EFFECTS OF ANGIOTENSIN-II ON INTRACELLULAR CALCIUM AND CONTRACTURE INMETABOLICALLY INHIBITED CARDIOMYOCYTES

Angiotensin II (A-ll) is known to potentiate ischemic dysfunction duri ng ischemia, but the mechanisms involved are not completely establishe d. We examined the effects of A-ii on intracellular calcium concentrat ion ([Ca++](i)) and cell contracture caused by metabolic inhibition in isolated adult rabbit ventricular myocytes. [Ca++](i) was assessed by flow cytometry, using the Ca++-sensitive fluorescent probe, fluo-3. A fter 90 min of exposure to 2 mM cyanide (CN) and 0 glucose, there was a significant increase in myocyte [Ca++](i). This increase was slightl y augmented in the presence of 100 nM A-ii. In the presence of partial Na+/K+ ATP pump inhibition ([K+](o) = 0.8 mM), there was a more signi ficant increase in [Ca++](i) associated with exposure to CN+A-II vs. C N alone. Similar results were obtained with CN plus 2-deoxyglucose, an d the effect of A-ii was inhibited by 10 mu M 5-(N-ethyl-N-isopropyl)a miloride. Myocytes exposed to 2 mM CN and 0 glucose gradually develope d contracture over a 3-hr period. Addition of 100 nM A-ii significantl y (P < .01) enhanced loss of rod shape morphology during 3 hr of CN ex posure. Partial inhibition of the Na+ pump by exposure to 0.8 mM K+ ha d no effect on myocyte survival in the absence of CN, but augmented th e harmful effect of A-ii on cell contracture caused by CN exposure. Th is effect of A-ii was completely reversed by the addition of 1 mM amil oride, a Na+/H+ exchange inhibitor. We conclude that A-ii directly enh ances cell injury during CN exposure in isolated rabbit ventricular my ocytes. We postulate that this effect of A-it is mediated by stimulati on of Na+/H+ exchange with resultant increased [Na+](i) and subsequent [Ca++](i) loading, possibly via reverse Na+/Ca++ exchange.