© 1999 American Heart Association, Inc.
Original Contribution |
Direct Preconditioning of Cardiac Myocytes via Opioid Receptors and KATP Channels
From the Department of Medicine (B.T.L.), Cardiovascular Division, University of Pennsylvania Medical Center, Philadelphia, and the Department of Pharmacology and Toxicology (G.J.G.), Medical College of Wisconsin, Milwaukee.
Correspondence to Bruce T. Liang, MD, 504 Johnson Pavilion, University of Pennsylvania Medical Center, 3610 Hamilton Walk, Philadelphia, PA 19104. E-mail liangb{at}mail.med.upenn.edu
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Abstract |
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Abstract—Previous studies demonstrated that opioid receptor activation mimics the cardioprotective effect of ischemic preconditioning via KATP channels in the intact heart. However, it is unknown whether this beneficial effect is exerted at the level of the cardiac myocyte or coronary vasculature or is mediated via the sarcolemmal or the mitochondrial KATP channel. Thus, the purpose of the present study was to investigate whether opioid receptor stimulation could mimic the cardioprotective effect of preconditioning in a cardiac myocyte model of simulated ischemia. Cardiac ventricular myocytes cultured from chick embryos 14 days in ovo were used as an in vitro model for ischemic preconditioning. A 5-minute exposure of the myocytes to the opioid receptor agonist morphine protected the myocytes during a subsequent 90-minute period of simulated ischemia, which was manifested as a pronounced reduction in the percentage of cardiac cells killed and the amount of creatine kinase released during ischemia. The preconditioning-like effect of morphine was concentration-dependent, reached a maximal effect at 1 µmol/L, and was reversed by naloxone (0.1 to 10 µmol/L). When KATP channel antagonists, such as glibenclamide, or the mitochondrial selective inhibitor 5-hydroxydecanoic acid were present during preexposure to morphine, they abolished the protective effect of morphine. Thus, cardiac myocytes express functional opioid receptors, and their activation mimics the cardioprotective effect of ischemic preconditioning. These results provide direct evidence that the preconditioning-like effect of morphine in the intact heart can be exerted at the level of cardiac myocytes and is most likely the result of mitochondrial KATP channel activation.
Key Words: myocyte • cardioprotection • receptor • morphine • channel
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Activation of opioid receptors has been shown to exert a protective effect in various organ systems during hypoxia or ischemia.1 2 Recent studies showed that the nonselective opioid receptor antagonist naloxone could abolish the cardioprotective effect of ischemic preconditioning (IPC) in rat3 and rabbit.4 Activation of opioid receptors by morphine can mimic the protective effect of IPC in the rat in a naloxone-reversible manner.5 In addition, this beneficial effect of morphine was abolished by the KATP channel antagonist glibenclamide, which suggests a role for an opioid receptor–KATP channel signaling pathway in mediating the cardioprotective effect of morphine.5
Although these studies provided important evidence for a protective function of opioids in the heart, it is unknown whether the beneficial effect of opioids such as morphine is exerted at the level of the central or the peripheral nervous systems or both. In addition, because opioid receptors are present on the vasculature and can mediate hypoxia-induced vasodilatation,6 it is possible that, in addition to the involvement of the nervous system, the vascular opioid receptor may also play a role in mediating the cardioprotective effect of morphine. Recent studies have shown that cardiac myocytes can be directly preconditioned by simulated ischemia,7 8 9 10 which suggests that the cardioprotective effect of IPC in the intact heart is exerted, at least partially, at the level of the cardiac myocytes. Thus, it is possible that the preconditioning-like effect of morphine in the intact animal is also mediated by opioid receptors on the cardiac myocyte.
Liang and colleagues7 8 9 10 have established a cardiac myocyte model of preconditioning that exhibits characteristics similar to those found in the intact heart model of IPC.5 Thus, the purpose of the present study was to investigate whether cardiac myocytes express functional opioid receptors and whether activation of these receptors can mimic the cardioprotective effect of IPC. Another objective was to elucidate the underlying cellular mechanism by determining whether the mitochondrial KATP channel is involved in mediating the preconditioning-like effect of opioid receptor stimulation by attempting to block this effect with the mitochondrial selective KATP channel inhibitor 5-hydroxydecanoic acid (5-HD).11
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Methods
Preparation and Preconditioning of Cultured Ventricular Cells
Cardiac ventricular myocytes were cultured from chick embryos 14 days in ovo, according to a previously described procedure.7 8 Myocytes were cultivated in a humidified 5% CO2/95% air mixture at 37°C for 3 days, during which time the cells grew to confluence and exhibited rhythmic spontaneous contraction. All experiments were performed on day 3 in culture. For preconditioning studies, the medium was changed to a HEPES-buffered medium that contained (in mmol/L) 139 NaCl, 4.7 KCl, 0.5 MgCl2, 0.9 CaCl2, 5 HEPES, and 2% fetal bovine serum, pH 7.4, before the cells were exposed to the various conditions at 37°C. Control cells were maintained in the HEPES-buffered media under room air. Ischemia was simulated by placing the cells in a hypoxic incubator (NuAire) in which O2 was replaced by N2. The percentage of O2 was monitored by both an oxygen gas analyzer (Fyrite, Bacharach) and an oxygen analyzer (model OX630, Engineered Systems and Designs) and was <1%.7 Preconditioning was induced by exposing the cells to 5 minutes of simulated ischemia, called IPC, before a second 90 –minutes of ischemia. To study the ability of the opioid receptor agonist morphine to mimic the protective effect of IPC, cells were exposed to different concentrations of morphine for 5 minutes and incubated in fresh drug-free media for 10 minutes before being exposed to 90 minutes of simulated ischemia. Cells not subjected to preconditioning were exposed only to 90 minutes of ischemia (nonpreconditioned cells). The extracellular pH was similarly maintained at 7.4 by HEPES in both preconditioned and nonpreconditioned cells. Determination of basal level of cell injury was made after parallel incubation of control cells under a normal percentage of O2. Cell injury was determined for all cells at the end of the 90-minute ischemia period.
Quantitative Determination of the Extent of Myocyte Injury
The extent of hypoxia-induced injury to the
ventricular cell was quantitatively determined by the
percentage of cells killed and the amount of creatine kinase (CK)
released into the media, according to previously described
methods.7 8 9 10 To quantify the percentage of cells killed,
cells were detached after exposure to a trypsin-EDTA Hanks balanced
salt solution for 10 minutes for detachment. Viable cells were
sedimented by centrifugation (300g for 10
minutes) and resuspended in culture media for counting in a
hemocytometer. Only the cells that were alive sedimented, and the cells
that were counted represented those that
survived.12 None of the sedimented cells subsequently
counted included trypan blue. Control experiments performed in previous
studies7 8 indicated that trypsin treatment, reexposure to
Ca2+-containing media, or 300g
sedimentation did not cause any significant damage to the control
normoxia-exposed cells. The trypsin-EDTA media from cells exposed to 90
minutes of hypoxia contained substantial amount of proteins
(0.15±0.03 mg, n=9) and CK activity (16±3 U/mg, n=8). Such proteins
and CK activity could arise from hypoxia-damaged cells that
failed to sediment because of lighter cellular density from the loss of
soluble proteins or from hypoxia-exposed cells that were
further damaged by the trypsin treatment. In either case, the cell
viability assay clearly separated the control healthy cells from the
hypoxia-exposed damaged cells. In support of the notion that
90-minute hypoxia caused significant cell injury and loss of
membrane integrity, there was also a marked release of LDH
(hypoxia-exposed cells, 35.5±2.7 U/mg, n=8, mean±SE versus
control cells, 6.1±0.4 U/mg, n=8) and proteins
(hypoxia-exposed cells, 0.15±0.03 mg, n=8, versus control
cells, 0.034±0.01 mg, n=8) from cells incubated under prolonged
hypoxia. Parallel changes in the amount of CK released into the
media and in the percentage of cells killed under every experimental
condition studied7 8 9 10 further validated the cell
viability assay. In support of the hypothesis that 90 minutes of
hypoxia caused significant cell injury and loss of membrane
integrity, there was also marked release of LDH and proteins from the
cells incubated under prolonged hypoxia.7 8 Thus,
the cell viability assay separated the hypoxia-damaged from the
control normoxia-exposed cells. Parallel changes in the percentage of
cells killed and CK released7 8 further validated this
assay for the percentage of cells killed. The amount of CK was measured
as enzyme activity (U/mg), and increases in CK activity above the
control level were determined. The percentage of cells killed was
calculated as the number of cells obtained from the control group
(representing cells not subjected to any hypoxia or
drug treatment) minus the number of cells from the treatment group
divided by number of cells in the control group multiplied by 100.
Materials
Morphine sulfate was obtained from A.H. Robins Co. Naloxone,
glibenclamide, and 5-HD were obtained from Research Biochemicals
International. Embryonated chick eggs were obtained from Spafas, Inc
(Storrs, Conn).
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Results |
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Opioid Receptor Activation Mimics the Protective Effect of IPC in Cardiac Myocytes
Simulated ischemia, which was induced by glucose deprivation and hypoxia, caused significant injury to the cardiac ventricular myocytes, as evidenced by the increased release of CK and the appearance of the cells killed (Figure 1
). Brief exposure to 5 minutes of
simulated ischemia, which does not injure the myocytes,
protected cardiac ventricular myocytes against
injury induced by the subsequent prolonged ischemia (Figure 1). These data are similar to those obtained previously in both
the cardiac myocyte model and the intact heart model of
preconditioning.5 7 8 A 5-minute exposure of the myocytes
to morphine sulfate (1 µmol/L) followed by a 10-minute drug-free
period also protected myocytes against injury during the subsequent
90-minute period of ischemia (Figure 1). There was a
significant reduction in the percentage of cells killed and the amount
of CK released in myocytes that were preexposed to morphine versus
myocytes that had not been exposed to morphine or to IPC
(nonpreconditioned; 1-way ANOVA and posttest
comparison, P<0.01). The extent of cardioprotection
achieved by the preconditioning-like effect of morphine was similar to
that induced by IPC (P>0.1).
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To examine the hypothesis that the preconditioning-like effect of
morphine sulfate is mediated by an opioid receptor on the cardiac
myocyte, the effect of morphine was further characterized. First,
previous exposure of the myocytes to various concentrations of morphine
resulted in a concentration-dependent cardioprotection, with a
reduction in the percentage of cells killed and in the amount of CK
released during the prolonged ischemia (Figure 2). Second, the nonselective opioid
receptor antagonist naloxone was able to block the
preconditioning-like effect of morphine in a concentration-dependent
manner. The concomitant presence of naloxone during myocyte exposure to
1 µmol/L morphine antagonized its protective effect during the
subsequent prolonged ischemia (Figure 3). Naloxone did not cause additional
myocyte injury when it was present during the 90-minute period of
simulated ischemia (Table).
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To identify the opioid receptor that mediates the
preconditioning-like effect of morphine, the ability of the
1-opioid receptor-selective
antagonist 7-benzylidenenaltrexone (BNTX) to block the
morphine effect was examined. Figure 4
shows that 10 µmol/L of BNTX reversed the morphine-induced
preconditioning-like effect in these cardiac myocytes when it was
present during the 5-minute exposure to morphine. These data are
consistent with the hypothesis that morphine mimics the
cardioprotective effect of IPC via activation of the
1-opioid receptor.
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Role of KATP Channels in the Preconditioning-Like
Effect Mediated by Morphine
To examine the signaling mechanism downstream of the opioid
receptor, we examined whether the KATP channel is
involved in the mediation of the preconditioning-like effect of
morphine. Concomitant presence of either glibenclamide or the
mitochondrial selective KATP channel
antagonist, 5-HD, during the 5-minute exposure to morphine
(1 µmol/L) blocked its cardioprotective effect during the
subsequent prolonged ischemia. This was manifested by an
increase in the percentage of cardiac cells killed (Figure 5) and in the amount of CK released (data
not shown) in the presence of the KATP channel
blockers. The antagonistic effect of the
KATP channel blockers was evident at
concentrations as low as 0.1 µmol/L and was complete at 10
µmol/L.
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The potency of 5-HD in blocking the preconditioning-like effect of morphine, in which a significant effect was observed at 0.1 µmol/L, is similar to the potency of glibenclamide. A previous study13 showed that 5-HD is less potent than glibenclamide. The reason for this difference is unclear but may relate to the possibility that the negatively charged 5-HD may have limited diffusion accessibility to the myocytes in the intact heart preparation.13 Alternately, the mitochondrial KATP channel in the embryonic chick myocyte may be more sensitive to the blockade by 5-HD than in the adult mammalian myocyte, in which 100 µmol/L 5-HD was required to attenuate the mitochondrial KATP channel activity.14 Additional studies in isolated myocytes and mitochondria are necessary to confirm this hypothesis directly.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The present data suggest that functional opioid receptors are present on the chick cardiac ventricular myocyte and that activation of these receptors by the nonselective opioid receptor agonist morphine can produce a preconditioning-like effect. Although the cardiac ventricular myocytes are isolated from chick embryos, extensive characterization of the chick myocyte model for IPC demonstrated that it exhibits characteristics similar to the adult mammalian model of preconditioning.7 8 9 10 Present data on the opioids and IPC in the chick myocyte are consistent with data recently published by Schultz et al5 and Miki et al15 in the intact rat and rabbit heart and by Xenopoulos et al16 in humans that underwent percutaneous transluminal coronary angioplasty (PTCA). These data suggest that the cardioprotective effect produced by morphine in vivo is at least partially mediated at the level of the cardiac myocyte. Miki et al15 found that 0.3 µmol/L of morphine, a concentration similar to that which is cardioprotective in the isolated myocyte (0.1 to 1.0 µmol/L), was equally cardioprotective to the effect of IPC in the isolated rabbit heart. In addition, a portion of the cardioprotective effect of morphine was lost at a higher concentration of 10 µmol/L, which suggests that this compound demonstrates a bell-shaped concentration-response curve. The reason for this finding is unclear, but it may be the result of stimulation of another opioid receptor at a higher concentration of morphine that antagonizes the protective effect mediated by another receptor at a lower concentration. The present data provide additional evidence to support the concept that the opioid-induced preconditioning effect in the whole animal is at least partially mediated at the level of the cardiac ventricular myocyte.
Because morphine is somewhat selective for the µ-opioid receptors as
opposed to - and 
-opioid receptors,17 it is possible
to assume that the effect observed in the present study may be
mediated via a µ-opioid receptor. However, recent data obtained by
Schultz et al18 19 20 suggest that this is not the case.
These investigators found that the -opioid receptor, more
specifically, the 1-receptor that acts via the
KATP channel, is responsible for the
cardioprotective effect of IPC in the intact rat heart and that the
-receptor mediates the cardioprotective effect of morphine. The
present data, which show that the 1-opioid
receptor-selective antagonist BNTX can block the
morphine-induced preconditioning, are consistent with the
hypothesis that activation of a 1-opioid
receptor also mediates this potentially important effect in the cardiac
myocyte.
In support of these data, Bell et al21 have recently shown
that the -receptor mediates the cardioprotective effect of the
peptide opioid agonist (D-Ala2, D-Leu5) enkephalin and also mediates
IPC in isolated human cardiac muscle. In a group of patients who
underwent PTCA, Xenopoulos et al16 found that
intracoronary administration of morphine mimicked the effect of
IPC, thus demonstrating the cardioprotective efficacy of opioid
receptor activation in humans. Combined, the data on the cardiac
myocyte, intact heart, and patients suggest that an opioid receptor or
an opioid receptor subtype may represent a new target for the
development of novel therapeutics in the treatment of patients who
undergo coronary artery bypass surgery or PTCA.
Previous studies with morphine have demonstrated an interaction of opioid receptors and KATP channels in other organ systems as well. Kang et al22 and Robles et al23 have shown that antinociception produced by morphine or morphine withdrawal could be blocked or prevented by glibenclamide, respectively. In agreement, Raffa and Martinez24 found that glibenclamide antagonized the antinociceptive effect of several opioid agonists such as morphine and methadone but not fentanyl citrate or ß-endorphin, which indicated some selectivity of certain opioids in transducing their effects via the KATP channel. The present results, which show that the KATP channel is a downstream effector from the opioid receptor, extend these previous findings and are the first to demonstrate a signaling pathway that involves opioid receptors and KATP channels at the level of the ventricular myocyte.
Recent studies have suggested the involvement of a mitochondrial
KATP channel in the mediation of the
cardioprotective effect of KATP channel
openers11 25 and possibly IPC.14 These claims
are based on the relative selectivity shown for the
KATP channel opener diazoxide for activating
mitochondrial KATP channels at an 
1000-fold
lower concentration than that necessary to open the sarcolemmal
channel25 and on the observation that 5-HD blocked the
opening of the mitochondrial KATP channel,
although it had no effect on the sarcolemmal channel.11
The current data, which show that the mitochondrial selective blocker
5-HD abolishes the cardioprotective effect of morphine at low
concentrations (1 to 10 µmol/L), imply that the mitochondrial
KATP channel is the likely distal effector in
this response. Although the KATP channel blockers
were present during only the 5-minute exposure to morphine, the
protection induced by their preconditioning-like effect was completely
abolished. These data raised the possibility that activation of the
channel is important in initiating the morphine-mediated
preconditioning process. Alternatively, the channel blocker may remain
bound to its intracellular mitochondrial site during the subsequent
simulated ischemia and thus abolish the cardioprotection. Proof
of this concept requires additional study.
It is unknown whether protein kinase C (PKC) plays a role in the mediation of the preconditioning-like effect of morphine in these cardiac myocytes. Miki et al15 showed that PKC is an important downstream effector in mediating the preconditioning effect of opioids in the intact rabbit heart. It is possible that PKC also acts downstream from the opioid receptor to cause the cardioprotective effect of morphine in the cardiac myocyte. The relationship between PKC and the KATP channel in the mediation of the morphine effect in the myocyte is unknown. These important questions deserve additional investigation.
In summary, these studies are the first to demonstrate a cardioprotective effect of opioid receptor activation in isolated cardiac myocytes exerted by morphine. Because the nonselective antagonist naloxone blocked the cardioprotective effect of morphine at relatively low concentrations, this suggested that this was an opioid receptor–mediated event. However, the subtype of the opioid receptor involved and the intracellular signaling pathways that lead from the receptor to the mitochondrial KATP channel in the mediation of the preconditioning-like effect of morphine and other opioids remain unknown but deserve further investigation.
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Acknowledgments |
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This study was supported by an Established Investigatorship from the American Heart Association and by grants R01-HL-48225 (B.T.L.) and R01-HL-08311 (G.J.G.) from the National Institutes of Health.
Received December 18, 1998; accepted April 9, 1999.
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G. Lebuffe, P. T. Schumacker, Z.-H. Shao, T. Anderson, H. Iwase, and T. L. Vanden Hoek ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel Am J Physiol Heart Circ Physiol, January 1, 2003; 284(1): H299 - H308. [Abstract] [Full Text] [PDF]
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K. Shinmura, M. Nagai, K. Tamaki, M. Tani, and R. Bolli COX-2-derived prostacyclin mediates opioid-induced late phase of preconditioning in isolated rat hearts Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2534 - H2543. [Abstract] [Full Text] [PDF]
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E. Kodani, Y.-T. Xuan, K. Shinmura, H. Takano, X.-L. Tang, and R. Bolli delta -Opioid receptor-induced late preconditioning is mediated by cyclooxygenase-2 in conscious rabbits Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1943 - H1957. [Abstract] [Full Text] [PDF]
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R. Domenech, P. Macho, H. Schwarze, and G. Sanchez Exercise induces early and late myocardial preconditioning in dogs Cardiovasc Res, August 15, 2002; 55(3): 561 - 566. [Abstract] [Full Text] [PDF]
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H. Y. Zhang, B. C. McPherson, H. Liu, T. Baman, S. S. McPherson, P. Rock, and Z. Yao Role of Nitric-Oxide Synthase, Free Radicals, and Protein Kinase C delta in Opioid-Induced Cardioprotection J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 1012 - 1019. [Abstract] [Full Text] [PDF]
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H. Liu, H. Y. Zhang, X. Zhu, Z. Shao, and Z. Yao Preconditioning blocks cardiocyte apoptosis: role of KATP channels and PKC-epsilon Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1380 - H1386. [Abstract] [Full Text] [PDF]
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K. Mubagwa and W. Flameng Adenosine, adenosine receptors and myocardial protection: An updated overview Cardiovasc Res, October 1, 2001; 52(1): 25 - 39. [Abstract] [Full Text] [PDF]
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R. Carroll, V. A Gant, and D. M Yellon Mitochondrial KATP channel opening protects a human atrial-derived cell line by a mechanism involving free radical generation Cardiovasc Res, September 1, 2001; 51(4): 691 - 700. [Abstract] [Full Text] [PDF]
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J.-J. Zhou, J.-M. Pei, G.-Y. Wang, S. Wu, W.-P. Wang, C.-H. Cho, and T.-M. Wong Inducible HSP70 mediates delayed cardioprotection via U-50488H pretreatment in rat ventricular myocytes Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H40 - H47. [Abstract] [Full Text] [PDF]
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R. Schulz, P. Gres, and G. Heusch Role of endogenous opioids in ischemic preconditioning but not in short-term hibernation in pigs Am J Physiol Heart Circ Physiol, May 1, 2001; 280(5): H2175 - H2181. [Abstract] [Full Text] [PDF]
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R. M. Fryer, Y. Wang, A. K. Hsu, and G. J. Gross Essential activation of PKC-{delta} in opioid-initiated cardioprotection Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1346 - H1353. [Abstract] [Full Text] [PDF]
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B. C. McPherson and Z. Yao Morphine Mimics Preconditioning via Free Radical Signals and Mitochondrial KATP Channels in Myocytes Circulation, January 16, 2001; 103(2): 290 - 295. [Abstract] [Full Text] [PDF]
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J. Huh, G. J. Gross, H. Nagase, and B. T. Liang Protection of cardiac myocytes via {delta}1-opioid receptors, protein kinase C, and mitochondrial KATP channels Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H377 - H383. [Abstract] [Full Text] [PDF]
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G.-Y. Wang, S. Wu, J.-M. Pei, X.-C. Yu, and T.-M. Wong {kappa}- but not {delta}-opioid receptors mediate effects of ischemic preconditioning on both infarct and arrhythmia in rats Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H384 - H391. [Abstract] [Full Text] [PDF]
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 A. T. SAURIN, J. L. MARTIN, R. J. HEADS, C. FOLEY, J. W. MOCKRIDGE, M. J. WRIGHT, Y. WANG, and M. S. MARBER The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes FASEB J, November 1, 2000; 14(14): 2237 - 2246. [Abstract] [Full Text]
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T. Pain, X.-M. Yang, S. D. Critz, Y. Yue, A. Nakano, G. S. Liu, G. Heusch, M. V. Cohen, and J. M. Downey Opening of Mitochondrial KATP Channels Triggers the Preconditioned State by Generating Free Radicals Circ. Res., September 15, 2000; 87(6): 460 - 466. [Abstract] [Full Text] [PDF]
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R. R. Morrison, R. Jones, A. M. Byford, A. R. Stell, J. Peart, J. P. Headrick, and G. P. Matherne Transgenic overexpression of cardiac A1 adenosine receptors mimics ischemic preconditioning Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1071 - H1078. [Abstract] [Full Text] [PDF]
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R. M. Fryer, A. K. Hsu, H. Nagase, and G. J. Gross Opioid-Induced Cardioprotection against Myocardial Infarction and Arrhythmias: Mitochondrial versus Sarcolemmal ATP-Sensitive Potassium Channels J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 451 - 457. [Abstract] [Full Text]
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M. S. Marber Ischemic Preconditioning in Isolated Cells Circ. Res., May 12, 2000; 86(9): 926 - 931. [Full Text] [PDF]
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Y. Takasaki, R. A. Wolff, G. L. Chien, and D. M. van Winkle Met5-enkephalin protects isolated adult rabbit cardiomyocytes via delta -opioid receptors Am J Physiol Heart Circ Physiol, December 1, 1999; 277(6): H2442 - H2450. [Abstract] [Full Text] [PDF]
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