedure attempts to set the passive distension tocorrespond with that caused by transmural pressureexperienced in vivo. Clearly this will vary from arterialpressure for arterial grafts to the lower hydrostatic pres-sure in veins.

Segments of human arteries or veins collected frompatients undergoing CABG procedures are taken to thelaboratory. Rings are cut from these vessels and mountedon wires in organ baths for isometric force measurement.Many investigators set the resting tension (force per unitlength) at 2 to 4 g regardless of the type or size of theblood vessel being studied. However, a more physiologicapproach is to set the vessel at an optimal point accord-ing to its own length–tension curve, which will allow fordifferences in length of vessel segment and smoothmuscle geometry. This concept was initially applied toisolated resistance arteries [5]. The principle is to estab-lish individual length–tension exponential curves foreach vessel by relating the isometric tension, obtainedfrom a strain gauge, with the corresponding diameterand circumferential length determined by a micrometer.This technology was successfully transferred to largeblood vessels [3, 6] and has been continuously used inour studies and adopted by others for studying CABGpharmacology [7, 8].

Concentration–Response RelationshipIsolated tissue experiments allow the drug concentrationin the bathing solution to come into equilibrium through-out the tissue. This may take considerable time forthick-walled arteries, especially if the drug is not li-pophilic. Metabolism of the test drug and stability inKrebs solution at 37°C are important considerations.Access is also an issue. In the operating room, drugs suchas papaverine are usually applied topically to the adven-

titial surface alone, whereas in the organ bath, drugsaccess the smooth muscle through both the adventitiaand the lumen. Endogenous vasoactive constrictor stim-uli such as serotonin (5-HT), thromboxane A2 (TXA2), orendothelin 1 (ET-1) may access the IMA in vivo onlythrough the endothelial surface with little access to theouter medial smooth muscle by way of the vasa vasorum.

The two parameters that are obtained from organ bathstudies of greatest predictive value are (1) potency, ie,sensitivity of the vessel to a drug, and (2) range of themaximum response of the drug at high concentration.The sensitivity to each drug is given by the EC50, which isthe effective concentration that reduces the contractionby 50%. This value can vary considerably with the natureof the agent used to precontract the vessel and theamount of contraction that a chosen concentration ofconstrictor will develop. The latter concept reflects func-tional antagonism—how effectively the dilator agent canrelax a vessel precontracted by a particular constrictor.

Vasoconstrictor AgentsIf the mechanism of contraction involves activating aspecific receptor, eg, an a-adrenoceptor, then a selectivea-adrenoceptor antagonist will be highly effective be-cause the locus of the interaction is identical. In the caseof a functional antagonist such as nifedipine, it will relaxK1-contracted vessels at a lower concentration thanrequired if a receptor-operating constrictor such as nor-epinephrine (NE) had been used to precontract thevessel, even if the level of contraction from the K1 andNE was similar.

Raised extracellular K1 causes closure of the hyperpo-larizing K1 channels on smooth muscle, allowing thevoltage-operated Ca21 channels (VOCC) to open andintracellular [Ca21] to rise, resulting in contraction.Therefore, a VOCC antagonist such as nifedipine wouldreadily relax a tissue precontracted by K1. Converselythe contraction caused by NE is only partly caused bydepolarization of the tissue through VOCC and partlycaused by calcium release from intracellular sources.Thus, this latter mechanism would be more resistant tonifedipine.

Vasodilator AgentsThese are usually studied by establishing concentration–relaxation curves after precontracting the vessel. Therelaxation is expressed as a percentage of the precontrac-tion force. In relaxation studies, particular attention ispaid to the following: (1) The level of precontraction forceshould be chosen in the range of 50% to 80% of themaximum achievable by that agent. This is easily deter-mined as the EC50 to EC80 concentration from the con-strictor concentration–response curve. (2) The precon-traction force should be stable for the period needed forcompleting the cumulative concentration–relaxationcurve. A time control often is necessary to demonstratethe stability of the precontraction [9, 10]. Unless this isdone, the investigator may falsely ascribe relaxation tothe added drug rather than spontaneous, time-depen-dent dissipation of contraction.

Table 1. Strengths and Weaknesses of Techniques Used toStudy Vascular Graft Pharmacology

FactorsOrgan Bath

StudiesOperating Room

Studies

Preparation Isolated vessel In situ vesselConcentration–

response curvesYes No

Clinically relevant doses Not always YesProduction of contraction Vasoconstrictor

drugsTrue spasm

Study of side effects No Yes

879Ann Thorac Surg REVIEW ROSENFELDT ET AL1999;67:878–88 PHARMACOLOGY OF CORONARY ARTERY BYPASS GRAFTS



The effective concentration causing 50% of the maxi-mal response (contraction or relaxation) is used to de-scribe the sensitivity of the vessel to an agent. This isoften calculated by the formula E 5 MAp / ( Ap 1 Kp),where E is response, M is maximal contraction (or relax-ation), A is concentration, K is EC50 concentration, and pis the slope parameter [6].

Endothelium in Arterial and Venous GraftsThe role of the endothelium in maintaining vascular toneand preventing platelet aggregation has been extensivelystudied. Studies of endothelial function of CABGs haveshown that arterial endothelium has more ability toproduce nitric oxide (NO) than venous endothelium [11].Among the arterial grafts, the gastroepiploic artery(GEA) has been demonstrated to have similar endothe-lium-dependent relaxation to the inferior epigastric ar-tery (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 theIEA [13]. In the human IMA, as in other vessels, endo-thelium plays a modulatory role in contractility [14].Endothelium-derived hyperpolarizing factor (EDHF) alsoplays a role in arterial grafts [9].

Pharmacology of the Internal Mammary Artery

IntroductionRoutine harvesting of the IMA is associated with amoderate degree of contraction of the vessel because theadministration of a dilator drug causes a twofold increasein free flow from the open tip of the IMA [15, 16].Occasionally there is severe contraction (spasm), whichmay be visible or be inferred by minimal free flow. Forsevere spasm it is essential to use a dilator drug, prefer-ably a fast-acting one suitable for intraluminal use, todetermine whether the IMA should be discarded oralternatively relegated to graft a minor vessel. Maximalpharmacologic dilation of the IMA allows the surgeon toevaluate the flow-carrying capacity of the IMA and pro-vides a relaxed, dilated distal vessel that facilitates aprecise anastomosis. Vasodilation of the IMA pediclemay also unmask small bleeding points at the time ofsurgery and thus improve hemostasis.

Constrictor StimuliVasoconstriction may be evoked by various stimuli suchas mechanical trauma, nerve stimulation, and vasocon-strictor substances. Endothelin is one of several endothe-lium-derived contracting factors (EDCF) and is the mostpotent vasoconstrictor known [17]. Thromboxane A2 isalso considered as one of the EDCFs [18] but it is alsoderived from platelets. These two vasoconstrictors arevery potent in arterial grafts. Elevated plasma levels of ET[19] or TXA2 [20] have been found during cardiopulmo-nary bypass. Therefore, these two vasoconstrictors areprime candidates as spasmogenic agents for arterialgrafts during CABG surgery. Other possible spasmo-genic agents are prostaglandin F2a (PGF2a), 5-HT (whichis derived from platelets), circulating sympathomimetic

substances (NE and epinephrine), angiotensin II, andvasopressin.

ADRENOCEPTORS. b-Adrenoceptors. The clinical importanceof studying b-adrenoceptors in the IMA is first to deter-mine whether administered sympathomimetic agentscan stimulate b-adrenoceptors to mediate relaxation, andsecond, whether b-adrenoceptor antagonists can blockactive relaxation and thus evoke vasospasm in the IMAas has been reported for the coronary artery. Although a-and b-adrenoceptors have been demonstrated by auto-radiography on smooth muscle and endothelium in thehuman IMA [21], b-adrenoceptor-mediated relaxation isminimal in the human IMA. We found that isoproterenolinduced only a maximum response of 24% relaxation inthe human IMA compared with 89% in the canine coro-nary artery [22]. Therefore it is inferred that in the humanIMA, b-adrenoceptor agonists will not induce a signifi-cant relaxation and that the use of b-adrenoceptor antag-onists should not evoke IMA vasospasm.

a-Adrenoceptors. a-Adrenoceptors (AR) are composed oftwo subtypes, a1 and a2. Both may mediate contraction invascular smooth muscle. The predominance of subtypesof ARs varies from one blood vessel to another. In theIMA, the nonselective a1- and a2-AR agonist NE and theselective a1-AR agonists methoxamine and phenyleph-rine cause contraction [23]. The IMA has been shown tobe an a1-AR predominant vessel with little a2-AR func-tion [24, 25]. Therefore, circulating catecholamines maycontract the artery mainly through an a1-AR mechanism.

a2-Adrenoceptors are located on endothelial cells ofsome arteries and mediate smooth muscle relaxationthrough the endothelium-dependent relaxing factor(NO) mechanism [26]. However, in the IMA, althoughthere is evidence that when the a2-AR is blocked thecontraction induced by electrical stimulation is en-hanced, this effect is not significant in the contractioninduced by NE [25]. Therefore, a2-ARs located in the IMAendothelium may not be functionally important.

ENDOTHELIN RECEPTORS. Endothelin induces strong contrac-tion in the IMA [27, 28]. Both ETA and ETB receptorsubtypes mediate contraction and have been found in theIMA smooth muscle [29].

THROMBOXANE A2 RECEPTORS. The TXA2 receptor is one of themost important receptors in the IMA, judged by thepowerful contraction induced by the synthetic and stableanalog U46619, which acts through TXA2 receptors [23].

OTHER RECEPTORS. Serotonin receptors, PGF2a (FP) recep-tors [30], and dopaminergic receptors [31] have all beendemonstrated in the IMA. The agonists for those recep-tors may also be spasmogenic agents for the IMA.

VasodilatorsFACTORS INFLUENCING THE ACTION OF DILATORS. Nature of theConstriction. The response to some dilator agents dependson the nature of the vasoconstriction, that is, whether it ismediated through receptors or depolarizing agents. This

880 REVIEW ROSENFELDT ET AL Ann Thorac SurgPHARMACOLOGY OF CORONARY ARTERY BYPASS GRAFTS 1999;67:878–88



is particularly important in the case of calciumantagonists.

Timing. The effect of a vasodilator may depend onwhether it is given before or after a vasoconstrictor. Somedilator agents are ineffective if applied before the con-strictor stimulus but will be effective if applied to analready contracted vessel. This is especially important forglyceryl trinitrate (GTN) in the human IMA [23, 32]. Here,GTN may effectively reverse an already established con-traction, but it has little efficacy to prevent contraction ifused before the contraction is initiated, whether bypotassium ion or TXA2, a-AR agonists, or ET [32]. Thecause of this difference, depending on the order ofadministration, is probably related to the short burst ofcyclic guanosine 59-monophosphate (cGMP) generatedby GTN [23] or rapid tolerance [10], which causes theGTN effect to wear off before the vasoconstrictor devel-ops its full effect.

Tolerance. When used repeatedly, some vasodilators mayhave a diminishing effect, ie, tolerance occurs. Toleranceis a well-recognized phenomenon for some nitrates thatrequire a metabolic step to generate NO before stimulat-ing cGMP and relaxing the vessel [10]. This can be adisadvantage in clinical use.

Concentration of Vasodilator. The plasma concentration of avasodilator is also a key point in its efficacy. Vasodilatorsmay completely reverse the vasoconstriction in vitro athigh concentrations, but these concentrations may not beachievable in vivo after systemic administration of thevasodilator. For example, nifedipine at a concentrationmore than 10 mmol/L completely depresses the contrac-tion induced by ET in the human IMA, but this concen-tration is far higher than the plasma concentrationachievable clinically.

Onset of the Effect. The onset of activity after dosing isparticularly important in surgery in which a rapid onsetis desirable. In regard to the onset of the effect for eachvasodilator, nitrates are the fastest, calcium antagonistsare intermediate, and papaverine the slowest [3].

The above discussion is focused on the IMA. Althoughthe effect of vasodilators on other arterial conduits (IEA,GEA, and radial artery) is less well studied, the resultsfrom the limited studies are in accordance with the aboveobservations [7, 8, 13, 33–35]. Taken together, we mayconclude that there is no perfect vasodilator for dilatingIMA or other arterial grafts. Consequently, a combina-tion of vasodilators may offer a better effect.

SPECIFIC DILATORS. Calcium Antagonists. When the IMA iscontracted by a depolarizing agent such as K1, nifedipineor other calcium-channel antagonists are very effective ineither preventing or reducing the contraction [23]. This isbecause of the fact that calcium antagonists contractblood vessels through a specific mechanism. Calciumantagonists reduce Ca21 influx by blocking VOCCs,which is the major mechanism of the constricting actionof depolarizing agents such as K1 (Fig 1). However, in the

case of contraction mediated by membrane receptors,such as TXA2 receptors, a-ARs, or ET receptors, calciumantagonists such as nifedipine are less effective [23]. Inaddition nifedipine has a limited effect in preventing orreducing a-AR-mediated contraction [36]. Therefore, al-though calcium antagonists such as nifedipine are veryeffective under some circumstances (contraction medi-ated by depolarizing agents such as K1), one cannot saythese vasodilators are satisfactory as sole agents for useduring IMA surgical procedures, because they may beless effective in situations when the contraction is medi-ated by specific receptors that raise intracellular calcium.This mechanism is resistant to blockade by L-type calci-um-channel antagonists.

Nitrates. In contrast, organic nitrates such as GTN orsodium nitroprusside (SNP) are effective against a rangeof constrictor stimuli. The mechanism of action for thesevasodilators is that they release NO, a powerful stimulantfor guanylate cyclase, which raises cGMP in the smoothmuscle cell. This subsequently reduces intracellular cal-cium concentrations and leads to the relaxation of thesmooth muscle cell. In general, nitrates are effective inreversing vascular spasm, regardless of the nature of thecontraction, ie, they are effective in reversing eitherreceptor-mediated or depolarizing agent (K1)-mediatedcontraction, although they are slightly more effective inblocking receptor-operated channels [23, 32] than block-ing depolarizing agent-mediated contraction (Fig 1).

Papaverine. This is a nonspecific vasodilator substance,which relaxes blood vessels through multiple mecha-nisms. It is a phosphodiesterase inhibitor, so it may raisecGMP level in smooth muscle cells [37]. Papaverine-induced relaxation is also caused by other actions such asdecreased calcium influx [38] or inhibition of the releaseof calcium from intracellular stores [39]. At high concen-trations it usually relaxes vessels (such as the humanIMA) regardless of the nature of the contraction. How-ever, papaverine is not recommended for systemic use atthese high concentrations. Although this vasodilator maybe used topically with good results, its solution is highlyacidic at concentrations used during surgery (pH 4.4 at2.5 mmol/L and pH 4.8 at 0.03 mmol/L as measured inour laboratory). Papaverine hydrochloride is relativelyunstable in nonacidic solutions and a white precipitatesometimes forms when papaverine is added to plasma-lyte solution (pH approximately 7.4). Acidic solutionshave been shown to damage the endothelium [40]. Thisproblem may be overcome by mixing papaverine withblood to a final concentration of 1 mmol/L (pH 7.4) orwith albumin [41].

Combination Vasodilator—Glyceryl Trinitrate–Verapamil So-lution. In human IMA, calcium-entry blockers are verypotent in inhibiting potassium-induced contractions, butless potent when applied to prevent contraction causedby TXA2 [23]. However, GTN is a potent vasodilatoragainst TXA2 or a-AR agonists [10, 23]. Glyceryl trinitrateis very effective in reversing contraction of the human




IMA, but less effective in preventing contraction (spasm)[10, 23]. Calcium-entry blocking drugs act selectively onthe voltage-dependent calcium channel, whereas GTNacts by releasing NO in the muscle cell, which stimulatesguanylate cyclase to raise cGMP. This in turn leads toCa21 removal from the cell (Fig 1). Thus on theoreticalgrounds the combination of verapamil and GTN withdifferent mechanisms of action should be more effectivein preventing or reversing spasm than either agent givenalone.

Therefore, a combined vasodilator solution (GTN andverapamil, GV solution) has been developed to relaxgrafts during CABG. The formula for GV solution isverapamil, 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 lactatesolution, 300 mL. In this solution, the concentrations ofverapamil and GTN were each 30 mmol/L (24.5 logmol/L). This concentration of each agent given separatelycauses full relaxation of human IMA in vitro. The addi-tion of NaHCO3 is necessary to bring the pH from about4.8 to 7.4. The solution can be used both topically andintraluminally.

Other Vasodilators. The effect of other vasodilators, such asTXA2 antagonists (GR32191B) [30], the phosphodiester-ase inhibitor milrinone [42, 43], and the potassium-channel opener aprikalim [44], have also been studied.These new vasodilators may prove to have therapeuticvalue in CABG.

Anatomic FactorsThus far we have considered the IMA as a uniformconduit, such that the structure and the pharmacologicreactivity of a segment of the IMA is the same regardlessof its location along the length of the vessel. We now goon to show that the IMA is not uniform from its proximalto its distal extent, which has important implications forthe 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 theproximal and very distal sections, where it is elastomus-cular. The very proximal section of the superior epigas-tric artery and musculophrenic artery, which are thecontinuation of the bifurcation of the distal end of theIMA, are muscular with few elastic lamellae. Althoughsuperior long-term patency rate of the IMA graft has ledto its extensive use, and most patients are renderedasymptomatic, there is evidence that blood flow througharterial grafts in some patients in whom IMA grafts wereused is inadequate for maximal exercise [46]. In somecases in the postoperative period, inadequate graft flowmay cause left ventricular failure manifested by a lowoutput state [47]. In some cases this may be caused bytechnical problems at the coronary anastomosis, but inothers this is not so. Low cardiac output tends to occurearly in the patient’s course, and this situation may beworsened by high-dose vasopressor therapy that couldfurther reduce arterial graft flow [47, 48].

There are two questions to be answered. First, is thepharmacologic reactivity of the human IMA different inits various sections? Second, is the human IMA a nonre-active passive conduit in the part used for most of thegraft, that is, the mid and the proximal section? This maybe important in a situation of flow limitation because anycontraction may further reduce the IMA flow to a criticallevel. An in vitro study was designed to answer thesequestions [47]. The study demonstrated that the reactiv-ity of the human IMA is variable along its full length andthe distal section of this artery has the highest reactivity.This was demonstrated by the fact that the distal sectionwas more responsive to two receptor agonists, NE and

Fig 1. Schematic diagram of calcium entry into a smooth muscle cellthrough receptor-operated (ROC) and voltage-operated (VOC)channels (upper panel). Calcium-entry blocking drugs selectivelyreduce the open state of VOC. Glyceryl trinitrate (GTN) releasesnitric oxide (NO) into the cell, which stimulates guanylate cyclaseto raise cyclic guanosine 59-monophosphate (cGMP) that subse-quently leads to Ca21 being removed from the cell (lower panel).(Em 5 membrane potential; GTP 5 guanosine triphosphate;[Ca21]o 5 extracellular calcium concentration; TXA2 5 thrombox-ane A2; [Ca21]; 5 intracellular calcium concentration. Reprintedfrom [23] by permission of Circulation 1989;80(Suppl):I-141–50




ET, and more sensitive to the TXA2 mimetic U46619. TheEC50 was as much as 100-fold lower for these agents inthe 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, regulatesblood flow in this artery, which allows it to shut downwhen vital organs of the body need better perfusion. Themid and proximal sections of the IMA are also not simplypassive conduits. He [48] found that the mid section ofthe IMA contracted somewhat to all four vasoconstrictorstested, which suggests that even this part of the IMA is areactive conduit despite the fact that there are fewersmooth muscle cells in the mid section than in the othersections.

Vasospasm is usually more readily encountered in thesmaller and more reactive distal segment rather than inthe mid and the proximal section of the IMA. In amarginal situation such as postoperative low output, theflow limitation may be critical and require pharmacologictherapy. Furthermore, in the most reactive section of theartery, the distal 3 to 4 cm proximal to the bifurcation, thepharmacologic reactivity is inversely correlated to itsdiameter, ie, the smaller the diameter, the more reactivethe artery [48–50]. In other words, the more distal thesection, the greater the tendency to develop spasm be-cause of the more marked reactivity to vasoconstrictoragents. Therefore, to avoid spasm, we believe that asmuch of the distal IMA as possible should be trimmed off.

GREATER CONTRACTILITY OF INTERNAL MAMMARY ARTERY BIFUR-

CATION. Under certain circumstances, such as when boththe left anterior descending artery and the diagonalbranch require grafts, the distal bifurcation of the IMAmay be used for Y-grafting. Despite the popular use ofthis part of the IMA, a recent report has revealed that thepatency rate for the bifurcation of the IMA is poor [51]. Arecent study [49] has shown that at the bifurcation of theIMA, the contractility is greater than that at the distalsection of the main IMA. This is because (1) the standard-ized contraction force of the bifurcation to ET and NE ishigher; and (2) the bifurcation is more sensitive to TXA2.This may contribute to the poor long-term patency of thesmall-diameter IMA bifurcation grafts.

Pharmacology of Other Arterial Grafts

Gastroepiploic ArteryCONTRACTION. Spasm of the GEA is a well-described clin-ical phenomenon [52]. Dignan and associates [7] havefound that the GEA is more reactive than the IMA to K1,NE, and 5-HT, whereas others have suggested that theGEA and the IMA have similar response to NE, phenyl-ephrine, and 5-HT [34, 53], and that the IMA is morereactive to the TXA2 mimetic, U46619 [54]. The diverseresults from different groups may reflect the variation oftechniques used in the studies. In general, the GEA has astronger contractility than the IMA and the above men-tioned vasoconstrictors may be the spasmogenic agentsfor the GEA [7].

He and Yang [55, 56] compared the contractility of the

GEA, the IMA, and the IEA and found that amongarterial grafts the GEA has the highest contractility. Theyclassified arterial grafts into three types (type I, somaticarteries; type II, visceral arteries; type III, limb arteries).Types II and III are prone to spasm [55, 56]. On the otherhand, if the contraction force is normalized as a percent-age of K1-induced contraction, there is no differencebetween these two vessels, which suggests that the spas-mogenic agents for these two vessels may be similar. It isimportant to measure contractility in this context asDT/ri, where the increase in active tension (DT) is relatedto the normalized internal radius (ri). This absolutemeasure can then be used to compare contractile re-sponses of different arteries.

RELAXATION. Relaxation of the GEA to SNP [7] or toendothelium-dependent vasodilators [12] appears to besimilar to the IMA.

Inferior Epigastric ArteryVASOCONSTRICTORS. Mugge and coworkers [57] have sug-gested that compared with the IMA, the IEA contractsless in response to histamine, but relaxes more in re-sponse to endothelium-dependent vasodilators. Anotherstudy [58] has shown different contractile responses toTXA2 and NE between the IEA and the IMA. However,He and coworkers [13] have demonstrated that the max-imal contraction force and the EC50 value in response toET, NE, K1, and U46619 in IEA is similar to that of IMA.There was no difference between the IEA and the IMAfor these four vasoconstrictors, either in the maximalcontraction or EC50. This suggests that the contractileresponse of the IEA is basically similar to that of theIMA [13].

RELAXATION. The non–receptor-mediated endothelium-dependent relaxation (induced by calcium ionophoreA23187) in the IEA is less than in the IMA, although thereceptor-mediated endothelium-dependent relaxationinduced by acetylcholine is similar. This impaired non–receptor-mediated endothelium-dependent relaxationmay indicate that decreased endothelium-dependent re-laxation 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 comparedwith the IMA [35].

Radial ArteryIn the 1970s spasm of the radial artery graft and a lowpatency rate led to the abandonment of this arterial graftat an early stage of its usage [59]. With improved under-standing of the characteristics of this vessel and thedevelopment of techniques for preventing and treatingthe spasm (using local papaverine and systemic diltiazemintraoperatively and postoperatively), use of this arterialgraft has been recently revived [33]. Contraction to KCl inthe radial artery is stronger than in the IMA or the GEA[8]. The radial artery is more reactive than the IMA toangiotensin II and ET-1, but the endothelial function ofthe radial artery is similar to the IMA [60]. Regarding




relaxation, all three arteries (radial artery, GEA, andIMA) relax equally well to an endothelium-dependentagent, acetylcholine, and the endothelium-independentagent GTN [60, 61]. The radial artery studied in vitro wasfound to relax fully either to GV solution or to papaver-ine, but the relaxation to GV solution was more rapid inonset and of longer duration than for papaverine [61].Recently in our clinical practice we have used GV solu-tion on the radial artery to dilate it during harvesting andpreparation and have found it to be satisfactory.

Guidelines for the Use of Vasodilators forArterial Grafts During CABG

1. There is no perfect vasodilator that is effective inevery situation. Vasoconstriction (or spasm) iscaused by multiple mechanisms. Vasodilators relaxvascular smooth muscles through a specific mecha-nism or mechanisms. Selective vasodilators, such ascalcium antagonists, are more potent when thevessel is constricted by agents, such as potassium,which act indirectly to open VOCCs, but are lesspotent when the vessel is constricted through areceptor-operated mechanism, such as for TX con-striction. Nitrodilators, although effective in revers-ing established spasm, may be much less effectivethan calcium antagonists if given before the con-strictor stimulus [23].

2. In the operating room, papaverine (1 mg/mL, 2.7mmol/L) is satisfactory for topical use; however, itsonset is not as rapid as GTN and in its unbufferedform it is highly acidic and therefore probably notideal for intraluminal use unless diluted with bloodor albumin. Sodium nitroprusside (1.7 mmol/L,0.5 mg/mL), used topically, is very potent but maycause hypotension if it enters the systemic circula-tion. For intraluminal use, a buffered mixture of anitrate and a calcium antagonist such as GV solutionproduces full vasodilation of rapid onset withoutconcern about endothelial damage.

3. When the patient has signs of myocardial ischemiaand is already receiving a vasodilator, the dose ofthe vasodilator should be reduced, stopped, or evenchanged to a dilator working by a different mecha-nism. When a patient is receiving a sympathomi-metic agent, it should be kept in mind that theseagents may evoke arterial graft spasm through thea1-adrenergic mechanism.

4. With a fall of the mean arterial blood pressure, thereis a disproportionate reduction in arterial graft flow[62]. This has major implications if the patient be-comes hypotensive after extensive arterial grafting.Hypotension should be corrected urgently by cessa-tion of vasodilator therapy or by the addition of anappropriate vasoconstrictor. The restoration of anormal mean arterial blood pressure is of moreimportance than the potential loss of blood flowthrough the a1-adrenergic constrictor mechanism.

Pharmacology of the Saphenous Vein

Importance of Protecting the Saphenous Vein DuringHarvestingThe two situations in which spasm of the SV may occurare during harvesting and during the postoperative pe-riod. Postoperative spasm is a rarity and can be readilyreversed by GTN [63]. However, spasm of the SV duringharvesting is a common phenomenon. Therefore it isimportant to appreciate the detrimental effects of spasmand to be aware of techniques that can be used to preventor reverse this spasm.

The occlusion rate of SV grafts in the first year isbetween 15% and 26% [64]. By 10 years, one third of veingrafts are occluded, and of those patent, half showmarked arteriosclerotic changes [65]. Although the mech-anism 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 isa contributing factor. The immediate effects of excessivedistention pressure are loss of the endothelium anddamage to the media [66, 67]. The delayed effects areenhanced uptake of lipid by the vein wall [68] andreduced patency. In an important study of vein grafts tothe carotid arteries in pigs, Angelini and associates [69]found that compared with undistended grafts, veinsdistended to 600 mm Hg had reduced patency up to 6weeks. The use of vasodilator agents during vein harvest-ing may reduce the need for high-pressure distentionand thereby improve long-term patency. Historically thevasodilator used in the human SV has been that usedmost commonly in the human IMA, namely papaverine.However, because it is not certain that papaverine is theideal venodilator and there are concerns about the effectsof concentrated papaverine on venous endothelium, it isimportant to consider alternative agents.

What Causes Spasm of the Saphenous Vein?To make a rational choice of agents to prevent or reversespasm in venous grafts, it is desirable to know the causeand mechanism of venospasm. Surprisingly, despitemany studies, the cause of spasm of a vein duringharvesting is not well understood. The most likely causeis the response of smooth muscle to mechanical stimula-tion during handling and dissection. From the pharma-cologic point of view, there are a number of substancesthat are known to be potent venoconstrictors: 5-HT andPGs from platelets, ET-1 from the endothelium, and thecirculating constrictors, angiotensin II, catecholamines,and vasopressin. Although these substances may not beimplicated in the genesis of venous spasm during sur-gery, nevertheless they are useful tools for generatingvenous contraction in the laboratory so that dilators ofthe vein can be studied.

Method of Studying Reactivity of Saphenous VeinThe same organ bath techniques developed for use in theIMA [3] can be used to study contraction and relaxationof veins [70]. Human SV segments are removed frompatients undergoing CABG procedures. A discarded,




undistended, 1- to 2-cm segment of vein or a large branchnot required for grafting is collected. The vein isstretched to an equivalent transmural pressure of20 mm Hg, which corresponds to the in vivo pressure inthe standing position. The vein is then relaxed to acircumference equal to 90% of that corresponding to apressure of 20 mm Hg, and held at this degree of stretchfor the remainder of the experiment. This level of passivestretch (resting force) is considered optimal for the de-velopment of the active force in veins [70].

ConstrictorsBefore testing vasodilators it is necessary to contract thevein segments. In a study by He and associates [70] thereactivity of the SV was tested to a variety of vasocon-strictors: the TXA2 analog U46619, 5-HT, NE, phenyleph-rine, and potassium. The most powerful constrictor wasU46619. Potassium also produced a powerful contraction.The concentration of each vasoconstrictor required togive 50% to 80% of maximum response (EC50 to EC80)was determined, and these concentrations were thenapplied to new rings to develop a stable submaximalcontraction from which cumulative concentration–relaxation curves were obtained.

DilatorsGlyceryl trinitrate caused nearly full relaxation of veinsprecontracted by potassium or U46619. Verapamil causedfull relaxation (100%) in potassium-contracted veins butless relaxation (75%) in U46619-contracted rings [70]. Thesensitivity to verapamil was similar for these two con-strictor agents. Verapamil was more potent than papav-erine. Papaverine also caused full (100%) relaxation inrings precontracted by K1 and U46619. The EC50 valueswere similar to those obtained using GTN and calciumantagonists. In potassium-contracted rings, the sensitiv-ity to papaverine was less than to GTN. Sodium nitro-prusside was found in a later study to be a less powerfuldilator than the other three agents [71]. Nicorandil, anovel dilator with blocking activity for both potassiumand calcium channels, had low potency in SV [71].

The onset and offset of relaxation for GTN and vera-pamil individually and in combination was tested. Themixture of GTN (10 mmol/L) and verapamil (10 mmol/L)combined the rapid onset (less than 2 minutes) of GTNwith the prolonged duration (more than 2 hours) ofverapamil. Papaverine, at least in canine tissue, had aslower onset than GTN [3].

Endothelial-Dependent RelaxationThere is much interest in the role of basal or stimulatedNO release from endothelium in relaxing vascularsmooth muscle. Drugs such as acetylcholine, bradykinin,or substance P release NO from the endothelium, whichthen acts to relax the vessel. However, therapeutically,giving NO donor drugs such as GTN or SNP will have thesame effect, ie, to raise cGMP in the smooth muscle andrelax the vessel without requiring endothelial receptorstimulation. In the SV the endothelium may be damaged

or lost during harvesting and thus endothelial-depen-dent vasodilation may be impaired.

A possible future therapeutic target for venodilation isthe NO synthase enzyme in the endothelium, in whicheither giving the substrate l-arginine or inducing moreenzyme could enhance NO production. At present in theperioperative setting, NO donor drugs seem of mostbenefit.

Pharmacologic Relaxation of the Saphenous VeinDuring Harvesting

Method of Application of SolutionHaving selected the optimal venodilator(s) on the basis oforgan bath studies, the next question arises as to the bestmethod of application to the SV during harvesting. Ide-ally the dilator solution would be applied early enoughduring the procedure to prevent spasm before it occurs.LoGerfo and associates [72] recommended injecting pa-paverine subcutaneously along the track of the saphe-nous vein before cutting the skin. This technique has thepotential disadvantage that it is difficult to ensure that thesubcutaneously injected solution actually ends up in thesame tissue plane as the vein. Also, the injecting needleitself could damage the vein.

An alternative method of introducing the dilator solu-tion into the vein before it is exposed is to cannulate thevein at the ankle and inject solution so that it can act oneach vein segment before it is exposed. Additional solu-tion can be sprayed on the surface of the vein as it isprogressively exposed [70, 73]. Thus the vein is exposedinternally and externally to the optimal concentration ofvasodilator. This technique has been used in many thou-sands of patients in our units.

Benefit of Pharmacologic RelaxationHaudenschild and coworkers [2] found good preserva-tion of the endothelium and the entire venous wall indogs during preparation and harvesting using a subcu-taneous injection of papaverine combined with low-pressure perfusion with tissue culture medium contain-ing papaverine. Catinella and associates [74] found thatthe use of heparinized electrolyte solution containingpapaverine for bathing and distending the vein duringharvesting for CABG improved early postoperative graftpatency. A prospective randomized clinical study hasshown that the use of GV solution during harvesting ofthe SV reduced the distension pressure necessary toreverse spasm, improved the energy status of the veinwall, and was superior to topical papaverine in preserv-ing the endothelium (Fig 2) [75].

Choice of Vasodilator Agent for Vein HarvestingOne concern with the use of dilator solutions by intralu-minal injection into the SV during harvesting is thatwhen the dilator agent enters the systemic circulation byway of the proximal end of the SV it might cause systemicvasodilation and hypotension. We have never observedsignificant hypotension after injection of the GV solution




into the SV provided that bolus injections are limited to 1to 2 mL. However, when SNP (10 mmol/L) was usedduring harvesting of the SV in approximately 50 patientsin our unit, hypotension was troublesome. Papaverine inblood (1 mg/mL) is injected into the SV by some surgeonswithout troublesome hypotension. This has also been ourexperience.

For many years papaverine has been the most com-monly used topical agent for relaxing blood vessels,including the SV [76]. There are several concerns aboutthe use of papaverine in the lumen of the SV. Roberts andcoworkers [41] found that flushing the human SV with asolution of papaverine (0.36 mg/mL) caused depletion of

the platelet-inhibitory substance prostacyclin and alsocaused ultrastructural damage. By contrast, if a balancedelectrolyte solution was used to flush the vein, theseeffects were much less. Another concern with papaverinesolution used intraluminally is its acidity. As mentionedpreviously, undiluted papaverine solution is highlyacidic at concentrations used during cardiac surgery (pH4.4 at 2.5 mmol/L and pH 4.8 at 0.03 mmol/L as measuredin our laboratory). Acidic solutions have been shown todamage the endothelium [40] and hence are best avoidedfor intraluminal use. This problem can be countered bymixing papaverine with blood (1 mg/mL) or albumin [76].In our experience, when the blood–papaverine mixturewas used topically on the vein during harvesting, theblood obscured the operative field. In our own compar-ative clinical study, topical papaverine in Ringer’s lactatesolution was less protective than intraluminal GV solu-tion [75]. The GV solution reduced the pressure neces-sary to distend the vein adequately and reduced the lossof endothelium during preparation of the vein graft (Fig2). Whether the benefit of reduced distention pressureand reduced endothelial damage translates into im-proved long-term graft patency has not yet been deter-mined in man.

Conclusions

There are many possible causes of graft spasm duringCABG but undoubtedly the most common is surgicaltrauma. In the case of arterial grafts, surgical trauma canusually be minimized by careful surgical technique andby harvesting the artery as a pedicle rather than skele-tonizing it. In the case of the SV, the vessel is alwaysskeletonized during harvesting and is often subjected tosurgical trauma especially during minimally invasiveharvesting techniques. Thus unless specific pharmaco-logic measures are taken, the SV is always in spasm afterharvesting. In general spasm of vascular graft conduits isbest managed by prevention rather than treatment afterit has occurred.

Fig 2. Human saphenous veins were treated with either Ringer’slactate electrolyte solution (Saline), papaverine, or combination glyc-eryl trinitrate–verapamil (GV) solution during harvesting. Afterpreparation and distention for grafting, endothelial coverage wasassessed microscopically and compared with an unprepared undis-tended segment of vein (Control, 95% confidence limits). Endothelialcoverage was greater with GV treatment than with papaverine or notreatment, but there was still substantial loss of endothelium com-pared with unprepared vein.

Table 2. Intraoperative Dilators for Use With Vascular Grafts

AgentOptimal

Concentration Advantages Disadvantages Comment

Papaverine in electrolytesolution [41]

1.6 mmol/L(0.6 mg/mL)

Powerful dilatorregardless of thecause of spasm

Acid pH could damageendothelium

Improves early patencySuitable for topical use

Papaverine in blood oralbumin [76]

2.7 mmol/L(1 mg/mL)

Blood or protein tobuffer acidity

When blood-basedsolution usedtopically it obscuresthe operative field

Suitable for topical andintraluminal use

Glyceryl trinitrate-verapamilcombination [15, 75]

GTN: 37 mmol/L(8.3 mg/mL)V: 34 mmol/L(16.7 mg/mL)

Rapid onset,prolonged action

Suitable for allvessels

Multi-ingredient Has been validated inIMA, saphenous vein,and radial artery

Sodium nitroprusside [44] 1.7 mmol/L(0.5 mg/mL)

Effective on IMA Systemic hypotensionif it enters circulation

Weak dilation insaphenous vein

More effective inarterial than invenous grafts

GTN 5 glyceryl trinitrate; IMA 5 internal mammary artery; V 5 verapamil.




In the organ bath it can be shown that there are manydilators of arterial and venous grafts that vary in potency,rapidity of onset, and duration of action. Using thesefindings to make a rational choice of type of dilator andoptimal concentration for clinical use requires consider-ation of many additional factors, including the systemiceffects of the agent if it enters the circulation, the effect ofthe agent and its vehicle on the endothelium, conve-nience of preparation, and cost. We have summarizedthese considerations in Table 2.

Ultimately the rational use of pharmacologic therapyof coronary bypass grafts by the surgeon requires famil-iarity with the pharmacologic reactivity of the conduitsand the actions of the available dilators. There is exten-sive evidence that the use of appropriate vasodilatorsduring CABG surgery can facilitate the operative proce-dure as well as improve graft flow and reduce structuraldamage to the graft conduit.

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1999;67:878-888 Ann Thorac SurgFranklin L. Rosenfeldt, Guo-Wei He, Brian F. Buxton and James A. Angus

Pharmacology of coronary artery bypass grafts

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