Opioid receptor stimulation acts as mediator of protection in ischaemic preconditioning.
Involvement of the opioid receptors in preconditioning-induced protection has recently been described. The aims of this study were to establish whether: (i) opioid receptor stimulation acts as a trigger ( during the preconditioning protocol) or as a mediator ( during sustained ischaemia) of cardioprotection using either morphine or [D-ala(2), D-leu(5)] enkephalin (DADLE), a synthetic delta-opioid receptor agonist; ( ii) the beneficial effects of DADLE are protein kinase C ( PKC) -mediated; and (iii) inhibitory 'cross-talk' occurs between the beta-adrenergic and phosphatidylinositol pathways activated by release of endogenous catecholamines and opioids respectively during sustained ischaemia. The isolated, perfused working rat heart, subjected to 25 minutes' global ischaemia and 30 minutes' reperfusion, was used as the experimental model. The results showed that delta-opioid receptor stimulation with DADLE (10(-8) M), when administered for 3 x 5 minutes, had no effect, while when given 10 minutes before sustained ischaemia the drug significantly improved functional recovery during reperfusion. This indicates that opioid receptor stimulation acts as a mediator rather than a trigger in the protection elicited. Morphine ( 3 x 10(-7)) when administered in the same manner was without effect. Opioid receptor stimulation caused a marked reduction in the beta -adrenergic response to isoproterenol, indicating inhibitory cross-talk between the phosphatidyl-inositol and beta-adrenergic signal transduction pathways. However, reduction of the beta-adrenergic response to ischaemia does not appear to be the mechanism of opioid-induced protection, as indicated by 3',5' -cyclic adenosine monophosphate (cAMP) levels at the end of 25 minutes' global ischaemia. Opioid receptor-mediated protection against ischaemic damage is PKC-dependent, since DADLE-induced protection could be abolished by the inhibitor chelerythrine.
Genade
S
S
Department of Medical Physiology and Biochemistry, University of Stellenbosch and Medical Research Council Experimental Biology Programme, Tygerberg, Western Cape, South Africa.
Moolman
J A
JA
Lochner
A
A
D000318:Adrenergic beta-Agonists / Q000008:administration & dosage; D000470:Alkaloids; D000818:Animals; D001426:Bacterial Proteins / Q000187:drug effects; D053119:Benzophenanthridines; D001794:Blood Pressure / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D016308:Enkephalin, Leucine-2-Alanine / Q000008:administration & dosage / Q000819:agonists / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006460:Hemolysin Proteins; D019157:Ischemic Preconditioning, Myocardial; D007545:Isoproterenol / Q000008:administration & dosage; D008297:Male; D009020:Morphine / Q000008:administration & dosage / Q000819:agonists; D009270:Naloxone / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D009292:Narcotic Antagonists / Q000008:administration & dosage; D010617:Phenanthridines / Q000008:administration & dosage / Q000037:antagonists & inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000187:drug effects; D011493:Protein Kinase C / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000008:administration & dosage* / Q000819:agonists*; D020127:Recovery of Function / Q000187:drug effects; D012039:Regional Blood Flow / Q000187:drug effects; D015424:Reperfusion / Q000379:methods; D013268:Stimulation, Chemical
D000318:Adrenergic beta-Agonists; D000470:Alkaloids; D001426:Bacterial Proteins; D053119:Benzophenanthridines; C039092:CAMP protein, Streptococcus; D004791:Enzyme Inhibitors; D006460:Hemolysin Proteins; D009292:Narcotic Antagonists; D010617:Phenanthridines; D011957:Receptors, Opioid; D009270:Naloxone; D016308:Enkephalin, Leucine-2-Alanine; D009020:Morphine; C016299:chelerythrine; D017853:Phosphotransferases (Alcohol Group Acceptor); C051038:Inositol 1,4,5-trisphosphate 3-kinase; D011493:Protein Kinase C; D007545:Isoproterenol