Effect of treatment of hypertensive rats with losartan on cardiac cellular electrophysiology.

Cardiac hypertrophy due to pressure overload is associated with cellular electrophysiological alterations such as prolongation of action potential duration (APD), decrease in transient outward current (Ito) and occurrence of the pacemaker current If (Cerbai et al., 1994; 1996). These alterations may play a role in sudden arrhythmic death, a major risk factor in myocardial hypertrophy and failure. Since angiotensin II (AII) is a key signal for myocyte hypertrophy, we tested if a 8-week treatment of 16-month old spontaneously hypertensive rats (SHR) with the AII receptor antagonist losartan (10 mg/Kg/die) could influence the development of cellular electrophysiological alterations associated with cardiac hypertrophy. Left ventricular myocytes (LVM) were isolated from control (CTR) or losartan-treated (LOS) rats. Patch-clamped LVM were superfused with a normal Tyrode's solution (to measure action potential) or appropriately modified Tyrode's solutions (to measure Ito and If). Membrane capacitance, an index of cell size, was significantly reduced in LOS (342±12, n=92) vs. CTR (422±14 pF, n=96, p<.001). APD was significantly shorter in LOS than in CTR (at -60 mV: 197±23 ms vs. 277±19 ms, n=28, p<0.001) and maximum Ito density was larger in the LOS group (LOS:15±1 pA/pF, CTR:10±1 27, p<.02). If, elicited by hyperpolarizing steps was consistently recorded in SHR cells; however, its maximal conductance was significantly lower in LOS than in CTR (29±4 pS/pF vs. 54±8 55, p<.001). Voltage of half-maximal activation of both Ito and If was unchanged by the treatment. Thus, AII receptor blockade prevents the development of myocyte hypertrophy and associated electrophysiological alterations.