Losartan improves recovery of contraction and inhibits transient inward current in a cellular model of cardiac ischemia and reperfusion.
Losartan, a selective angiotensin II (AII) type I receptor antagonist, may protect against myocardial stunning and arrhythmia in ischemia and reperfusion. To examine the cellular basis for these protective actions, we studied effects of losartan and AII on contractile and electrical activity of ventricular myocytes exposed to simulated ischemia and reperfusion. Ionic currents were measured with voltage-clamp techniques and contractions were measured with a video edge detector. After 10 min of superfusion with Tyrode's solution at 37 degrees C, cells were exposed to simulated ischemia (hypoxia, acidosis, hyperkalemia, hypercapnia, lactate accumulation, and substrate deprivation) for 30 min followed by 25 min of reperfusion with normal Tyrode's solution. During ischemia, drug-treated cells were exposed to either 0.1 microM AII, 10 microM losartan, or both simultaneously. In reperfusion, contractions were depressed to 42% of preischemic levels in untreated cells. Losartan treatment significantly improved contractile recovery to 84% (P <. 05) of preischemic levels. AII-treated cells showed contractile recovery similar to untreated cells (40%), whereas cells treated with losartan plus AII recovered to 101% of preischemic levels. Cells exposed to losartan or losartan plus AII also exhibited reduced incidence of transient inward current (I(TI)) (20%, P <.05; 36%) relative to untreated cells (60%). However, I(TI) incidence was not altered by treatment with AII alone (57%). Treatment with exogenous agonist did not potentiate contractile depression or I(TI) incidence, and losartan exerted protective effects in the presence and absence of AII. Thus, losartan may have effects that are independent of AII receptor blockade.
Louch
W E
WE
Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
Ferrier
G R
GR
Howlett
S E
SE
D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000502:physiology; D020747:Calcium Channels, T-Type / Q000502:physiology*; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D017682:Myocardial Stunning / Q000188:drug therapy / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2
D057911:Angiotensin Receptor Antagonists; D000889:Anti-Arrhythmia Agents; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020747:Calcium Channels, T-Type; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D019808:Losartan