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CARDIOVASCULAR

Attentuation of Cardiac Stunning by Losartan in a Cellular Model of Ischemia and Reperfusion Is Accompanied by Increased Sarcoplasmic Reticulum Ca²⁺ Stores and Prevention of Cytosolic Ca²⁺ Elevation

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

This study investigates whether protective effects of an angiotensin II type 1 receptor antagonist (losartan) in ischemia and reperfusion are mediated by actions on Ca²⁺ cycling. Effects of exposure to losartan (10 µM) in ischemia were evaluated in isolated guinea pig ventricular myocytes exposed to simulated ischemia and reperfusion at 37°C. Field-stimulated myocytes were exposed to 30 min of simulated ischemia (hypoxia, acidosis, lactate, hyperkalemia, and glucose-free) and reperfusion with Tyrode's solution for 40 min. Cell shortening was measured with a video edge detector, and Ca²⁺ concentration was measured with fura-2. Field-stimulated myocytes exhibited stunning in reperfusion, which was abolished in cells exposed to losartan. In microelectrode studies, losartan did not alter the responses of resting potentials or action potentials to ischemia and reperfusion. In the absence of losartan, diastolic Ca²⁺ increased in ischemia, and Ca²⁺ transients exhibited a rebound overshoot in early reperfusion. Losartan did not affect amplitudes of Ca²⁺ transients in ischemia but prevented elevations in diastolic Ca²⁺ in ischemia. Furthermore, losartan prevented the overshoot of Ca²⁺ transients in early reperfusion and increased the magnitude of Ca²⁺ transients in late reperfusion. Sarcoplasmic reticulum (SR) Ca²⁺ stores, determined as Ca²⁺ released by rapid application of 10 mM caffeine, were not altered in ischemia and reperfusion. However, losartan increased SR Ca²⁺ stores in late reperfusion, even in cells that were not exposed to simulated ischemia. We conclude that losartan abolishes stunning in reperfusion by preserving normal diastolic Ca²⁺ in ischemia and by increasing Ca²⁺ transients through elevation of releasable SR Ca²⁺.

Address correspondence to: Dr. G. R. Ferrier, Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7. E-mail: gregory.ferrier{at}dal.ca

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