PRETREATMENT WITH ANGIOTENSIN-II ACTIVATES PROTEIN-KINASE-C AND LIMITS MYOCARDIAL-INFARCTION IN ISOLATED RABBIT HEARTS

We have proposed that ischemic preconditioning in the rabbit heart is initiated by adenosine A(1) receptor stimulation which results in an upregulation of protein kinase C (PI(C), Subsequent sustained ischemia then causes renewed stimulation of adenosine A(1) receptors with rapid reactivation of PKC and phosphorylation of a target protein(s) which mediates the protection, If the above theory is correct then angiotensin II (AII) receptor stimulation, which is known to activate PKC, should also protect the heart. Isolated rabbit hearts were subjected to 30 min of regional ischemia and 2 h of reperfusion. Infarct size was determined by tetrazolium staining. Pretreating hearts with 100 mM AII for 5 min, followed by 10 min of drug-free perfusion prior to the prolonged ischemia limited infarction (7.2 +/- 2.0% of the risk area v 31.1 +/- 3.4% in control animals, P<0.01). This protection could be blocked by the AT(1) receptor blocker losartan (10 mu M), but not by the AT(2) receptor blocker PD 123319 (10 mu m). Polymyxin B (50 mu M), a PI(C inhibitor, also blocked the protective effect of All. These observations demonstrated that activation of PKC by AT(1) receptor stimulation prior to ischemia does mimic ischemic preconditioning. Following AII infusion, administration, during the SO min ischemic period, of either SPT [8-(p-sulfophenyl)theophylline] (an adenosine receptor blocker) or losartan failed to block AII's protective effect. However, co-administration of SPT and losartan did abort All's protection suggesting that AII may not be completely washed out during the 10 min drug-free perfusion allowing residual agonist to reactivate PI(C during the 30 min ischemia even when adenosine receptors are blocked. Thus, if only one of the receptors (AT(1), or adenosine) were activated during the ischemic period, protection would occur. We conclude that activation of PKC by AII, prior to ischemia, can limit; myocardial infarction. While PKC must be reactivated during ischemia to realize protection, the specific receptor type initiating reactivation is not crucial.