Differential effects of opioid peptides on myocardial ischemic tolerance.
BACKGROUND
Opioid peptides, which can induce mammalian hibernation, may provide protection against subcellular and molecular changes during hypothermic myocardial ischemia. This study examined the differential effects of the three known myocyte opioid receptors, Mu (micro), Delta (delta), and Kappa (kappa), in augmenting myocardial ischemic tolerance.


METHODS
Control hearts (CH) were compared to hearts pretreated with either the micro-agonist, fentanyl, the delta-agonist, DADLE, or delta-antagonist, NTB, or the kappa-agonist, U50488H (U50), or kappa-antagonist, nor-BNI. The percent return of isovolemic developed pressure (LVDP), myocardial oxygen consumption (MVO(2)), and coronary flow (CF) following 2 h of global hypothermic cardioplegic ischemia were recorded in isolated Langendorff perfused hearts.


RESULTS
At 45 min of reperfusion, hearts pretreated with either DADLE or U50488H demonstrated significantly improved functional recovery versus controls (P < 0.05) and significantly depressed recovery with NTB or nor-BNI pretreatment (P < 0.05). Pretreatment with fentanyl was not significantly different than controls. Furthermore, DADLE, U50488H, or fentanyl resulted in increased MVO(2) versus controls (P < 0.05). There was no difference in CF between all groups.


CONCLUSIONS
This study demonstrates that the micro-receptor does not appear to confer a beneficial effect. However, selective delta- and kappa-agonists provide significant myocardial protection. Moreover, hearts pretreated with an opioid antagonist showed a marked decrement in both functional and metabolic integrity. These results taken together would imply a positive and negative constitutive role of delta- and kappa-opioids in the regulation of myocardial ischemic tolerance. This utilization of opioid receptor stimulation may have profound clinical applications.
Romano
Matthew A
MA
Division of Cardiac Surgery, University of Michigan, Ann Arbor 48105-0348, USA.
McNish
Robert
R
Seymour
Elisabeth M
EM
Traynor
John R
JR
Bolling
Steven F
SF
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000222:Adaptation, Physiological / Q000187:drug effects*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D005283:Fentanyl / Q000494:pharmacology; D006321:Heart / Q000503:physiopathology; D066298:In Vitro Techniques; D008854:Microscopy, Electron; D017202:Myocardial Ischemia / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018847:Opioid Peptides / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D020127:Recovery of Function
D002316:Cardiotonic Agents; D018847:Opioid Peptides; D016308:Enkephalin, Leucine-2-Alanine; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D005283:Fentanyl