Effects of Opioids on Vasoresponsiveness of Porcine Coronary Artery Takao Yamanoue, MD, Jose M. Brum, MD, Fawzy G. Estafanous, Carlos M. Ferrario, MD, and Philip A. Khairallah, MD
MD,
Division of Anesthesia, Cleveland Clinic Foundation, Cleveland, Ohio
Myocardial ischemia during surgery can be caused by coronary vasospasm. Neurohumoral mechanisms are involved in this phenomenon, and various substances have been suggested as possible causes, including acetylcholine, histamine, and norepinephrine. The responses of isolated puIcine coronary arteries (from 117 pig hearts) with (E t )and without (E-) endothelium to these agents were investigated in the presence of fentanyl, sufentanil, and morphine. Fentanyl significantly shifted to the right, in a concentration-dependent fashion, the concentrationresponse curve to acetylcholine. This effect wds not different between E + and E- rings. Neither sufentanil nor morphine altered acetylcholine-induced con-
I
ntraoperative myocardial ischemia has been investigated extensively (1,2). Coronary vasospasm is probably one important cause of intraoperative myocardial ischemia (3). It is difficult to establish this diagnosis precisely during surgery because in most instances information on coronary vasomotor tone is not available. The mechanisms of intraoperative occurrences of coronary vasospasm and the possible effects of anesthetic agents in this pathology are still unclear. Nevertheless, many reports suggest the occurrence of coronary vasospasm during both cardiac (4,5) and noncdrdidc surgery ( 5 7 ) . Cholinergic activation of muscarinic receptors has been proposed as a mechanism responsible for coronary vasospasm (8). Angina can be induced by subcutaneous injection of inethaiholine, a muscarinic agonist, and suppressed by atropine in humans (9). This effect of methacholine was associated with contraction of coronary arteries and confirmed by coronary arteriograms (10) in humans. Further studies Presented in part at the International Anesthesia Research Society 65th Congress, San Antonio, Texas, March 1991. Winner of “The Robert Tarazi Award” for Cardiovascular Research, 1991. Accepted for publicdtion January 21, 1932. Address correspondence to Dr. Bruiii, Cleveland Clinic Foundation, Research Institute NC3-114, 9500 Euclid Avenue, Cleveland, OH 44195-5286. 81992 by the Iiitemational Anesthesia Research Socielv 0003-2999/92/$5.00
traction of porcine coronary arteries. Naloxone did not antagonize the suppressive effect of fentanyl on acetylcholine-induced contraction. The response of porcine coronary arteries to norepinephrine was decreased only at very high concentrations of fentanyl. Neither sufentanil nor morphine altered norepinephrine-induced contraction of porcine coronary arteries. Fentanyl, sufentanil, and morphine had no effect on histamine-induced contraction. We conclude that tentanyl antagonized acetylcholine-induced contraction of porcine coronary arteries. This effect of fentanyl seems to be caused by a direct effect on smooth muscle cells and is not opioid-receptor mediated. (Anesth Analg 1992;74:889-96)
with isolated human coronary arteries, obtained from recipient and cadaver hearts (11,12), showed that acetylcholine contracted coronary arteries and that the contraction was suppressed by atropine. Muscarinic agonists also produce coronary contraction in porcine (13-15) and many other species, although canine coronary rings with intact endothelium relax in the presence of muscarinic agonists (13). Because of lack of significant effects on myocardial contractility, opioids are widely used in anesthesia for patients who have poor cardiac reserve. In addition, opioid anesthetic agents have little elfect on coronary vasoreactivity. Blaise et al. (16) reported that fentanyl had no direct effect on coronary arteries of dogs, pigs, and rats. They also reported that fentanyl slightly attenuated canine coronary arterial contraction caused by phenylephrine but had no effect on contraction caused by serotonin. They did not investigate the effect of fentanyl on cholinergic-mediated coronary vasoconstriction. Although it is difficult to determine whether cholinergic activation is responsible for intraoperative coronary vasospasm, cholinergic mechanisms do participate in coronary vasospasm in many species, including humans (8). Therefore, cholinergic-mediated coronary vasoconstriction under the effects of anesthetic agents seems worthy of investigation. Anesth Analg 1992;74:889-96
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ANESTH ANALG 1992;74:889-96
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The purpose of this study was to assess the effect of opioid anesthetic agents, such as fentanyl, sufentanil, and morphine, on coronary vasoconstriction caused by cholinergic, a-adrenergic, and histaminergic agents.
Methods This study was approved by the Cleveland Clinic Animal Care and Use Committee. One hundred seventeen hearts of adult pigs of either sex were obtained immediately postmortem at a nearby slaughterhouse (Polansky Market, Amherst, Ohio) and transported in ice-cold buffered salt solution. Within 1 h, left anterior descending coronary arteries were removed from the animal heart and placed in cold buffered salt solution (millimolar composition: NaC1, 118.3; KCl, 4.7; CaCl,, 2.5; MgSO,, 1.2; KH,PO,, 1.2; NaHCO,, 25.0; edetate calcium disodium, 0.026; and glucose, 11.1).Arteries, 3-4 mm in diameter, were cleansed of surrounding fat and connective tissue and cut into 5-mm-long rings, with care taken not to damage the intimal surface. The endothelium was deliberately removed in some rings by gently rubbing a fine stainless steel rod against the vessel intima. Rings were suspended between two stainless steel wires in organ chambers filled with 25 mL of buffered salt solution at 37°C bubbled with 95% 0,5% CO, gas mixture. One of the wires was anchored in the organ chamber, and the other was connected to a force transducer. Before the actual experiment, the preparations were progressively stretched and repeatedly exposed to 40 mM of KCl to induce contraction at each level of stretching, until a maximal contractile response was obtained. As the basal tension generated by this process indicates the optimal point of a length-tension curve, this response was used as a reference tension. All of the contractions induced by agonists during experiments were expressed as percentages to this reference tension. The effectiveness of the endothelium denudation was assessed by exposing the rings (contracted by KCl) to l o p 7 M of substance P, because porcine coronary artery is relaxed by substance P in the presence of intact endothelium (17); this endothelium-dependent relaxation does not occur with acetylcholine (14,18). The rings were then allowed to equilibrate for 45 min. Rings with (E+) and without endothelium (E-) each were preincubated with fentan 1 (3.16 x lop7, 3.16 X lop6M), sufentanil(3.16 X 10- Y,3.16 x 1OP6M), or morphine (lo-', lop4M). These experiments were done in parallel, where artery rings from the same pig were used as control. Cumulative concentrations of acetylcholine (from lo-'' M up to the concentration that made maximal response, 3.16 x l o p hto 3.16 x l o p 5M), norepineph-
rine (lo-'' up to lo-, M), and histamine (lo-'' up to M) were added to each organ chamber, and the tension generated by the rings was measured in grams. The responses to norepinephrine were obtained in the presence of a concentration (5 X M) of propranolol known to produce total P-adrenergic blockade. To investigate the participation of opioid receptors in the effects of fentanyl in the dose-response curve to acetylcholine, these experiments were repeated on rings with endothelium in the presence and absence of naloxone (lop6, M). The EC,, values (concentration of acetylcholine causing 50% of maximal response) were calculated by using linear regression analysis from data between 20% and 80% of maximal responses. Within this range, linearity was well maintained (0.97 < correlation coefficient [R] 5 1.00). The following drugs were used: acetylcholine, norepinephrine, histamine, propranolol (Sigma, St. Louis, Mo.), fentanyl citrate, sufentanil citrate (Janssen, Piscataway, N.J.), morphine sulfate (ElkinsSinn, Cherry Hill, N.J.), and naloxone hydrochloride (Du Pont, Manati, P.R.). The drugs were prepared daily in distilled deionized water or in 0.1% solution of ascorbic acid in water and kept on ice during the experiments. The results were expressed as mean ? S E . Comparison of concentration-response curves was accomplished by the following procedure: (a) The parallelism was analyzed by comparing the slopes of linear regression lines from data between 20% and 80% of maximal responses. (b) As the parallelism was confirmed in every protocol, EC,, values were compared by one-way analysis of variance. When paired data from animals were compared in parallel, Student's t-test was done for paired observations. Data not from the same population of animals were analyzed by Student's t-test for unpaired observation. Values were considered statistically significant when P < 0.05.
Results The porcine coronary artery rings contracted in response to acetylcholine within the concentration range lo-* to 3.16 x lop6 M. There were no differences in the contractile responses between vessels with and without endothelium. The concentrationresponse curve to acetylcholine was significantly shifted to the right when the experiment was done in the presence of fentanyl (3.16 X l o p 7 M). No significant differences were detected at the level of maximal contraction. This effect was present in vessel rings with and without endothelium, and no differences were observed in this regard. A 10 times higher
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Figure 1. Cumulative concentration-response curve to acetylcholine of porcine coronary arteries with (E+) and without (E-) endothelium in the presence and absence of fentanyl ( n = 20), sufentanil (n = 12), or morphine (n = 9). Responses of control rings (circles); responses in the presence of lower concentrations of fentanyl(3.16 x M, n = 13), sufentanil (3.16 x M, n = 5 ) (lozenges); responses in the presence of higher concentrations of fentanyl (3.16 x M, n = 7), sufentanil (3.16 x M, n = 7), and morphine M, n = S), and M, n = 4) (squares). Contractions are expressed as a percentage of the maximal response to standard 40 mM KCl challenge. Fentanyl shifted equally the morphine concentration-response to acetylcholine in both vessels with and without endothelium. No significant differences among maximal contraction were observed. Neither sufentanil nor morphine altered the contractile response to acetylcholine.
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ANESTH ANALG
YAMANOUE ET AL. OPlOlDS AND CORONARY VASORESPONSIVENESS
1992:74:88%96
Table 1. Acetylcholine-Induced Coronary Artery Vasoconstriction (log EC5,,): Effect of Fentanyl
I00
With fentanyl
Without fentanyl Control group ( n = 20)
3.16 x lo-’ M ( n = 13)
3.16 x lo-’ M ( n = 7)
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E t , rings with endothelium; E-, rings without endothelium Values are expressed as mean ? S E M . “P < 0.05 compared with control group. “P < 0.05 compared with 3.16 x lo-’ M fentanyl group.
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Without naloxone
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-6.76
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All rin s are with endothelium. The concentration of fentanyl used is 3.16 x 10- M. In both control and fentanyl-pretreated groups, no significant differences are shown among rings with the two concentrations wlth and without naloxone. Values are expressed as mean 2 S E M .
3
concentration of fentanyl (3.16 x l o p 6 M) caused a further shift to the right in the concentrationresponse curve of acetylcholine, without any significant influence of the endothelium (Figure 1). The dose-dependent suppressive effects of fentanyl were also expressed by a significant increase of EC,, values (Table 1). Neither sufentanil nor morphine (Figure 1) altered the concentration-response curve to acetylcholine. Naloxone, a nonspecific opioid antagonist, did not alter the vasoconstriction produced by acetylcholine. Naloxone did not change the shift in the acetylcholine vasoconstriction caused by fentanyl (Figure 2). The EC,, values of acetylcholine-induced contraction, both in the presence and absence of fentanyl, were not altered by pretreatment with naloxone (Table 2). Norepinephrine at the range lo-’ to l o p 4 induced a significant contraction of the porcine coronary artery rings. The vasoconstriction caused by norepinephrine was significantly increased in rings without endothelium at the concentrations of norepinephrine >3.16 X l o p 7 M. Fentanyl in the organ bath at 3.16 x l o p 7 M did not alter the response to norepinephrine (Figure 3A). Fentanyl at a very high concentration (3.16 x l o p 6 M) significantly decreased the response to higher concentrations of norepinephrine ( l o p 6 to 10 M) in rings with and without endothelium
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log [acetylcholine] Figure 2. Cumulative concentration-response curve to acetylcholine of porcine coronary rings with endothelium. Responses of control rings (cirrlcs) and responses of rings in the presence of fentanyl (3.16 x 10 M) (lozen~es).Rightward shift of the curve of rings with fentanyl ( t i = 10) as compared with control rings (ti = 11) is shown in the irpp’r \ J O t i d . Influences of two concentrations of naloxone, 10 M ( n = 8) and lo-‘ M ( t i = 5-7), are shown in the riiiddle and h e r pitick, respectively. Contractions are expressed as a percentage of the maximal response to standard 40 mM KCI challenge. Naloxone, at either concentration, did not affect the contractile response to acetylcholine. Further, naloxone did not alter the rightward shift of the concentration-response curve to acetylcholine by fentanyl.
’
(Figures 3B and 3C). Neither sufentanil nor morphine in any concentration used in this study altered significantly the concentration-response curve to norep-
ANESTH ANALC 1992;74:889-96
YAMANOUE ET AL. OPIOIDS AND CORONARY VASORESPONSIVENESS
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Figure 3. Cumulative concentration-response curve to norepinephrine of porcine coronary rings with ( E + , solid s!/rribols) and without (E-, open symbols) endothelium in the presence and absence of fentanyl. Contractions are expressed as a percentage of the maximal response to standard 40 mM KCI challenge. (A) Responses of control rings ( 1 1 = 17) (circlcs); responses of rings in the presence of fentanyl (3.16 x lo-' M, II = 8) ( l o z ~ r i p )Contractile . response to norepinephrine i n rings without endothelium was significantly larger than that in rings with endothelium at the concentration of norepinephrine >3.16 x 70 M. Fentanyl did not alter the contractile response to norepinephrine. (B,C) Responses of control rings ( i i = 17) ( i i d c s ) ; responses of rings in the presence of high concentration of fentanyl (3.16 X 10 ' M, I I = 9) (sqrurcs). A very high concentration of fentanyl significantly attenuated the contractile response to norepinephrine in rings both with and without endothelium at the concentration of norepinephrine from 10 " to 10 M.
inephrine in intact or endothelium-denuded vessels (data not shown). Histamine caused concentration-dependent contraction in the coronary artery rings with onset at M and maximal response at lo-' M. The responses to histamine were not significantly altered by endothelium. Fentanyl, sufentanil, or morphine at the concentrations used in this study did not significantly affect the histamine-induced contraction (Figure 4).
Discussion The current study indicates that fentanyl attenuates muscarinic-mediated contraction of porcine coronary arteries. This attenuation is probably due to a direct effect of fentanyl on vascular smooth muscle because it occurs independently of endothelial integrity. Other investigators have shown that acetylcholineinduced contraction of porcine coronary arteries is endothelium independent (14,18). These findings were also reported in isolated human coronary arteries (19,20). Further, binding assays demonstrated the presence of muscarinic receptors solely in porcine coronary arterial smooth muscle cells but not in the endothelium (18). These studies substantiate our findings that porcine coronary vasoconstriction due to acetylcholine is independent of the integrity of the endothelium. In contrast, endothelium-dependent relaxation due to other agents is present in porcine coronary arteries. For example, responses tc) sub-
stance P, bradykinin, and serotonin were well demonstrated in porcine coronary arteries, suggesting participation of endothelium-derived relaxing factor on the responsiveness of these vessels (13). Nevertheless, the vasoconstriction caused by acetylcholine in the porcine coronary arteries is not affected by the endothelium, and the attenuation of this contraction probably occurs on the vascular smooth muscle cells. The fact that naloxone did not alter the effect of fentanyl on muscarinic response strongly suggests that this phenomenon is not opioid-receptor mediated. Further, sufentanil, which is five to ten times more potent than fentanyl, and morphine did not reproduce the effect of fentanyl on cholinergicmediated contraction. An opioid receptor-mediated modulatory role has been observed in prejunctional muscarinic cholinergic responses of canine bronchial smooth muscle (21) and rabbit isolated heart (22). In the present study, the effect of fentanyl on muscarinic-mediated vasoconstriction seems to be independent of opioid receptor activation. One possible explanation of the effects of fentanyl on cholinergic vasoconstriction is through direct interference by fentanyl with the muscarinic receptor in the porcine coronary arteries. Differences in the molecular structure and not in the opioid character among fentanyl, sufentanil, and morphine would favor the hypothesis of an "antimuscarinic" activity particular to fentanyl. Further, the solvent vehicle for fentanyl and sufentanil is the same. A comparison of the sufentanil and fentanyl molecules reveals struc-
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Figure 4. Cumulative concentration-response curve to histamine of porcine coronary arteries with (E+, solid sylnbols) and without (E-, open symbols) endothelium in the presence and absence of fentanyl (11 = 13), sufentanil ( n = S), or morphine ( r r = 10). Responses of control rings (circles); responses in the presence of lower concentrations of fentanyl (3.16 x lo-' M, ti = S), sufentanil (3.16 x lo-' M, ) I = 4), and morphine (lo-' M, ti = 4) ( l o z e q c s ) ;responses in the presence of higher concentrations of fentanyl (3.16 x M, ri = 5 ) , sufentanil (3.16 x M, n = 41, and morphine (lo-' M, n = 6) (squares). Contractions are expressed as a percentage of the maximal response to standard 40 mM KCI challenge. All of the opioid anesthetic agents did not alter the contractile response to histamine.
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ANESTH ANALG 1992;74:889-96
tural dissimilarities that may account for the differential muscarinic-mediated vascular responses. Therefore, a nonopioid, direct effect of fentanyl on the muscarinic receptor is possible. Another possible explanation of the suppressive effect of fentanyl is through interference in the muscarinic process of signal transduction in the coronary vascular smooth muscle cells. Some anesthetic agents directly affect the guanine nucleotide binding proteins (G-protein), which has been suggested to be the primary site for the action of anesthetics (23). The present study does not provide any evidence concerning the interaction of fentanyl with the process of signal transduction. Our observation that fentanyl not only has a significant modulatory effect on cholinergic mechanisms, but on adrenergic mechanisms as well, may suggest the possibility that fentanyl affects a second-messenger mechanism common to both types of receptors. Our results with regard to the effect of fentanyl on adrenergic contraction of porcine coronary arteries agree with the findings of other authors. Toda and Hatano (24) observed that fentanyl shifted to the right the concentration-response curve of the rabbit aorta to norepinephrine only at a very high concentration of fentanyl. They also observed that the effect was not mediated by opioid receptors and suggested that fentanyl antagonized in a competitive manner the a-adrenergic receptors in the vascular smooth muscle. Blaise et al. (16) reported that fentanyl induced a small attenuation in phenylephrine-induced contraction of canine coronary arteries. In agreement, our results also indicate attenuation of adrenergicmediated coronary vasoconstriction only at a concentration of fentanyl that has no clinical application. Histamine has been used to induce experimental coronary vasospasm, as have ergonovine and acetylcholine. Coronary vasospasm in atherosclerotic miniature pigs was induced by histamine mainly in vessels with intimal thickening, suggesting that structural changes over time are responsible for enhancing histamine effects (25). Histamine also induces vasoconstriction in human coronary arteries that is enhanced by damaged endothelium (26). Our results confirm that histamine is a coronary vasoconstrictor in the adult pig coronary artery with or without endothelium. This vasoconstriction was not altered by any opioid anesthetic agents used in this study. These findings may suggest that high-dose opioid anesthesia would not offer any protective effect against coronary vasospasm induced by histamine. Furchgott and Zawadzki (27) showed that endothelium modulates the acetylcholine vasoconstrictor effect on the vascular smooth muscle by releasing a relaxing factor. This modulatory role of the endothe-
YAMANOUE ET AL. OPlOlDS AND CORONARY VASORESPONSIVENESS
895
lium was described in coronary arteries of dogs and other species in response to many pharmacologic agents and also in vivo (28). A similar phenomenon was also observed in isolated human coronary arteries (29). Most investigations concerning the reactivity of human coronary arteries to muscarinic agonists show a n endothelium-independent contraction (13,19,20). The contractile response in humans resembles that in pigs (13,14) and other species (13). Responses of porcine coronary arteries to acetylcholine and histamine are very similar to those of human coronary arteries (30). Therefore, we believe porcine coronary artery to be a valid animal model. The concentration of fentanyl used in the present study (-6.5 log M) is equivalent to approximately 70 nglmL. This is within the upper range of the plasma level of fentanyl when used as high-dose fentanyl anesthesia, although the plasma level of fentanyl usually becomes lower than this concentration over time during surgery (31). In contrast, sufentanil did not affect cholinergic porcine coronary contraction even at concentrations far higher than any of clinical relevance. Sufentanil did not provide any attenuation of coronary vasoconstriction caused by neurohumoral agents used in this study. We focused on the effect of the opioid anesthetic agents that are most widely used for cardiac surgery. Volatile anesthetic agents have coronary vasodilator effects (3). Whether those volatile agents also interfere with muscarinic-mediated coronary reactivity is unknown. We report here the suppressive effect of fentanyl on acetylcholine-induced contraction of isolated porcine coronary arteries. This phenomenon was endothelium independent and did not occur through an opioid receptor mechanism. Other properties of fentanyl, especially its effects on the central nervous system, may alter the possible protective effect of fentanyl against cholinergic-mediated coronary constriction. Our work suggests that high-dose fentanyl anesthesia might have a protective effect against cholinergic coronary vasoconstriction. It is not clear whether cholinergic activation plays a major role in intraoperative coronary vasospasm. If so, such intraoperative coronary vasospasm might be blunted by high-dose fentanyl anesthesia.
References 1. Mangano DT, Browner WS, Hollenberg M, et al. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med 1990;323:1781-8. 2. Slogoff S, Keats AS, Dear WE, et al. Steal-prone coronary anatomy and myocardial ischemia associated with four primary anesthetic agents in humans. Anesth Analg 1991;72:22-7.
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3. Reiz S. Coronary vasomotion during anesthesia. Acta Chir Scand Suppl 1988;550:63-73. 4. Skarvan K, Graedel E, Hasse J, Stulz P, Pfisterer M. Coronary artery spasms after coronary artery bypass surgery. Anesthesiology 1984;61:323-7. 5. Yamanoue T, Horibe M, lzumi H, Tsuchiya T. Intraoperative coronary artery spasm: retrospective review of 10 cases. Jpn J Anesthesiol 1990;39:37&82. 6. Biard C, Coriat P, Commin P, Chollet A, Menasche P, Echter E. Coronary artery spasm during noncardiac surgical procedure. Anaesthesia 1983;38:467-70. 7. Yamanoue T, Mukaida K, Yoshida A, et al. Coronary spasm during non-cardiac surgery. Jpn J Anesthesiol1986;35:1119-25. 8 Kalsner S. Cholinergic constriction in the general circulation and its role in coronary artery spasm. Circ Res 1989;65:237-57. 9 Yasue H, Touyania M, Shimamoto M, Kato K, Tanaka S, Akiyama F. Role of autonomic nervous system in the pathogenesis of Prinzmetal’s variant form of angina. Circulation 1974;50:53&9. 10 Endo M, Hirosawa K, Kaneko N, Hase K, Inoue Y, Konno S. Coronary arteriogram and left ventriculogram during angina attack induced by methacholine. N Engl J Med 1976;294:252-5. 11 Ginsburg R, Bristow MR, Harrison DC, Stinson EB. Studies with isolated human coronary arteries: some general observations, potential mediators of spasm, role of calcium antagonists. Chest 1980;78(Suppl):180-6. 12 Toda N. Isolated human coronary arteries in response to vasoconstrictor substances. Am J Physiol 1983;245:H937-41. 13 Kalsner S. Cholinergic mechanisms in human coronary preparations: implications of species differences. J Physiol 1985;358: 509-26. 14 Graser T, Leisner H, Tiedt N. Absence of role of endothelium in the response of isolated porcine coronary arteries to acetylcholine. Cardiovasc Res 1986;20:299-302, 15 Cowen CL, McKenzie JE. Cholinergic regulation of resting coronary blood flow in domestic swine. Am J Physiol 1990;259: H109-15. 16 Blaise G, Witzeling TM, Sill JC, Vinay P, Vanhoutte PM. Fentanyl is devoid of major effects on coronary vasoreactivity and myocardial metabolism in experimental animals. Anesthesiology 1990;72:53541, 17 Beny JL, Brunet PC, Huggel H. Effect of mechanical stimulation, substance P and vasoactive intestinal polypeptide on the electrical and mechanical activities of circular smooth muscle from pig coronary arteries contracted with acetylcholine: role of endothelium. Pharmacology 1986;33:61-8. 18 Yamada S, Yamazawa T, Nakayama K. Direct binding and
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19.
20. 21.
22. 23. 24. 25. 26. 27. 28. 29.
30.
31.
functional studies on muscarinic cholinoceptors in porcine coronary artery. J Pharmacol Exp Ther 1990;252:765-Y. Ginsburg R, Bristow MR, Davis K, Dibiase A, Billingham ME. Quantitative pharmacologic responses of normal and atherosclerotic isolated human epicardial coronary arteries. Circulation 1984;69:43&40. Toda N, Okamura T, Shimizu I , Tatsuno Y. Postmortem functional changes in coronary and cerebral arteries from humans and monkeys. Cardiovasc Res 1985;19:707-13. Barnette MS, Grous M, Manning CD, Callahan JF, Barone FC. Inhibition of neuronally induced relaxation of canine esophageal sphincter by opioid peptides. Eur J Pharmacol 1990;182: 363-8. Weitzell R, Ilks P, Stark K. Inhibition via opioid mu- and kappa-receptors of vagal transmission in rabbit isolated heart. Naunyn Schmiedebergs Arch Pharmacol 1984;328:18&90. Anthony BL, Dennison RL, Aronstam RS. Disruption of muscarinic receptor-G protein coupling is a general property of liquid volatile anesthetics. Neurosci Lett 1989;99:191-6. Toda N , Hatano Y. Alpha-adrenergic blocking action of fentanyl on the isolated aorta of the rabbit. Anesthesiology 1977;46: 411-6. Shimokawa H, Toinoike H, Nabeyama S, Yainamoto Y, Araki H, Nakamura M. Coronary artery spasm induced in atherosclerotic miniature swine. Science 1983;221:560-2. Toda N. Mechanism of histamine action in human coronary arteries. Circ Res 1987;61:280-6. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial sniooth muscle by acetylcholine. Nature 1980;288:37=. Brurii JM, Sufan Q, Lane G, Bove AA. Increased vasoconstrictor activity of proximal coronary arteries with endothelial damage in intact dogs. Circulation 1984;70:106673. Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5’-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest 1987;79:17W. Sakaino N, Araki H, Nishi K, Kimura T, Yasue H. Effects of vasoconstrictor agents on flow rate of isolated epicardial coronary artery of humans with various degrees of atherosclerosis and of young pigs. Cardiovasc Res 1988;22:555-61. Wynands JE, Townsend GE, Wong P, Whally DG, Srikant CB, Patel YC. Blood pressure response and plasma fentanyl concentrations during high- and very high-dose fentanyl anesthesia for coronary artery surgery. Anesth Analg 1983;62:661-5.
MD,
Division of Anesthesia, Cleveland Clinic Foundation, Cleveland, Ohio
Myocardial ischemia during surgery can be caused by coronary vasospasm. Neurohumoral mechanisms are involved in this phenomenon, and various substances have been suggested as possible causes, including acetylcholine, histamine, and norepinephrine. The responses of isolated puIcine coronary arteries (from 117 pig hearts) with (E t )and without (E-) endothelium to these agents were investigated in the presence of fentanyl, sufentanil, and morphine. Fentanyl significantly shifted to the right, in a concentration-dependent fashion, the concentrationresponse curve to acetylcholine. This effect wds not different between E + and E- rings. Neither sufentanil nor morphine altered acetylcholine-induced con-
I
ntraoperative myocardial ischemia has been investigated extensively (1,2). Coronary vasospasm is probably one important cause of intraoperative myocardial ischemia (3). It is difficult to establish this diagnosis precisely during surgery because in most instances information on coronary vasomotor tone is not available. The mechanisms of intraoperative occurrences of coronary vasospasm and the possible effects of anesthetic agents in this pathology are still unclear. Nevertheless, many reports suggest the occurrence of coronary vasospasm during both cardiac (4,5) and noncdrdidc surgery ( 5 7 ) . Cholinergic activation of muscarinic receptors has been proposed as a mechanism responsible for coronary vasospasm (8). Angina can be induced by subcutaneous injection of inethaiholine, a muscarinic agonist, and suppressed by atropine in humans (9). This effect of methacholine was associated with contraction of coronary arteries and confirmed by coronary arteriograms (10) in humans. Further studies Presented in part at the International Anesthesia Research Society 65th Congress, San Antonio, Texas, March 1991. Winner of “The Robert Tarazi Award” for Cardiovascular Research, 1991. Accepted for publicdtion January 21, 1932. Address correspondence to Dr. Bruiii, Cleveland Clinic Foundation, Research Institute NC3-114, 9500 Euclid Avenue, Cleveland, OH 44195-5286. 81992 by the Iiitemational Anesthesia Research Socielv 0003-2999/92/$5.00
traction of porcine coronary arteries. Naloxone did not antagonize the suppressive effect of fentanyl on acetylcholine-induced contraction. The response of porcine coronary arteries to norepinephrine was decreased only at very high concentrations of fentanyl. Neither sufentanil nor morphine altered norepinephrine-induced contraction of porcine coronary arteries. Fentanyl, sufentanil, and morphine had no effect on histamine-induced contraction. We conclude that tentanyl antagonized acetylcholine-induced contraction of porcine coronary arteries. This effect of fentanyl seems to be caused by a direct effect on smooth muscle cells and is not opioid-receptor mediated. (Anesth Analg 1992;74:889-96)
with isolated human coronary arteries, obtained from recipient and cadaver hearts (11,12), showed that acetylcholine contracted coronary arteries and that the contraction was suppressed by atropine. Muscarinic agonists also produce coronary contraction in porcine (13-15) and many other species, although canine coronary rings with intact endothelium relax in the presence of muscarinic agonists (13). Because of lack of significant effects on myocardial contractility, opioids are widely used in anesthesia for patients who have poor cardiac reserve. In addition, opioid anesthetic agents have little elfect on coronary vasoreactivity. Blaise et al. (16) reported that fentanyl had no direct effect on coronary arteries of dogs, pigs, and rats. They also reported that fentanyl slightly attenuated canine coronary arterial contraction caused by phenylephrine but had no effect on contraction caused by serotonin. They did not investigate the effect of fentanyl on cholinergic-mediated coronary vasoconstriction. Although it is difficult to determine whether cholinergic activation is responsible for intraoperative coronary vasospasm, cholinergic mechanisms do participate in coronary vasospasm in many species, including humans (8). Therefore, cholinergic-mediated coronary vasoconstriction under the effects of anesthetic agents seems worthy of investigation. Anesth Analg 1992;74:889-96
889
890
ANESTH ANALG 1992;74:889-96
YAMANOUE ET AL. OPlOlDS AND CORONARY VASORESPONSIVENESS
The purpose of this study was to assess the effect of opioid anesthetic agents, such as fentanyl, sufentanil, and morphine, on coronary vasoconstriction caused by cholinergic, a-adrenergic, and histaminergic agents.
Methods This study was approved by the Cleveland Clinic Animal Care and Use Committee. One hundred seventeen hearts of adult pigs of either sex were obtained immediately postmortem at a nearby slaughterhouse (Polansky Market, Amherst, Ohio) and transported in ice-cold buffered salt solution. Within 1 h, left anterior descending coronary arteries were removed from the animal heart and placed in cold buffered salt solution (millimolar composition: NaC1, 118.3; KCl, 4.7; CaCl,, 2.5; MgSO,, 1.2; KH,PO,, 1.2; NaHCO,, 25.0; edetate calcium disodium, 0.026; and glucose, 11.1).Arteries, 3-4 mm in diameter, were cleansed of surrounding fat and connective tissue and cut into 5-mm-long rings, with care taken not to damage the intimal surface. The endothelium was deliberately removed in some rings by gently rubbing a fine stainless steel rod against the vessel intima. Rings were suspended between two stainless steel wires in organ chambers filled with 25 mL of buffered salt solution at 37°C bubbled with 95% 0,5% CO, gas mixture. One of the wires was anchored in the organ chamber, and the other was connected to a force transducer. Before the actual experiment, the preparations were progressively stretched and repeatedly exposed to 40 mM of KCl to induce contraction at each level of stretching, until a maximal contractile response was obtained. As the basal tension generated by this process indicates the optimal point of a length-tension curve, this response was used as a reference tension. All of the contractions induced by agonists during experiments were expressed as percentages to this reference tension. The effectiveness of the endothelium denudation was assessed by exposing the rings (contracted by KCl) to l o p 7 M of substance P, because porcine coronary artery is relaxed by substance P in the presence of intact endothelium (17); this endothelium-dependent relaxation does not occur with acetylcholine (14,18). The rings were then allowed to equilibrate for 45 min. Rings with (E+) and without endothelium (E-) each were preincubated with fentan 1 (3.16 x lop7, 3.16 X lop6M), sufentanil(3.16 X 10- Y,3.16 x 1OP6M), or morphine (lo-', lop4M). These experiments were done in parallel, where artery rings from the same pig were used as control. Cumulative concentrations of acetylcholine (from lo-'' M up to the concentration that made maximal response, 3.16 x l o p hto 3.16 x l o p 5M), norepineph-
rine (lo-'' up to lo-, M), and histamine (lo-'' up to M) were added to each organ chamber, and the tension generated by the rings was measured in grams. The responses to norepinephrine were obtained in the presence of a concentration (5 X M) of propranolol known to produce total P-adrenergic blockade. To investigate the participation of opioid receptors in the effects of fentanyl in the dose-response curve to acetylcholine, these experiments were repeated on rings with endothelium in the presence and absence of naloxone (lop6, M). The EC,, values (concentration of acetylcholine causing 50% of maximal response) were calculated by using linear regression analysis from data between 20% and 80% of maximal responses. Within this range, linearity was well maintained (0.97 < correlation coefficient [R] 5 1.00). The following drugs were used: acetylcholine, norepinephrine, histamine, propranolol (Sigma, St. Louis, Mo.), fentanyl citrate, sufentanil citrate (Janssen, Piscataway, N.J.), morphine sulfate (ElkinsSinn, Cherry Hill, N.J.), and naloxone hydrochloride (Du Pont, Manati, P.R.). The drugs were prepared daily in distilled deionized water or in 0.1% solution of ascorbic acid in water and kept on ice during the experiments. The results were expressed as mean ? S E . Comparison of concentration-response curves was accomplished by the following procedure: (a) The parallelism was analyzed by comparing the slopes of linear regression lines from data between 20% and 80% of maximal responses. (b) As the parallelism was confirmed in every protocol, EC,, values were compared by one-way analysis of variance. When paired data from animals were compared in parallel, Student's t-test was done for paired observations. Data not from the same population of animals were analyzed by Student's t-test for unpaired observation. Values were considered statistically significant when P < 0.05.
Results The porcine coronary artery rings contracted in response to acetylcholine within the concentration range lo-* to 3.16 x lop6 M. There were no differences in the contractile responses between vessels with and without endothelium. The concentrationresponse curve to acetylcholine was significantly shifted to the right when the experiment was done in the presence of fentanyl (3.16 X l o p 7 M). No significant differences were detected at the level of maximal contraction. This effect was present in vessel rings with and without endothelium, and no differences were observed in this regard. A 10 times higher
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Figure 1. Cumulative concentration-response curve to acetylcholine of porcine coronary arteries with (E+) and without (E-) endothelium in the presence and absence of fentanyl ( n = 20), sufentanil (n = 12), or morphine (n = 9). Responses of control rings (circles); responses in the presence of lower concentrations of fentanyl(3.16 x M, n = 13), sufentanil (3.16 x M, n = 5 ) (lozenges); responses in the presence of higher concentrations of fentanyl (3.16 x M, n = 7), sufentanil (3.16 x M, n = 7), and morphine M, n = S), and M, n = 4) (squares). Contractions are expressed as a percentage of the maximal response to standard 40 mM KCl challenge. Fentanyl shifted equally the morphine concentration-response to acetylcholine in both vessels with and without endothelium. No significant differences among maximal contraction were observed. Neither sufentanil nor morphine altered the contractile response to acetylcholine.
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ANESTH ANALG
YAMANOUE ET AL. OPlOlDS AND CORONARY VASORESPONSIVENESS
1992:74:88%96
Table 1. Acetylcholine-Induced Coronary Artery Vasoconstriction (log EC5,,): Effect of Fentanyl
I00
With fentanyl
Without fentanyl Control group ( n = 20)
3.16 x lo-’ M ( n = 13)
3.16 x lo-’ M ( n = 7)
-6.81 t 0.06 -6.87 ? 0.10
-6.29 t 0.06“ -6.38 t 0.14”
-5.58 2 0.05”.” -5.66 t 0.09”.”
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E t , rings with endothelium; E-, rings without endothelium Values are expressed as mean ? S E M . “P < 0.05 compared with control group. “P < 0.05 compared with 3.16 x lo-’ M fentanyl group.
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Table 2. Acetylcholine-Induced Coronary Artery Vasoconstriction (log EC,,,): Effect of Naloxone and Fentanyl
110
r
T
100
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Without naloxone
Control
-6.72 t 0.05 (tl = 11) -6.29 2 0.09 ( t i = 10)
Fentanyl
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-6.76
?
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-6.39
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All rin s are with endothelium. The concentration of fentanyl used is 3.16 x 10- M. In both control and fentanyl-pretreated groups, no significant differences are shown among rings with the two concentrations wlth and without naloxone. Values are expressed as mean 2 S E M .
3
concentration of fentanyl (3.16 x l o p 6 M) caused a further shift to the right in the concentrationresponse curve of acetylcholine, without any significant influence of the endothelium (Figure 1). The dose-dependent suppressive effects of fentanyl were also expressed by a significant increase of EC,, values (Table 1). Neither sufentanil nor morphine (Figure 1) altered the concentration-response curve to acetylcholine. Naloxone, a nonspecific opioid antagonist, did not alter the vasoconstriction produced by acetylcholine. Naloxone did not change the shift in the acetylcholine vasoconstriction caused by fentanyl (Figure 2). The EC,, values of acetylcholine-induced contraction, both in the presence and absence of fentanyl, were not altered by pretreatment with naloxone (Table 2). Norepinephrine at the range lo-’ to l o p 4 induced a significant contraction of the porcine coronary artery rings. The vasoconstriction caused by norepinephrine was significantly increased in rings without endothelium at the concentrations of norepinephrine >3.16 X l o p 7 M. Fentanyl in the organ bath at 3.16 x l o p 7 M did not alter the response to norepinephrine (Figure 3A). Fentanyl at a very high concentration (3.16 x l o p 6 M) significantly decreased the response to higher concentrations of norepinephrine ( l o p 6 to 10 M) in rings with and without endothelium
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log [acetylcholine] Figure 2. Cumulative concentration-response curve to acetylcholine of porcine coronary rings with endothelium. Responses of control rings (cirrlcs) and responses of rings in the presence of fentanyl (3.16 x 10 M) (lozen~es).Rightward shift of the curve of rings with fentanyl ( t i = 10) as compared with control rings (ti = 11) is shown in the irpp’r \ J O t i d . Influences of two concentrations of naloxone, 10 M ( n = 8) and lo-‘ M ( t i = 5-7), are shown in the riiiddle and h e r pitick, respectively. Contractions are expressed as a percentage of the maximal response to standard 40 mM KCI challenge. Naloxone, at either concentration, did not affect the contractile response to acetylcholine. Further, naloxone did not alter the rightward shift of the concentration-response curve to acetylcholine by fentanyl.
’
(Figures 3B and 3C). Neither sufentanil nor morphine in any concentration used in this study altered significantly the concentration-response curve to norep-
ANESTH ANALC 1992;74:889-96
YAMANOUE ET AL. OPIOIDS AND CORONARY VASORESPONSIVENESS
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Figure 3. Cumulative concentration-response curve to norepinephrine of porcine coronary rings with ( E + , solid s!/rribols) and without (E-, open symbols) endothelium in the presence and absence of fentanyl. Contractions are expressed as a percentage of the maximal response to standard 40 mM KCI challenge. (A) Responses of control rings ( 1 1 = 17) (circlcs); responses of rings in the presence of fentanyl (3.16 x lo-' M, II = 8) ( l o z ~ r i p )Contractile . response to norepinephrine i n rings without endothelium was significantly larger than that in rings with endothelium at the concentration of norepinephrine >3.16 x 70 M. Fentanyl did not alter the contractile response to norepinephrine. (B,C) Responses of control rings ( i i = 17) ( i i d c s ) ; responses of rings in the presence of high concentration of fentanyl (3.16 X 10 ' M, I I = 9) (sqrurcs). A very high concentration of fentanyl significantly attenuated the contractile response to norepinephrine in rings both with and without endothelium at the concentration of norepinephrine from 10 " to 10 M.
inephrine in intact or endothelium-denuded vessels (data not shown). Histamine caused concentration-dependent contraction in the coronary artery rings with onset at M and maximal response at lo-' M. The responses to histamine were not significantly altered by endothelium. Fentanyl, sufentanil, or morphine at the concentrations used in this study did not significantly affect the histamine-induced contraction (Figure 4).
Discussion The current study indicates that fentanyl attenuates muscarinic-mediated contraction of porcine coronary arteries. This attenuation is probably due to a direct effect of fentanyl on vascular smooth muscle because it occurs independently of endothelial integrity. Other investigators have shown that acetylcholineinduced contraction of porcine coronary arteries is endothelium independent (14,18). These findings were also reported in isolated human coronary arteries (19,20). Further, binding assays demonstrated the presence of muscarinic receptors solely in porcine coronary arterial smooth muscle cells but not in the endothelium (18). These studies substantiate our findings that porcine coronary vasoconstriction due to acetylcholine is independent of the integrity of the endothelium. In contrast, endothelium-dependent relaxation due to other agents is present in porcine coronary arteries. For example, responses tc) sub-
stance P, bradykinin, and serotonin were well demonstrated in porcine coronary arteries, suggesting participation of endothelium-derived relaxing factor on the responsiveness of these vessels (13). Nevertheless, the vasoconstriction caused by acetylcholine in the porcine coronary arteries is not affected by the endothelium, and the attenuation of this contraction probably occurs on the vascular smooth muscle cells. The fact that naloxone did not alter the effect of fentanyl on muscarinic response strongly suggests that this phenomenon is not opioid-receptor mediated. Further, sufentanil, which is five to ten times more potent than fentanyl, and morphine did not reproduce the effect of fentanyl on cholinergicmediated contraction. An opioid receptor-mediated modulatory role has been observed in prejunctional muscarinic cholinergic responses of canine bronchial smooth muscle (21) and rabbit isolated heart (22). In the present study, the effect of fentanyl on muscarinic-mediated vasoconstriction seems to be independent of opioid receptor activation. One possible explanation of the effects of fentanyl on cholinergic vasoconstriction is through direct interference by fentanyl with the muscarinic receptor in the porcine coronary arteries. Differences in the molecular structure and not in the opioid character among fentanyl, sufentanil, and morphine would favor the hypothesis of an "antimuscarinic" activity particular to fentanyl. Further, the solvent vehicle for fentanyl and sufentanil is the same. A comparison of the sufentanil and fentanyl molecules reveals struc-
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Figure 4. Cumulative concentration-response curve to histamine of porcine coronary arteries with (E+, solid sylnbols) and without (E-, open symbols) endothelium in the presence and absence of fentanyl (11 = 13), sufentanil ( n = S), or morphine ( r r = 10). Responses of control rings (circles); responses in the presence of lower concentrations of fentanyl (3.16 x lo-' M, ti = S), sufentanil (3.16 x lo-' M, ) I = 4), and morphine (lo-' M, ti = 4) ( l o z e q c s ) ;responses in the presence of higher concentrations of fentanyl (3.16 x M, ri = 5 ) , sufentanil (3.16 x M, n = 41, and morphine (lo-' M, n = 6) (squares). Contractions are expressed as a percentage of the maximal response to standard 40 mM KCI challenge. All of the opioid anesthetic agents did not alter the contractile response to histamine.
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ANESTH ANALG 1992;74:889-96
tural dissimilarities that may account for the differential muscarinic-mediated vascular responses. Therefore, a nonopioid, direct effect of fentanyl on the muscarinic receptor is possible. Another possible explanation of the suppressive effect of fentanyl is through interference in the muscarinic process of signal transduction in the coronary vascular smooth muscle cells. Some anesthetic agents directly affect the guanine nucleotide binding proteins (G-protein), which has been suggested to be the primary site for the action of anesthetics (23). The present study does not provide any evidence concerning the interaction of fentanyl with the process of signal transduction. Our observation that fentanyl not only has a significant modulatory effect on cholinergic mechanisms, but on adrenergic mechanisms as well, may suggest the possibility that fentanyl affects a second-messenger mechanism common to both types of receptors. Our results with regard to the effect of fentanyl on adrenergic contraction of porcine coronary arteries agree with the findings of other authors. Toda and Hatano (24) observed that fentanyl shifted to the right the concentration-response curve of the rabbit aorta to norepinephrine only at a very high concentration of fentanyl. They also observed that the effect was not mediated by opioid receptors and suggested that fentanyl antagonized in a competitive manner the a-adrenergic receptors in the vascular smooth muscle. Blaise et al. (16) reported that fentanyl induced a small attenuation in phenylephrine-induced contraction of canine coronary arteries. In agreement, our results also indicate attenuation of adrenergicmediated coronary vasoconstriction only at a concentration of fentanyl that has no clinical application. Histamine has been used to induce experimental coronary vasospasm, as have ergonovine and acetylcholine. Coronary vasospasm in atherosclerotic miniature pigs was induced by histamine mainly in vessels with intimal thickening, suggesting that structural changes over time are responsible for enhancing histamine effects (25). Histamine also induces vasoconstriction in human coronary arteries that is enhanced by damaged endothelium (26). Our results confirm that histamine is a coronary vasoconstrictor in the adult pig coronary artery with or without endothelium. This vasoconstriction was not altered by any opioid anesthetic agents used in this study. These findings may suggest that high-dose opioid anesthesia would not offer any protective effect against coronary vasospasm induced by histamine. Furchgott and Zawadzki (27) showed that endothelium modulates the acetylcholine vasoconstrictor effect on the vascular smooth muscle by releasing a relaxing factor. This modulatory role of the endothe-
YAMANOUE ET AL. OPlOlDS AND CORONARY VASORESPONSIVENESS
895
lium was described in coronary arteries of dogs and other species in response to many pharmacologic agents and also in vivo (28). A similar phenomenon was also observed in isolated human coronary arteries (29). Most investigations concerning the reactivity of human coronary arteries to muscarinic agonists show a n endothelium-independent contraction (13,19,20). The contractile response in humans resembles that in pigs (13,14) and other species (13). Responses of porcine coronary arteries to acetylcholine and histamine are very similar to those of human coronary arteries (30). Therefore, we believe porcine coronary artery to be a valid animal model. The concentration of fentanyl used in the present study (-6.5 log M) is equivalent to approximately 70 nglmL. This is within the upper range of the plasma level of fentanyl when used as high-dose fentanyl anesthesia, although the plasma level of fentanyl usually becomes lower than this concentration over time during surgery (31). In contrast, sufentanil did not affect cholinergic porcine coronary contraction even at concentrations far higher than any of clinical relevance. Sufentanil did not provide any attenuation of coronary vasoconstriction caused by neurohumoral agents used in this study. We focused on the effect of the opioid anesthetic agents that are most widely used for cardiac surgery. Volatile anesthetic agents have coronary vasodilator effects (3). Whether those volatile agents also interfere with muscarinic-mediated coronary reactivity is unknown. We report here the suppressive effect of fentanyl on acetylcholine-induced contraction of isolated porcine coronary arteries. This phenomenon was endothelium independent and did not occur through an opioid receptor mechanism. Other properties of fentanyl, especially its effects on the central nervous system, may alter the possible protective effect of fentanyl against cholinergic-mediated coronary constriction. Our work suggests that high-dose fentanyl anesthesia might have a protective effect against cholinergic coronary vasoconstriction. It is not clear whether cholinergic activation plays a major role in intraoperative coronary vasospasm. If so, such intraoperative coronary vasospasm might be blunted by high-dose fentanyl anesthesia.
References 1. Mangano DT, Browner WS, Hollenberg M, et al. Association of perioperative myocardial ischemia with cardiac morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med 1990;323:1781-8. 2. Slogoff S, Keats AS, Dear WE, et al. Steal-prone coronary anatomy and myocardial ischemia associated with four primary anesthetic agents in humans. Anesth Analg 1991;72:22-7.
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ANESTH ANALG
YAMANOUE ET AL. OPIOIDS AND CORONARY VASORESPOMIVENESS
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