PT - JOURNAL ARTICLE AU - William E. Louch AU - Gregory R. Ferrier AU - Susan E. Howlett TI - Attentuation of Cardiac Stunning by Losartan in a Cellular Model of Ischemia and Reperfusion Is Accompanied by Increased Sarcoplasmic Reticulum Ca<sup>2+</sup> Stores and Prevention of Cytosolic Ca<sup>2+</sup> Elevation AID - 10.1124/jpet.104.072769 DP - 2005 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 238--247 VI - 312 IP - 1 4099 - http://jpet.aspetjournals.org/content/312/1/238.short 4100 - http://jpet.aspetjournals.org/content/312/1/238.full SO - J Pharmacol Exp Ther2005 Jan 01; 312 AB - 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+. The American Society for Pharmacology and Experimental Therapeutics