Effect of 8-week treatment with irbesartan of spontaneously hypertensive rats on the electrophysiologic alterations associated with the development of myocardial hypertrophy.

Cardiac hypertrophy due to pressure overload is associated with several cellular electrophysiological alterations such as prolongation of action potential duration, decrease in transient outward current (Ito) and occurrence of the pacemaker current If. These alterations may play a role in sudden arrhythmic death which is 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 old SHR with the AII receptor antagonist irbesartan (IRBE) was able to influence the in vitro electrophysiologic arrhythmogenic alterations associated with cardiac hypertrophy. Methods: 16 month-old SHR were treated with IRB (20 mg/Kg/die) or saline in the tap water for 8 weeks up to the age of 18 months. Systolic blood pressure (SBP) was measured with the tail-cuff technique, at the end of the 8-week treatment. SBP was 230±9 mmHg in control SHR (n=8) and 195±11 mmHg in IRBE-treated SHR (n=9) (p<0.05). Heart weight to body weight ratio (HW/BW), an index of myocardial hypertrophy, was 5.67±0.24 mg/Kg in control (n=11) and 4.61±0.16 mg/Kg in IRBE (n=10) (p<0.05). Left ventricular myocytes were enzymatically isolated from the hearts. Patch-clamped myocytes were superfused with a normal Tyrode's solution (to measure action potential) or appropriately modified Tyrode's solutions (to measure Ito and If). Results: membrane capacitance, an index of cell size, was significantly reduced in IRBE (241±11 pF, n=89) vs. CTR (281±11 pF, n=90, p<0.01). Action potential duration measured at both –20 or –60 mV was significantly shorter in IRBE than in CTR (at –20: 30±4 ms vs. 60±9 m; at -60 mV: 119±24 ms vs. 187±20 ms) (n=11, p<0.05). This effect was paralleled by a larger maximum Ito density in the IRB group (IRB:25.4±2.8 pA/pF, CTR: 18.5±1.5 pA/pF) (n=21, p<0.05). If, elicited by hyperpolarizing steps (range: -60 to -130 mV), was consistently recorded in SHR cells; however, its maximal specific conductance was significantly lower in IRB than in CTR rats (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 (CTR: 31.2±1.6 mV; IRBE: 34.0±1.0 mV) and If (CTR: -95.2±1.3 mV; IRBE: -97.6±1.4 mV) was unchanged by the treatment, being . Thus, AII receptor blockade with IRBE prevents the development of myocyte hypertrophy and associated electrophysiological alterations.