British Journal of Anaesthesia, 2002, Vol. 89, No. 6 888-895
© 2002 The Board of Management and Trustees of the British Journal of Anaesthesia
Laboratory Investigations |
Electrophysiological effects of morphine in an in vitro model of the ‘border zone’ between normal and ischaemic–reperfused guinea-pig myocardium
1 Laboratory of Experimental Anesthesiology and Cellular Physiology, UPRES EA 3212, Centre Hospitalier Universitaire, Côte de Nacre, Caen, France. 2 Department of Anesthesiology, Centre Hospitalier Universitaire, Caen, France Département d’Anesthésie-Réanimation, CHU de Caen, Avenue Côte de Nacre, F-14033 Caen Cedex, France. E-mail: hanouz-jl@chu-caen.fr
Accepted for publication: July 23, 2002
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Background. Morphine is commonly used in clinical practice in pain management. Although morphine has been shown to precondition the myocardium, its effects on action potential parameters and ischaemia–reperfusion-induced arrhythmias and conduction blocks remain unknown.
Methods. In a double-chamber bath, guinea-pig right ventricular muscle strips were subjected partly to normal conditions and partly to 30 min of simulated ischaemia (hypoxia, hyperkalaemia, acidosis, and lack of nutritional substrate) followed by 30 min of reperfusion. Action potential parameters were recorded continuously in the normal zone and in the ischaemic– reperfused zone. Spontaneous arrhythmias and conduction blocks were noted. The electro physiological effects of morphine were studied at 0.01 and 0.1 µM.
Results. In control conditions, morphine did not modify action potential parameters of resting membrane potential, maximal upstroke velocity (Vmax), action potential amplitude (APA) and action potential duration at 50 and 90% of repolarization. Morphine reduced ischaemia-induced depolarization and lessened the ischaemia-induced decrease in APA and Vmax. Morphine significantly decreased the occurrence of conduction block during simulated ischaemia (20% at 0.01 and 0.1 µM vs 67% in the control group, P<0.05) and reperfusion-induced arrhythmias (40% at 0.01 µM and 30% at 0.1 µM vs 92% in the control group, P<0.05).
Conclusions. In ischaemic–reperfused guinea-pig myocardium, morphine at clinically relevant concentrations decreased ischaemia-induced conduction blocks and reperfusion-induced ventricular arrhythmias.
Br J Anaesth 2002; 89: 888–95
Keywords: analgesics opioid, morphine; heart, arrhythmia; heart, ischaemia; heart, reperfusion injury
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Morphine, a µ-opioid receptor agonist, is used in daily clinical practice in the management of pain during acute myocardial infarction and in the postoperative period, when it is known to be associated with a high risk of myocardial ischaemia in patients with known or unknown coronary artery disease.1 A growing body of evidence suggests that opioid receptor stimulation may have cardioprotective effects.2–4 However, the clinical relevance of studies dealing with opioid-induced preconditioning remains limited, because in acute myocardial infarction morphine is administered during or after, but rarely before, myocardial ischaemia. Similarly, in the postoperative period myocardial ischaemia may occur even though patients are treated with morphine. Moreover, because ischaemia-induced ventricular arrhythmias are potentially fatal complications of myocardial ischaemia, it is important to examine the effects of morphine on ischaemia- and reperfusion-induced arrhythmias. The main mechanisms involved in ventricular arrhythmias related to myocardial ischaemia are abnormal automaticity and re-entrant rhythms.5 Rouet and colleagues developed an in vitro model simulating the ‘border zone’ between normal and ischaemic–reperfused ventricular myocardium,6 providing the opportunity to study ischaemia-related conduction blocks and reperfusion-induced spontaneous arrhythmias.7
The purpose of our study was to examine the effect of clinically relevant concentrations of morphine administered during ischaemia and reperfusion on the time-course parameters of the action potential and on the incidence of arrhythmias in isolated guinea-pig myocardium.
|
Material and methods |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Animal care was in agreement with the recommendations of the Helsinki Declaration and the study was performed in accordance with the official edict of the French Ministry of Agriculture.
Guinea-pigs of either sex weighing 300–400 g were killed by cervical dislocation after brief ether anaesthesia, and immediately exsanguinated. The heart was quickly removed at room temperature into oxygenated Tyrode’s solution containing (mM) 135 Na+, 4 K+, 1.8 Ca2+, 1.8 H2PO4–, 25 HCO3–, 117.8 Cl– and 5.5 glucose.
A myocardial strip (15 mm long, 5 mm wide, 1.5 mm thick) was carefully dissected from the free wall of the right ventricle. The strip was pinned, endocardial surface upwards, in a special perfusion chamber. This chamber (5 ml) was bisected by a thin latex membrane including a centrally located hole that allowed the preparation to be passed through and divided into two zones, called the normal zone (NZ) and the altered zone (AZ). The two compartments were perfused independently by a peristaltic pump at 2 ml min–1, bubbled with carbogen (95% oxygen, 5% carbon dioxide). The pH of the Tyrode’s solution was equilibrated to 7.35 (0.05) with dilute hydrochloric acid and the temperature was maintained at 36.5°C with a water-circulating thermostat-controlled bath (Polystat 5HP; Bioblock, Illkirch, France). To check for the absence of leakage between the two compartments, we injected methylene blue dye into one compartment after the experiment.
Data acquisition and analysis
Preparations were stimulated at 1 Hz with two bipolar silicon-coated electrodes positioned in the NZ and in the AZ. A commutator allowed stimulation of the preparation through one or the other stimulating electrode. Stimuli were rectangular pulses of 1–2 V depolarizing voltage, duration 2 ms, delivered by a programmable stimulator (model SMP 310; Biologic, Grenoble, France). Preparations that needed pulses stronger than 5 V to elicit action potentials were discarded because there could have been a conduction block at the level of the latex separating membrane. During the protocol, stimulation was stopped whenever sustained spontaneous arrhythmias occurred. Action potential parameters were recorded simultaneously in both myocardial regions using glass microelectrodes pulled from borosilicate filament tubes (GC 200F-15; Phymep, France) on a single-barrelled microelectrode puller (Narashige, distributed by OSI, France). Microelectrodes were filled with potassium chloride 3 M (tip resistance 10–30 M
) and coupled to a silver–silver chloride microelectrode holder leading to a home-built, high-impedance capacitance-neutralizing amplifier. A ball-shaped reference silver–silver chloride electrode was positioned in the superfusate of each compartment.
Action potentials (AP) were monitored on a digital oscilloscope (Gould Instrument Systems, Cleveland, OH, USA). The following AP parameters were automatically stored and measured using a cardiac AP automatic acquisition system and processing device (Datapac; Biologic): resting membrane potential (RMP); action potential amplitude (APA), action potential duration at 50% of full repolarization (APD50); action potential duration at 90% of full repolarization (APD90); and maximal upstroke velocity (Vmax). Whenever possible, the same impalement was maintained throughout the experiment; when it was lost, readjustment was attempted. If the readjusted parameters differed by less than 10% from previous values, experiments were continued; otherwise they were terminated.
Experimental protocol
After a 2 h equilibration period (when AP parameters were stabilized), simulated ischaemia was induced for 30 min in the AZ compartment by superfusion with modified Tyrode’s solution, while the NZ compartment was maintained in normal conditions. The modified Tyrode’s solution differed from normal by elevated potassium concentration (from 4 to 12 mM), decreased HCO3– concentration (from 25 to 9 mM), leading to a decrease in pH [from 7.35 (0.05) to 6.90 (0.05)], and decreased PO2 by replacement of 95% oxygen–5% carbon dioxide with a gas mixture containing 95% nitrogen and 5% carbon dioxide and withdrawal of glucose. These modifications, combining hypoxia, hyperkalaemia, acidosis and lack of substrate, reproduced in vitro the electrophysiological abnormalities induced in vivo by ischaemia.6 8–14 After 30 min of simulated ischaemia, a 30 min reperfusion period was initiated by reperfusing Tyrode’s solution rebubbled with 95% oxygen–5% carbon dioxide mixture.
During both simulated ischaemia and reperfusion, conduction disturbances10 13 and arrhythmias6 10 13 were recorded: (i) conduction blocks between the AZ and the NZ; (ii) spontaneous arrhythmias independent of stimulation [one or two extrasystoles, salvos (3–10 AP), sustained activities (>10 AP)]; and (iii) loss of responsiveness to a constant stimulation intensity. Stimulation was stopped whenever sustained arrhythmias occurred.
During the simulated ischaemia and reperfusion phases, Tyrode’s solution with 0.01 or 0.1 µM morphine (n=10 for each group) added or Tyrode’s solution alone (n=12) was superfused randomly in both compartments (NZ and AZ). Thus, the electrophysiological effects of morphine on AP parameters and the incidence of arrhythmias were investigated simultaneously in normal (NZ) and altered (AZ) conditions.
Statistical analysis
All results are expressed as mean (SD). Multiple comparison of continuous variables was performed by repeated-measures analysis of variance followed by comparison with control or initial values (measurement before initiation of the ischaemic period) using the Bonferroni post hoc test. Fisher’s exact test was used for comparison of non-parametric categorical data. All P values were two-tailed, and P<0.05 was required to reject the null hypothesis.
|
Results |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
Ischaemia and reperfusion effects on action potential parameters
In the NZ, all AP parameters recorded remained unchanged during 60 min of superfusion with normal Tyrode’s solution (Table 1). Simulated ischaemia-induced alterations of AP parameters are summarized in Table 2. In the control group, 5 min of simulated ischaemia induced significant membrane depolarization [–27 (5)% of baseline, P<0.01], significant decreases in Vmax [–62 (14)% of baseline, P<0.01] and APA [–28 (10)% of baseline, P<0.01], and significant decreases in APD50 [–70 (10)% of baseline, P<0.01] and APD90 [–66 (10)% of baseline, P<0.01]. The maximal electrophysiological modifications reached a plateau within the first 10 min. Reperfusion of the AZ was associated with rapid recovery of the AP parameter values (Table 2).
|
|
P<0.05 and 
P<0.01 morphine groups vs control group. RMP=resting membrane potential; Vmax=maximal upstroke velocity; APA=action potential amplitude; APD50 and APD90=action potential duration at 50 and 90% of repolarization respectively
Morphine effects on action potential parameters in normoxic conditions
As shown in Table 1, there were no differences in initial values of AP parameters between experimental groups. In the NZ, morphine at 0.01 and 0.1 µM did not modify the AP parameters RMP, Vmax, APA, APD50 and APD90 (Table 1).
Morphine effects on action potential parameters in ischaemic–reperfused simulated conditions
Morphine reduced the ischaemia-induced depolarization [–29 (5)% and –24 (5)% in the presence of morphine 0.01 and 0.1 µM respectively, compared with –32 (1)% for the control group after 30 min of ischaemia; P<0.001 for each group]. The ischaemia-induced decrease in APA [–31 (5)% and –27 (6)% in the presence of morphine 0.01 and 0.1 µM respectively, compared with –39 (9)% for the control group after 30 min of ischaemia; P<0.001 for each group] and Vmax [–54 (7)% and –56 (12)% in the presence of morphine 0.01 and 0.1 µM respectively, compared with –71 (19)% in the control group after 30 min of ischaemia; P<0.001 for each group] were significantly attenuated by morphine. As shown in Table 2, the ischaemia-induced AP shortenings were not affected by morphine whatever the concentration tested. At the end of the reperfusion, RMP, APA, Vmax, APD50 and APD90 in the AZ reached baseline values and were comparable between groups (Table 2).
Morphine effects on ischaemia–reperfusion-induced conduction disturbances
As shown in Figure 1, conduction blocks occurred after 15 (7) min in the control group, 16 (14) min in the presence of 0.01 µM morphine and after 21 (7) min in the presence of 0.1 µM morphine. At the end of the ischaemic period there was no significant difference between groups in the incidence of loss of responsiveness (1% for control group and 0% for the morphine groups). Reperfusion of AZ induced complete recovery of responsiveness in all experimental groups.
|
As summarized in Figure 2, morphine 0.01 and 0.1 µM significantly decreased the occurrence of conduction block during the 30 min ischaemic period (20% for morphine groups vs 67% for the control group, P<0.01). In each group, conduction blocks disappeared during the reperfusion period.
|
Morphine effects on ischaemia–reperfusion-induced arrhythmias
As illustrated in Figures 1 and 2, during the ischaemic period the number of preparations exhibiting spontaneous repetitive responses was not modified in the presence of morphine. During the reperfusion period, the occurrence of spontaneous repetitive responses was significantly decreased in the presence of morphine 0.01 and 0.1 µM (40% in the presence of 0.01 µM morphine and 30% in the presence of morphine 0.1 µM vs 92% in the control group; P<0.05).
|
Discussion |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
This study showed that: (i) morphine reduced ischaemia-induced membrane depolarization and attenuated the ischaemia-induced decrease in APA and Vmax; (ii) morphine decreased the occurrence of conduction block during simulated ischaemia; and (iii) morphine decreased the occurrence of reperfusion-induced arrhythmias.
Our results show that morphine did not affect AP parameters in normoxic conditions. This is in accordance with previous results showing that morphine, even at high concentrations, did not significantly modify electrophysiological parameters recorded on isolated myocardium.15 16 Although Hung and colleagues have shown that morphine decreases the sodium inward current (INa) in human and rat isolated myocytes, this effect became significant at concentrations 100-fold higher than those tested in our study.17 Additionally, Hung and colleagues showed that morphine at 30 µM did not affect the inward calcium current, the transient outward potassium current or the inwardly rectifying potassium currents.17 In our study we tested the effects of morphine 0.01 and 0.1 µM because these concentrations are in the range of plasma concentrations measured in clinical practice, taking the protein binding of morphine into account.18 To our knowledge, there are no studies dealing with the effects of clinically relevant concentrations of morphine on ion transmembrane currents in myocardial cells.
Our results confirm the ischaemia-induced decrease in RMP and AP parameters reported previously in similar studies.6 7 10 Furthermore, in AZ the ischaemia-induced decrease in RMP was attenuated by morphine at 0.01 and 0.1 µM. It is well known that depolarization of the RMP can lead to steady-state inactivation and slower reactivation of sodium channels, thereby reducing the number of channels available to carry INa during the action potential upstroke. Consequently, attenuated ischaemia-induced membrane depolarization measured in the presence of morphine should attenuate the ischaemia-induced decrease in INa, and thus the decreases in Vmax and APA. This is in agreement with our results showing that morphine attenuated the decrease in Vmax and APA measured during simulated ischaemia. Because depolarizing the RMP plays a pivotal role in the production of re-entrant arrhythmias during the acute phase of ischaemia,14 this result could explain, at least in part, the anti-arrhythmic effect of morphine reported here and in previous studies.2 19 20 Our study shows that morphine did not modify the ischaemia-induced decrease in APD50 and APD90. Although morphine 0.1 µM significantly attenuated the ischaemia-induced decrease in APD90, this effect remained modest. Ischaemia-induced shortening of AP duration has been related to the activation of an ATP-sensitive potassium (K-ATP) conductance.21 The direct effect of morphine on sarcolemmal K-ATP channels in myocytes remains unknown, but recent evidence suggests that mitochondrial K-ATP channels may be opened by opioid receptor stimulation, leading to a preconditioning state.2 22 Moreover, pretreatment of isolated rat hearts with a selective antagonist of the mitochondrial K-ATP channels abolished the anti-arrhythmic effect of 
1-opioid receptor stimulation.2 However, sarcolemmal, but not mitochondrial, K-ATP channels are involved in the repolarization phase of the cardiac AP, supporting the unchanged AP duration reported in our study.
Our study shows that, during simulated myocardial ischaemia, morphine significantly decreased the occurrence of conduction blocks in the border zone. It is well known that slowing of conduction velocity, occurrence of conduction blocks and dispersion of the refractory period between an ischaemic zone and a non-ischaemic zone (‘border zone’) favour the emergence of re-entry arrhythmias.13 14 This should be considered with the knowledge that morphine is used to treat chest pain associated with myocardial infarction. In contrast, morphine did not modify the occurrence of spontaneous arrhythmias during the ischaemic period, as reported previously.23 24 However, ischaemia-induced spontaneous arrhythmias are unlikely to be related to re-entry movement because it has been shown that they are independent of stimulation.7 Although Fryer and colleagues2 and Wang and colleagues19 reported an anti-arrhythmic effect of opioid receptor stimulation, in these studies opioid agonists were administered before myocardial ischaemia as triggers of preconditioning.3 4 In contrast, in our study morphine was administered throughout the duration of ischaemia and reperfusion, as might occur in clinical practice.
Our results show that morphine significantly decreased the incidence of reperfusion-induced repetitive responses around the ‘border zone’ between AZ and NZ. This is in agreement with previous results showing that chronic morphine exposure significantly reduced the incidence and severity of reperfusion-induced arrhythmias in isolated rat hearts.25 The mechanisms involved in arrhythmias that occur during reperfusion and were morphine-sensitive in our experimental model are not completely understood, but might involve 
-24 and -opioid2 receptors, adrenoceptor modulation,26 reduction of conduction block, sodium or calcium overload and possibly reactive oxygen species.27 The hypothesis of adrenoceptor modulation is supported by studies suggesting that the anti-arrhythmic effect of - and -opioid receptor stimulation resulted, at least in part, from negative modulation of ß-adrenoceptors and a decrease in intracellular calcium oscillations.26 28 So opioid receptor stimulation may be an important way to counteract the excitatory influence of the sympathetic nervous system, thus preventing dysrrhythmias arising from overactivity of adrenoceptors during ischaemia. Finally, further studies are needed to understand the precise mechanism involved in the anti-arrhythmic effect of morphine in ischaemic–reperfused myocardium.
There are several limitations to our study. First, the simulated ischaemia used modified Tyrode’s solution with acidosis, hyperkalaemia, hypoxia and lack of energetic substrates. As described previously,6 8–11 these conditions accurately reproduced the electrical alterations of cardiac APs observed in vivo during experimental myocardial ischaemia.12 Additionally, the reliability of the double-bath technique is demonstrated by the constancy of the AP parameters in the NZ, adjacent to the AZ. Secondly, the border between normal and ischaemic–reperfused myocardium is probably narrower and more regular than it might be in clinical conditions. As shown previously,6 this ‘border zone’ model reproduces arrhythmias similar to those observed in vivo during experimental transient coronary artery occlusion11 12 or in humans during coronary transluminal angioplasty and after thrombolytic therapy.28 Thirdly, the study was performed on guinea-pig myocardium, which differs from human myocardium, although the main ionic currents involved are qualitatively similar in the two species. Fourthly, the ischaemic conditions used here are severe and did not allow extrapolation of our results to less severe ischaemic insults. Finally, an in vitro model, however complex, cannot reproduce the in vivo situation exactly but may provide important information for the clinicians.29
In conclusion, our study of guinea-pig ventricular muscle shows that clinically relevant concentrations of morphine reduced ischaemia-induced electrophysiological changes, decreased the occurrence of conduction block during simulated ischaemia, and decreased the incidence of reperfusion-induced arrhythmias.
|
Acknowledgements |
|---|
This work was supported by the University of Caen.
|
References |
|---|
|
TopAbstractIntroductionMaterial and methodsResultsDiscussionReferences |
|---|
1 Mangano DT, Browner WS, Hollenberg M, London MJ, Tubau JF, Tateo IM and the Study of Perioperative Ischemia Research Group. Association of perioperative myocardial ischemia with morbidity and mortality in men undergoing noncardiac surgery. N Engl J Med 1990; 323: 1781–8[Abstract]
2 Fryer RM, Hsu AK, Nagase H, Gross GJ. Opioid-induced cardioprotection against myocardial infarction and arrhythmias: mitochondrial versus sarcolemmal ATP-sensitive channels. J Pharmacol Exp Ther 2000; 294: 451–7
3 Liang BT, Gross GJ. Direct preconditioning of cardiac myocytes via opioid receptors and KATP channels. Circ Res 1999; 25: 1396–400
4 Bell S, Sack MN, Patel A, Opie LH, Yellon DM. Delta opioid receptor stimulation mimics ischemic preconditioning in human heart muscle. J Am Coll Cardiol 2000; 36: 2296–302
5 Gallagher JD. Electrophysiological mechanisms for ventricular arrhythmias in patients with myocardial ischemia: anesthesiologic considerations. Part 1. J Cardiothorac Vasc Anesth 1997; 11: 495–505[Web of Science][Medline]
6 Rouet R, Adamantidis M, Honore E, Dupuis B. In vitro abnormal repetitive responses in guinea pig ventricular myocardium exposed to combined hypoxia, hyperkalemia and acidosis. J Appl Cardiol 1989; 4: 19–29
7 Rouet R, Picard S, Libersa C, Ghadanfar M, Albaster C, Gerard JL. Electrophysiological effect of dofetilide in an in vitro model of ‘border zone’ between normal an ischemic/reperfused myocardium. Circulation 2000; 101: 86–93
8 Belichard P, Pruneau D, Rouet R, Salzmann JL. Electrophysiological responses of hypertrophied rat myocardium to combined hypoxia, hyperkalemia and acidosis. J Cardiovasc Pharmacol 1991; 17 (Suppl 2): S141–5[Medline]
9 Schiariti M, Puddu PE, Rouet R. Multivariate prediction of spontaneous repetitive response in ventricular myocardium exposed in vitro to simulated ischemic conditions. Int J Cardiol 1994; 45: 9–22[Web of Science][Medline]
10 Picard S, Rouet R, Monti F, et al. Proarrhythmic effects of DL- and D-sotalol on the ‘border zone’ between normal and ischemic regions of isolated ventricular myocardium and antiarrhythmic effects on reperfusion. J Cardiovasc Pharmacol 1998; 31: 26–39
11 Morena H, Janse MJ, Fiolet JWT, Krieger WJG, Crijns H, Durrer D. Comparison of the effects of regional ischemia, hypoxia, hyperkalemia and acidosis on intracellular and extracellular potentials and metabolism in isolated porcine heart. Circ Res 1980; 46: 634–46
12 Janse MJ, Cinca J, Morena H, et al. The ‘border zone’ in myocardial ischemia. An electrophysiologial, metabolic and histochemical correlation in pig heart. Circ Res 1979; 44: 576–88
13 Pasnani JS, Ferrier GR. Pro-and anti-arrhythmic effects of D-sotalol and DL-sotalol in an isolated tissue model of ischemia and reperfusion. J Pharmacol Exp Ther 1994; 271: 184–92
14 Janse MJ, Wit AL. Electrophysiological mechanism of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989; 69: 1049–169
15 Nawrath H, Rupp J, Jakob H, Sack U, Mertzlufft F, Dick W. Failure of opioids to affect excitation and contraction in isolated ventricular heart muscle. Experientia 1989; 45: 337–9[Web of Science][Medline]
16 Brasch H. Influence of the optical isomers (+)- and (–)-naloxone on beating frequency, contractile force and action potentials of guinea-pig isolated cardiac preparations. Br J Pharmacol 1986; 88: 733–40[Web of Science][Medline]
17 Hung CF, Tsai CH, Su MJ. Opioid receptor independent effects of morphine on membrane currents in single cardiac myocytes. Br J Anaesth 1998; 81: 925–31
18 Sarton E, Olofsen E, Romberg R, et al. Sex differences in morphine analgesia: an experimental study in healthy volunteers. Anesthesiology 2000; 93: 1245–54[Web of Science][Medline]
19 Wang GY, Wu S, Pei JM, Yu XC, Wong TM. K- but not -opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats. Am J Physiol 2001; 280: H384–91[Web of Science]
20 Sarne Y, Flitstein A, Oppenheimer E. Anti-arrhythmic activities of opioid agonists and antagonists and their stereoisomers. Br J Pharmacol 1991; 102: 696–8[Web of Science][Medline]
21 Coetzee WA. ATP-sensitive potassium channels and myocardial ischemia: why do they open? Cardiovasc Drug Ther 1992; 6: 201–8[Web of Science][Medline]
22 Cohen MV, Yang XM, Liu GS, Heusch G, Downey JM. Acetylcholine, bradykinin, opioids, and phenylephrine, but not adenosine, trigger preconditioning by generating free radicals and opening mitochondrial K(ATP) channels. Circ Res 2001; 89: 273–8
23 Murphy DB, Murphy MB. Opioid antagonist modulation of ischaemia-induced ventricular arrhythmias: a peripheral mechanism. J Cardiovasc Pharmacol 1999; 33: 122–5[Web of Science][Medline]
24 Yu XC, Wang HX, Pei JM, Wong TM. Anti-arrhythmic effect of k-opioid receptor stimulation in the perfused rat heart: Involvement of a cAMP-dependent pathway. J Mol Cell Cardiol 1999; 31: 1809–19[Web of Science][Medline]
25 Wong TM, Lee AY. Chronic morphine treatment reduces the incidence of ventricular arrhythmias in the isolated rat heart induced by dynorphin 1–13 or myocardial ischemia and reperfusion. Neurosci Lett 1987; 77: 61–5[Web of Science][Medline]
26 Pepe S, Xiao RP, Hohl C, Altschuld R, Lakatta EG. Cross talk between opioid peptide and adrenoceptor signaling in isolated rat heart. Circulation 1997; 95: 2122–9
27 Corr PB, Witowski FX. Potential electrophysiologic mechanisms responsible for dysrrhythmias associated with reperfusion of ischemic myocardium. Circulation 1983; 68: 16–24
28 Tzivoni D, Keren A, Granot H, Gottlieb S, Benhorin J, Stern S. Ventricular fibrillation caused by myocardial reperfusion in Printzmetal angina. Am Heart J 1983; 105: 323–5[Web of Science][Medline]
29 Rosen MR. The links between basic and clinical cardiac electrophysiology. Circulation 1988; 77: 251–63
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  J.-L. Hanouz, Y. Repesse, L. Zhu, S. Lemoine, R. Rouet, L. Salle, B. Plaud, and J.-L. Gerard The Electrophysiological Effects of Racemic Ketamine and Etomidate in an In Vitro Model of "Border Zone" Between Normal and Ischemic/Reperfused Guinea Pig Myocardium Anesth. Analg., February 1, 2008; 106(2): 365 - 370. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Bovill Intravenous Anesthesia for the Patient with Left Ventricular Dysfunction Seminars in Cardiothoracic and Vascular Anesthesia, March 1, 2006; 10(1): 43 - 48. [Abstract] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||