Long-term treatment of spontaneously hypertensive rats with losartan and electrophysiological remodeling of cardiac myocytes

Objective: Cardiac hypertrophy due to pressure overload is associated with several cellular electrophysiological alterations such as prolongation of action potential duration (APD), decrease in transient outward current (I-to) and occurrence of the pacemaker current I-f. These alterations may play a role in sudden arrhythmic death, which is a major risk factor in myocardial hypertrophy and failure. Since angiotensin LI is a key signal for myocyte hypertrophy, we tested if an 8-week treatment of old spontaneously hypertensive rats (SHR) with the antagonist of type-1 angiotensin II receptor (AT(1)), losartan (10 mg/kg/day), was able to influence the cellular electrophysiologic remodeling associated with cardiac hypertrophy. Methods: Left ventricular myocytes were isolated from control (CTR) or losartan-treated (LOS) 18-month old SHR. Patch-clamped LVM were superfused with a normal Tyrode's solution (to measure action potential) or appropriately modified Tyrode's solution (to measure I-to and I-f). Results: Heart weight to body weight ratio (HW/BW) was significantly smaller in LOS (5.69+/-0.25 mg/g) than in CTR rats (6.67+/-0.37 mg/g; P<0.05). Membrane capacitance, an index of cell size, was significantly reduced in LOS (342+/-12, n=92) vs. CTR (422+/-14 pF, n=96, P<0.001). APD was significantly shorter in LOS than in CTR (at -60 mV: 197+/-23 vs. 277+/-19 ms, n=28, P<0.001); this effect was paralleled by a larger maximum I-to density in the LOS group (LOS: 15.1+/-1.4 pA/pF, CTR: 10.0+/-0.8 pA/pF) (n=27, P<0.02). I-f, elicited by hyperpolarizing steps (range: -60 to -130 mV), was consistently recorded in SHR cells; however, its maximal specific conductance was significantly lower in LOS than in CTR rats (28.6+/-3.6 vs. 54.2+/-8.0 pS/pF, n=55, P<0.001). Voltage of half-maximal activation (V-1/2) Of both I-to and I-f was unchanged by the treatment. Conclusions: AT(1) receptor blockade with losartan prevents the development of myocyte hypertrophy and associated electrophysiological alterations in old SHR. (C) 2000 Elsevier Science B.V. All rights reserved.