PRETREATMENT WITH ENDOTHELIN-1 MIMICS ISCHEMIC PRECONDITIONING AGAINST INFARCTION IN ISOLATED RABBIT HEART

We have proposed that ischemic preconditioning in rabbit hearts is ini tiated by adenosine receptor stimulation resulting in activation of pr otein kinase C. If this theory is correct then any agonist which can a ctivate PKC should also put the heart into a preconditioned state. Thi s study sought to determine whether endothelin-1 (ET-1), which is know n to activate protein kinase C, can also mimic ischemic preconditionin g. Isolated rabbit hearts experienced 30 min of regional ischemia foll owed by 120 min of reperfusion. Infarct size was measured with triphen yltetrazolium chloride. In control hearts infarction was 30.3 +/- 2.5% of the risk zone. Preconditioning with 5 min global ischemia and 10 m in reperfusion reduced infarct size to 5.6 +/- 0.7% (P<0.01). Perfusio n with either 10 pM ET-1 at constant coronary artery flow for 5 min in lien of ischemia or 50 pM ET-1 with 10 nM nicardipine to block the fo rmer's coronary constrictive effect was quite protective and equipoten t with preconditioning, Infarction averaged 7.2 +/- 0.8% and 5.8 +/- 1 .7% of the risk zone, respectively. This protection could be blocked b y PD 156 707 (10 mu M), a highly specific endothelin receptor antagoni st, Chelerythrine (5 mu M), a PKC inhibitor, also aborted protection ( 22.0 +/- 1.7% infarction). However, 8-(p-sulfophenyl)theophylline (100 mu M), an adenosine receptor blocker, given during ET-1 administratio n did not block ET-1's protective effect indicating that adenosine was not involved in the effect, PD 156 707 failed to block the protection from ischemic preconditioning (12.6 +/- 2.3% infarction) revealing th at endothelin is not an important physiological mediator of ischemic p reconditioning. We conclude that ET-1 can mimic ischemic preconditioni ng in isolated rabbit hearts as would be predicted since its receptors are PKC-coupled, but that endogenous endothelin contributes little to ischemic preconditioning. (C) 1996 Academic Press Limited