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.
This study investigates whether protective effects of an angiotensin II type 1 receptor antagonist (losartan) in ischemia and reperfusion are mediated by actions on Ca(2+) cycling. Effects of exposure to losartan (10 microM) in ischemia were evaluated in isolated guinea pig ventricular myocytes exposed to simulated ischemia and reperfusion at 37 degrees 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 Ca(2+) 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 Ca(2+) increased in ischemia, and Ca(2+) transients exhibited a rebound overshoot in early reperfusion. Losartan did not affect amplitudes of Ca(2+) transients in ischemia but prevented elevations in diastolic Ca(2+) in ischemia. Furthermore, losartan prevented the overshoot of Ca(2+) transients in early reperfusion and increased the magnitude of Ca(2+) transients in late reperfusion. Sarcoplasmic reticulum (SR) Ca(2+) stores, determined as Ca(2+) released by rapid application of 10 mM caffeine, were not altered in ischemia and reperfusion. However, losartan increased SR Ca(2+) 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 Ca(2+) in ischemia and by increasing Ca(2+) transients through elevation of releasable SR Ca(2+).
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada B3H 4H7.
William E
WE
Louch
Gregory R
GR
Ferrier
Susan E
SE
Howlett
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008564:Membrane Potentials / Q000187:drug effects; D008954:Models, Biological; D009200:Myocardial Contraction / Q000187:drug effects*; D017202:Myocardial Ischemia / Q000473:pathology; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D017682:Myocardial Stunning / Q000517:prevention & control; D009206:Myocardium / Q000473:pathology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D019808:Losartan; D002118:Calcium