Long-term treatment of spontaneously hypertensive rats with irbesartan influences cellular electrophysiologic remodeling associated with the development of myocardial hypertrophy.

Electrophysiologic remodeling (prolongation of action potential duration, decrease in transient outward current Ito, and occurrence of the pacemaker current If) in hypertrophied or failing ventricular myocytes is likely implicated in the increased propensity to arrhythmias in these settings. Angiotensin II (AII) is a key signal for myocyte hypertrophy; we tested the effect of 8-week treatment with irbesartan (IRB), a type-1 AII receptor antagonist, on hypertrophy-induced electrophysiologic remodeling. 16 month-old hypertensive rats (SHR) were treated with IRB (20 mg/Kg/die) or saline for 8 weeks. At the end of treatment, systolic blood pressure, measured with the tail-cuff technique, was 230±9 mmHg in control (n=8) and 195±11 mmHg in IRB-treated SHR (n=9) (p<0.05); heart weight to body weight ratio was 5.67±0.24 mg/Kg in control (n=11) and 4.61±0.16 mg/Kg in IRB group (n=10) (p<0.05). Myocytes enzymatically isolated from the left ventricle, were patch-clamped and 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 IRB (241±11 pF, n=89) vs control (281±11 pF, n=90, p<0.01). Action potential duration measured at -20 or -60 mV was significantly shorter in IRB than in control (at -20: 30±4 ms vs 60±9 ms; at -60 mV: 119±24 ms vs. 187±20 ms) (n=11, p<0.05). Peak Ito density was larger in the IRB group (25.4±2.8 pA/pF) than in control (18.5±1.5 pA/pF) (n=21, p<0.05). If was consistently recorded applying hyperpolarizing steps (range: -60 to -130 mV); maximal specific conductance was significantly lower in IRB group than in control (24.8±3.0 pS/pF, n=36 vs 35.2±4.0 pS/pF, n=27, p<0.05). Voltage of half-maximal activation of both Ito (control: 31.2±1.6 mV; IRB: 34.0±1.0 mV) and If (control: -95.2±1.3 mV; IRB: -97.6±1.4 mV) was unchanged by the treatment. Thus, AII receptor blockade with IRB prevents the development of myocyte hypertrophy and associated electrophysiological alterations.