The comparison of vascular reactivities of arterial and venous grafts to vasodilators: Management of graft spasm

International

Journal of

cardiology InternationalJournal of Cardiology53 (1996)137-145

ELSEVIER

The comparison of vascular reactivities of arterial and venous grafts to vasodilators: Management of graft spasm’ B.S. Uydeg-Dogan*a, M. Nebigilb, M.D. S-Aslamaci”, E. Onukd, i Kanzika, F. Akar” ‘Department of Pharmacology, Faculty of Pharmacy, Gazi University, Etiler, 06330 Ankara, Turkey bDepartment of Cardiovascular Surgery, Ankara Educational Hospital of SSK, Ankara, Turkey CDepartment of Cardiovascular Surgery, Faculty of Medicine, Bqkent University, Ankara, Turkey ‘Department of General Surgery, Faculty of Medicine, Gazi University, Bepevler. Ankara, Turkey

Received8 June 1995;accepted21 November1995

Graft spasmin the perioperative or postoperative period increasesthe risk of morbidity and mortality after coronary revascularixation and hence necessitatesurgent treatment. We have studied the effects of various vasodilators against noradrenaline- and endothelin-l-induced spasms in saphenous vein, internal mammary artery and gastroepiploic artery. In internal mammary and gastroepiploic arteries, the nitrovasodilators, sodium nitroprusside and glyceryl trinitrate, effectively reversedthe spasmsinduced either with noradrenaline (for sodium nitroprusside; internal mammary artery: 101.07%f 1.63%; gastroepiploic artery: 94.10% f 2.07%) or endothelin-1 (for sodium nitroprusside; internal mammary artery: 97.67% f 4.94%; gastroepiploic artery: 90.69% f 2.61%).However, in saphenousvein contracted with endothelin-1, the responsivenessto nitrovasodilators was significantly blunted (for sodium nitroprusside: 52.33%& 5.19%)than that of rings contracted with noradrenaline (for sodium nitroprusside: 95.04% f 1.94%).Both arterial and venous grafts exhibited moderate &receptor function in responseto isoproterenol. Isoproterenol was less effective in inhibiting the contractions of endothelin-1 in saphenousvein and gastroepiploic artery but not in internal mammaryartery. On the other hand, nifedipine and papaverine were fully effective in reversing all the spasmsin three of the graft materials. From these results, it can be deduced that saphenousvein is refractory against cyclic guanidine monophosphate (cGMP)-dependent and &receptor mediated relaxations when endothelin-1 was used as the spasmogenicagent. Internal mammary artery is the most responsive graft material to the vasodilators regardlessof the nature of spasmogenicstimulus. Gastroepiploic artery exhibits functional similarity with internal mammary artery, with the exception of D-receptor responsiveness. Keywords: Bypass graft materials; Vascular reactivity

Corresponding author.Tel.: 00 90 31221266450435; Fax: 00l 90 3122235018.

1. Introduction

I This study is Partly presentedin the XXX11 Congressof the International Union of Physiological!Iciences,August lst-6th, 1993,Glasgow.

Coronary bypass graft materials, saphenous vein, internal mammary artery and gastroepiploic

0167-5273/96/$15.00 0 1996ElsevierScienceIreland Ltd. All rights reserved SSDI 0167-5273(95)02533-3

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artery can go into spasmduring the perioperative an&or postoperative period [l-3]. Although the exact mechanismis unknown, perioperative spasm has generally been attributed to exposure to hypoxemia and endothelial injury during isolation and preparation of the graft materials [4-61. In the postoperative period, spasm may possibly be due to platelet activation secondary to abnormal endothelial function [7]. Graft spasm needs urgent treatment since it increasesthe risk of morbidity and mortality. The directly acting vasodilators such as sodium nitroprusside, glyceryl trinitrate, nifedipine and papaverine have generally beenused in the prevention and/or treatment of the spasm [2,8]. Experimental vasospasm created in isolated vascular segmentshas been widely used to investigate the mechanism of graft spasm [9-121 even though it does not reflect exactly the native pathologic condition. It has been reported that saphenous vein and internal mammary artery showed different responsiveness to vasodilators depending on the spasmogenic agent used [g-14]. This difference most probably results from functional and physical dissimilarities between venous and arterial grafts. On the other hand, knowledge of the vascular reactivity of the alternative graft material, gastroepiploic artery is, as yet, limited [ 15,161. An understanding of the vascular reactivities of currently used graft materials will be beneficial in the management of graft spasm. We have previously examined the endothelial function of gastroepiploic artery versus saphenous vein [ 171. In this study, we have compared the responsiveness of saphenousvein, internal mammary artery and gastroepiploic artery to various vasodilators which induced relaxations either by Ca++ channel blocking, cGMP-dependent or /3-receptor-mediated mechanismsagainst noradrenaline- and endothelin-l-induced spasms. 2. Materials and methods 2.1. Sampling and preparation of the vessels Gastroepipioic arteries were supplied from patients undergoing gastrectomy, whereassaphenous vein and internal mammary artery grafts were sup plied from patients undergoing coronary artery

Journal oj Cardiology 53 (19%) 137-145

Table 1 Clinical characteristicsof the patients undergoing coronary bypass and gastrectomy operations ParaIlEterS nm and sv Total sex Female Male Age Drug therapy GTN calcium antagonists &adrenoceptor antagonist

No. of patients 37 6 31 54.76 f 1.68 13 37 2

GEA

Total

22

Sex

Female Male A.?S Drug dewy

6 16 53.82 f 2.05 0

SV, saphenous vein; IMA, internal mammary artery; GEA, gastroepiploic artery, GTN; glyceryl trinitrate

revascularization. Some clinical characteristics of the patients and their drug therapies are given in Table 1. The responsivenessof glyceryl trinitrate and isoproterenol were studied in the vesselsobtained from the patients who were not exposed to thesedrugs. Use of the vesselswas approved by the Institutional Review Boards of Baskent and Gazi Universities, Faculties of Medicine. Care was taken during harvesting of the vesselsso as not to stretch and touch the inner surface. Saphenous vein and internal mammary artery were supplied before dilation procedure and papaverine administration, respectively. Saphenousvein and internal mammary artery were obtained from the samepatient. The vessel specieswere placed immediately into cold (4’C) Krebs-Ringer bicarbonate solution of the following composition (mM): NaCl 118, KC1 4.7, KH2P04 1.2, NaHC03 25, MgS0,,.7H,O 1.2, CaC1, 2.5, glutme Il. 1 and disodium ethylene diamine tetraacetic acid (EDTA) 0.026. The vesselswere cleaned of adherent connective tissues and cut into rings of 3-4 mm in length. Rings were suspendedbetween two stainless steel

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L-shaped hooks in a 10 ml jacketed organ bath containing Krebs-Ringer bicarbonate solution at 37’C and aerated with 95% 0, and 5% C&. One hook was fmed to the micrometric manipulator allowing adjustments in resting tension on the rings and the other was connected to a force displacement transducer (Nihon Kohden, TB 611T) for the measurementof isometric force. The optimal point of length-tension relation was determined by repeated exposure to noradrenaline (5 x 10e6M) at different levels of resting tension. In both arterial and venous grafts, 2 g was determined to be optimal for maximal noradrenaline contraction. Thus, the resting tensions of vessel rings were adjusted to 2 g during the equilibration period of 2 h. 2.2. Experimental protocol At the end of the equilibration period, the viabilities of vessel segments were checked by noradrenaline (5 x 10m6M) and preparations which developed a tension of less than 1 g were discarded.Gastroepiploic arteries which generated excessive spontaneous periodic contractions or fade effect to noradrenaline were also discarded. Endothelium intact rings of the vesselstaken from the samepatients were contracted in parallel with noradrenaline (5 x lo-’ M for saphenous vein; 5 x 10m6M for internal mammary artery and 10B6M for gastroepiploic artery) or endothelin-1 (lo-* M for saphenous vein and internal mammary artery; 3 x 10m8 M for gastroepiploic artery) to approximately 70%~90% of the maximum response.The presenceof endothelium was checked by the ability of acetylcholine (10s6 M) to induce relaxation on noradrenaline-contracted rings. Increasing concentrations of nifedipine, sodium nitroprusside, trinitrate, slY=Yl isoproterenol, and low4 M papaverine, were assessedon saphenous vein internal mammary artery and gastroepiploic artery rings precontracted either with noradrenaline or endothelin-1 . Three to five rings were obtained from each artery and vein specimenand each ring was subjected to only one vasodilator. 2.3. Drugs All drugs used, unless otherwise stated, were

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purchased from Sigma Chemical Co. (St. Louis, MO). Glyceryl trinitrate was purchased from Schwarz Pharma, and endothelin-1 from Peninsula Labs. A stock solution of noradrenaline was prepared in 0.001 N HCl and ascorbic acid (1 mdml) was added to prevent oxidation. All drugs were dissolved in distilled water, apart from nifedipine, which was suspendedin dimethyl sulfoxide (DMSO). DMSO was determined to have no effect on noradrenaline- or endothelin-linduced contractions. 2.4. Statistical analysis The results were given as mean f S.E.M. The relaxations were expressedas the percent decreases of the precontraction induced by noradrenaline or endothelin- 1. The concentrations of relaxing agents required to elicit 50% of their maximum responses (EC%) were calculated for each ring separately by probit analysis to compare the sensitivities, and expressedas negative log M. Maximum relaxations (E,-) were expressedas percent decreases of noradrenaline- or endothelin-linduced precontractions. In all experiments, n is the number of patients from whom the vessels were obtained. Statistical analysis was determined by Student’s unpaired t-test and a P-value less than 0.05 was considered significant. 3. Redts 3.1. Contraction The maximal contraction force (expressed in grams) induced by noradrenaline (10e4M) was significantly more pronounced in gastroepiploic artery and saphenousvein than in internal mammary artery. However, the contraction force induced by endothelin-1 (lo-’ M) did not differ significantly betweenthree of the vessels(Table 2). On the other hand, the precontraction forces elicited by submaximal concentrations of noradrenaline and endothelin-1 are similar in three tissue types (for noradrenaline; saphenous vein: 2.51 * 0.32 g, n = 8, internal mammary artery: 1.87 * 0.21 g, n = 12, gastroepiploic artery: 3.03 * 0.55 g, n = 11, P > 0.05). The time required to reach maximal contraction differed significantly between two contractile

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Table 2 The comparison of the contractility of saphenousvein (SV), internal mammary artery (IMA) and gastroepiploic artery (GEA) to noradrenahne (NA) and endothelin-I (ET-l) in terms of absolute tension (g) and time (min) to reach maximal contraction Maximal contraction Absolute tension (g)

sv IMA GEA

Time (min)

NA

ET-I

NA

3.53 f 0.39 (n = 8) 2.08 f 0.19a (n = 12) 4.26 i 0.73 (n= 11)

2.82 f 0.38 (n = 7) 2.14 f 0.29 (n = 10) 3.32 f 0.53 (n = 10)

4.94 f 0.51

31.14 l 4.41b

(n = 8)

(n = 7)

ET-l

4.92 f 0.35 (n = 12) 3.68 EIE0.28 (n= II)

12.50f 0.54 (n = 10)

14.80zt 1.11 (n = 10)

‘P < 0.05 when compared with the corresponding values in SV and GEA; bP < 0.05 when compared with the corresponding values in IMA and GEA.

Table 3 EC&, and E,, values for nifedipine (NIF), sodium nitroprusside (SNP), glyceryl trinitrate (GTN), isoproterenol (ISO) and papaverine (PAP) in human saphenousvein (Sk’), internal mammary artery (IMA) and gastroepiploic artery (GEA) contracted either with noradrenaline or endothelin-1 Not-adrenaline

Endothelin-1

n

-log Et&

8 9 9 10 6

6.98 f 0.09 6.63 f 0.13’ 6.76 f 0.17* 6.47 AZ0.19 -

6 11 11 7 6

6.66 f 7.05 f 7.27 + 5.72 f -

0.14 0.13 0.15 0.11

96.25 f 101.07rt 101.14f 45.94 f 100.00l

6 7 6 7 6

6.64 f 7.49 * 7.81 + 5.32 * -

0.16 0.19 0.23 0.16

97.05 f 94.10 f 88.40 + 60.28 f 100.00*

n

-log EC,

‘Lx

9 6 6 8 6

6.56 f 0.21 6.82 EIE0.05’ 6.83 ZIZ0.17s -

96.33 zt 2.17 52.33 f 5.19s” 37.38 f 5.17=gc 5.21 zk 2.3c 93.09 f 7.00

2.37 1.63b 1.56b 4.42 0.0

8 7 6 6 6

6.89 f 0.1I 7.35 f 0.12 7.30 f 0.11 -

97.04 * 1.74 97.67 EIZ4.94 94.90 zt 4.25 35.91 f 5.11b 97.40 E!E 2.47

2.75 2.07 3.43 5.51 0.0

6 6 6 6 6

7.00 * 0.17 7.20 zb0.09 7.60 l 0.12

95.53 + 3.81 90.69 t 2.61 87.92 ztz4.83 18.29zt 6.70c 97.79 zt 1.08

E max

sv NIF SNP GTN Is0 PAP

96.04 AZ2.42 95.04 l 1.94 96.30 f 1.31 46.58 zt 5.56 93.20 + 4.30

IMA

NIF SNP GTN Is0 PAP

au NIF SNP GTN IS0 PAP

-

*P < 0.05 when compared with corresponding values in GEA and IMA; bP < 0.05 when compared with corresponding values in GEA and SV; ‘P < 0.05 when compared with corresponding values obtained in noradrenahnecontracted rings. Et& values of papaverine were not estimated becauseonly a single dose of papaverine was used. ECsovalues of isoproterenol in endothelin-I contracted vesselscould not be estimated.

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agents.Noradrenaline evoked a quick responsein all the vessels, whereas endothelin-1 required a long period, especially in the saphenous vein. In time match control experiments, we determined that precontractions induced by noradrenaline and endothelin-1 were stable enough for the period required to construct the cumulative concentration-relaxation curves. 3.2. Relaxation 3.2.1. Nifedipine.

Nifedipine ( 10b9- 10s4 M) caused dose-dependentrelaxations in the arteries and vein contracted submaximally with noradrenaline or endothelin-1. The maximum relaxations (E,,,& to nifedipine were not different between three graft materials contracted either with noradrenaline or endothelin-1. In each of the vessels,the responsivenessto nifedipine did not show any significant difference depending on the contractile agent used (Table 3, Fig. la). The sensitivities (EC,) to nifedipine were also similar in arterial and venous grafts either contracted with noradrenaline or endothelin-1 (Table 3). 3.2.2. trinitrate.

Fig. 1. Concentration-response curves showing relaxations induced by (a) nifedipine, (b) sodium nitropmsside, (c) glyceryl trinitrate, (d) isoproterenol in either noradrenaline (left) or endothelin-1 (right) contracted saphenous vein (O), internal mammary artery (A) and gastroepiploic artery (q. Relaxations are expressed as percent decreases of tone induced by noradrenaline or endothelin-1. Values are expressed as mean f S.E.M. *P < 0.05, l * P < 0.001, when comparing saphenous vein versus internal mammary artery and gastroepiploic artery; OP < 0.05 when comparing internal mammary artery versus saphenous vein and gastroepiploic artery.

Sodium

nitroprusside

and

glyceryl

Sodium nitroprusside ( 10-9-10-4 M) and glyceryl trinitrate ( 10-9-10-4 M) caused dose-dependent relaxations in the vessels contracted either with noradrenaline or endothelin- 1. In rings contracted with noradrenaline, the maximum relaxation was similar between arterial and venous grafts but was significantly more pronounced in internal mammary artery (Table 3, Figs. lb and c). On the other hand, the sensitivity to sodium nitroprusside and glyceryl trinitrate was similar in internal mammary artery and gastroepiploic artery but was significantly lower in saphenousvein than in that of both arterial grafts (Table 3). In rings contracted with endothelin- 1, the maximum relaxation to sodium nitroprusside and glyceryl trinitrate did not differ in internal mammary artery and gastroepiploic artery but was significantly lower in saphenous vein when compared with the arteries (Table 3 and Figs. lb and c). Also, the sensitivity of the vessels to nitrovasodilators against endothelin-1 contraction was similar in internal mammary artery and

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gastroepiploic artery but was significantly lower in saphenousvein (Table 3). Thus, the maximum relaxation to sodium nitroprusside and glyceryl trinitrate was not different in arterial grafts depending on the contractile agent used, but was significantly reduced in saphenousvein rings contracted with endothelin1. Moreover, the sensitivity to sodium nitroprusside and glyceryl trinitrate was similar in both arterial grafts but was significantly lower in saphenousvein. 3.2.3. Zsoproferenol. Isoproterenol’ (10s9lo4 M) causeddose-dependentrelaxations in the vessels. The maximum relaxation obtained in noradrenaline contracted rings was not signiticantly different in arterial and venous grafts (Table 3, Fig. Id). However, in rings contracted with endothelin-1, maximum relaxation was signiticantly reduced in saphenous vein and gastroepiploic artery but not in internal mammary artery when compared with the corresponding relaxation in noradrenaline contracted rings (Table 3, Fig. Id). Propranolol (10m6M), a nonselective &antagonist, completely abolished the relaxation to isoproterenol in both arterial and venous grafts (data not shown). The Ecu, values for isoproterenol in noradrenaline contracted vessels are given in Table 3. However, these values could not be estimated in endothelin-1 -contracted vessels. 3.2.4. Papaverine.Papaverine was tested only at a maximal concentration ( lo4 M) in each of the vessels. Papaverine-induced maximal relaxations were similar in the arteries and the vein contracted with either noradrenaline or endothelin-1 (Table 3).

Hence, sodium nitroprusside, glyceryl trinitrate, nifdpine and papaverine were all found to be effective vasodilators in reversing noradrenalineinduced contractions in both arterial and venous grafts. Although thesevasodilators were also highly effective in reversing endothelin-l-induced contractions in arteries, in saphenous vein only nifedipine and papaverine were effective. 4. Dlseuwioll

Graft closure due to spasm and/or intimal pro-

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liferation limits the graft longevity. The percentage of reoperation in saphenous vein grafting is estimatedto be 30%at 10years after bypassoperation becauseof atherosclerotic luminal occlusion [ 181,whereas internal mammary artery grafts exhibited higher patency rate of 95% in the same period [19]. Another arterial graft, gastroepiploic artery, has been described recently from the necessityof an alternative graft tissue in place of venous graft [20], but its long term patency rate is unknown yet. Perioperative or postoperative spasm is the greatest problem which limits the maintenance of blood flow through bypass conduits, especially in the arteries [l-3]. The trigger of graft spasmis not well known, but suggestedto be mediated by the factors releasedduring operational ischemic intervals and endothelial injury [4-61. The ratio and the contribution of endogenous spasmogens to native spasm is so unpredictable. However, in vitro, setting up of the contraction by spasmogens can almost reflect the native spasm.In this study, we have mimicked the spasmby increasing the vascular tension with noradrenaline and endothelin-1, which are possibly involved in vasospasm[21,22]. The comparison of the maximal contraction force (gram tension) induced by thesespasmogensshowed that gastroepiploic artery and saphenous vein produced higher responsivenessto noradrenaline than internal mammary artery, consistent with other relevant studies [12,23,24]. GII the other hand, the time required to reach the maximal contraction was found to be considerably longer for endothelin-1, especially in saphenous vein, which is probably related to its molecular structure or mechanism of action. It can be proposed that spasm is initiated by noradrenaline, whereas its supportion for a long period is provided by endothelin- 1. Systemicor topical vasodilator treatment is used in the maintenance of conduit blood flow [2,8]. It is essentialto know the responsivenessof graft vessels to vasodilators against possible vasospastic agents in choosing the rational vasodilator in the prevention and/or treatment of graft spasm [g-12]. We investigated the effects of various vasodilator agents with different mechanism of action such as nifedipine, sodium nitroprusside,

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glyceryltrinitrate, isoproterenoland papaverinein reversingthe graft spasm. It has been reported that noradrenaline and endothelin-1causecontraction in vascularsmooth muscle by opening both receptor-dependent and/or voltage-operatedCa++channels[25,26].In this study, the Ca++ channel blocker, nifedipine, completely inhibited both noradrenaline- and endothelin-l-induced spasms in arterial and venous conduits. This result showed that either nifedipine is effectivein both receptor-dependent and voltage-operatedcalcium channels, or the contractile effects of both noradrenaline and endothelin-1 appear to be related to voltageoperatedcalciumchannelsassuggestedfor various vascularpreparations [26-281. We found that the nitrovasodilators, sodium nitroprussideand glyceryl trinitrate, were equally potent and comparablyeffectivein the reversalof noradrenaline- and endothelin-1-induced spasms in both internal mammary artery and gastroepiploic artery. This finding is inconsistent with recentreports in which sodium nitroprussidewas found to be more effective[lo] or potent [29] than glyceryl trinitrate in reversing noradrenalineinduced internal mammary artery spasm.These differences might be due to nitrate tolerance, which may occur with gylceryl trinitrate therapy beforeoperation.On the other hand, in saphenous vein, the reversalof endothelin-1-induced spasm by sodiumnitroprussideand glyceryltrinitrate was markedly less pronounced than the reversal of noradrenaline-induced spasm. The marked blunted relaxationsto nitrovasodilators in endothelin-lcontracted saphenous vein rings are similar to the resultsof Lilscher et al. [14] but differentfrom that of Costelloet al. [30]. In addition, saphenousvein graft, in contrary to a previous study (131,wasfound to be markedly lesssensitive to sodium nitroprusside and glyceryl trinitrate than arterial grafts in the presenceof either of thesetwo contractile agents. On the other hand, we found that. 8adrenoceptorfunction is moderatein arterial and venousgraft materials.The incompleterelaxation in responseto &agonist isoproterenolcan not be relatedto the useof a &antagonist drug beforeop eration becausethe vesselswereobtained from the

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patients who were not exposedto &antagonist therapy. other workers found that internal mammary artery has weak [10,31]or moderate [32] 8receptor function. Besides,isoproterenol also exhibited markedly reduced responsivenessagainst endothelin-1-induced contraction in saphenous veinand gastroepiploicartery. This markedrefractoriness to isoproterenol in saphenousvein and gastroepiploicartery contractedwith endothelin-1 seemsto be more considerablethan the moderate &receptor function observed in the graft materials. We have also used papaverine, a nonspecific vasodilator,to measurethe relaxationcapacitiesof graft tissues.Papaverineexhibited similar effectivenessto nifedipinein the reversalof arterial and venousgraft spasmsinduced either by noradrenaline or endothelin-1. However,therapeuticuse of papaverineis limited in topical or intraluminal applicationduring the preparation of the vesselat operation. Previous studies demonstratedthat nitrovasodilators and isoproterenolproducedrelaxationsby increasing intracellular cyclic guanidine monophosphate (cGMP) and cyclic adenine monophosphate (CAMP) levels, respectively 133,341. The fmdingsof the presentstudy indicated that the saphenousvein shows marked refractorinessagainstCGMPdependentand /3-receptormediatedrelaxation when endothelin-1 was used as the spasmogenicagent. Interestingly, similar refractorinesswas observed only to &receptormediated relaxations in endothelin-l-contracted gastroepiploicarteries,but to none of relaxations in internal mammary arteries. A recent study, which investigated Ca++ inward currents, reported that the increasesin intracellular cGMP and CAMP levelsresult in the inhibition of Ca++ channel activity in vascular smooth muscle [35]. However, we could not interpret the observation that endothelin-1-contracted saphenous vein showed lower responsivenessto both nitrovasodilators and isoproterenol, whereas the gastroepiploic artery showed lower responsivenessto isoproterenol alone. The different structural organisations of contractile elements between arteriesand veinsand low secondmessengersynthesis are probably not involved in this refrac-

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toriness. The most reliable explanation for this refractoriness may be that endothelin-1 demonstrates.different action characteristics on different vascular segments. 4.1. Clkical relevanceof the study Our study provides evidence that the implication of endothelin-1 in graft spasm reduced the effectiveness of some vasodilators, especially in saphenous vein graft. The internal mammary artery was found to be the most responsive graft material to vasodilators. The alternative graft material, gastroepiploic artery, displayed a close similarity to internal mammary artery with the exception of p-receptor responsiveness.Both arterial and venous grafts exhibit moderate /3adrenoreceptor function, which implies that the usageof fi-receptor agonists is not appropriate in reversing graft spasm. Our results clearly show that nitrovasodilators are fully effective and potent relaxing agentsin the reversal of arterial graft spasm,whereasnifedipine is comparably effective in both arterial and venous graft spasms, regardlessof the nature of spasmogenicstimulus. References [1] Victor MF, Kimbiris D, Iskandrian AS et al. Spasm of saphenousvein bypass graft: A possible mechanism for occlusion of the venous graft. Chest 1981;80: 413-415. [2] Sarabu MR, McClung JA, FassA, Reed GE. Early postoperative spasm in left internal mammary artery grafts. Ann Thorac Surg 1987;44: 199-200. [3] Suma H. Spasm of the gastroepiploic artery graft. Ann Thorac Surg 1990;49: 166-170. [4] Angelini GD, Christie MI, Bryan M, Lewis MJ. Surgical preparation impairs release of endothelium-derived relaxing factor from human saphenousvein. Ann Thorac Surg 1989;48: 417-420. [S] Lm PJ, Pearson PJ, SchatTI-IV. Endothelium-dependent contraction and relaxation of the human and canine internal mammary artery: Studies on bypass graft vasospasm.Surgery 1991; 110: 127-135. [6] Kuo J, Ramstead K, Salih V, Coumbe A, Graham TR, Lewis CT. Effect of vascular clamp on endothelial integrity of the internal mammary artery. Ann Thorac Surg 1993;55: 923-926. [7] Li XN, Stultz P, Siebenmann RP, Yang Z, Liischer TF. DitTerent effects of activated platelets in the right gastroepiploic and internal mammary arteries. J Thorac Cardiovasc Surg 1992; 104: 1294-1302. [8] Cooper GJ, Wilkinson GAL, Angelini GD. Overcoming

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perioperative spasm of the internal llMMlU3~artery: Which is the best vasodilator? J Thorac Cardiovasc Surg 1992; 104:465-468. Pl He GW, Rosenfeldt FL, Buxton BF, Angus JA. Reactivity of human isolated internal mammary artery to constrictor and dilator agents: Implications for treatment of internal mammary artery spasm. Circulation 1989; 80 (Suppl I): I-141-I-150. WI Jett GK, Guyton RA, Hatcher CR, Abel PW. Inhibition of human internal mammary artery contractions. J Thorac Cardiovasc Surg 1992; 104: 977-982. He GW, Rosenfeldt FL, Angus JA. Pharmacological relaxation of the saphenous vein during harvesting for coronary artery bypass grafting. AM Thorac Surg 1993; 55: 1210-1217. WI Thorin-Trescases N, Dimitri WR, Dominiczak AF, Hamilton CA, Reid JL. Vasorelaxant properties of isolated human internal mammary arteries and saphenous veins: Comparative effects of milrinone and sodium nitroprusside. J Cardiovasc Pharmacol 1993; 22: 673480. 1131Yang Z, Biihler FR, Diederich D, Ltischer TF. Different effects of endothelin-1 on CAMP- and &IMP-mediated vascular relaxation in human arteries and veins: Comparison with norepinephrine. J Cardiovasc Pharmacol 1989; 13 (Suppl 5): Sl29-Sl31. u41 Liischer TF, Yang Z, Tschudi M et al. Interaction between endothelin-1 and endothelium derived relaxing factor in human arteries and veins. Circ Res 1990; 66: 1088-1094. 1151Buikema H, Grandjean JG, van den Broek S, van Gilst WH, Lie KI, Wesselling H. Differences in vasomotor control between human gastroepiploic and left internal mammary artery. Circulation 1992; 86 (Suppl II): 11-205-11-209. [161 Dignan RJ, Yeh T, Dyke CM et al. Reactivity of gastroepiploic and internal mammary arteries. J Thorac Cardiovasc Surg 1992; 103: 116-123. 1171 Akar F, Uydes BS, Ayrancloglu K et al. Endothelial function of human gastroepiploic artery in comparison with saphenousvein. Cardiovasc Res 1994,28: 500-504. WI Grondin CM, Campeau L, Thornton JC, Engle JC, Cross FS, Schreiber H. Coronary artery bypass grafting with saphenous vein. Circulation 1989; 79 (Suppl I): I-24-1-29. WI Loop FD, Lytle SW, Cosgrove DM et al. Influence of the internal mammary artery graft on 10 year survival and other cardiac events. N Engl J Med 1986;314: l-6. PO1Pym J, Brown PM, Charette UP, Parker JO, West RO. Gastroepiploic-coronary anastomosis: A viable altemative bypass graft. J Thorac Cardiovasc Surg 1987; 94: 256-259. PU Yasue H, Touyama M, Kato H, Tanaka S, Akiyama F. Primmetal’s variant form of angina as a manifestation of alpha-adrenergic receptor mediated coronary artery spasm: Documentation by coronary arteriography. Am Heart J 1976;91: 148-255.

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