Chronic treatment of old hypertensive rats with irbesartan restores the electrophysiological and contractile properties of ventricular myocytes.

Action potential duration prolongation (APD), due to a decreased transient outward current Ito, and occurrence of the pacemaker current If are features of hypertrophied ventricular myocytes (VMs). In these cells, twitch shows a prolonged relaxation phase, due to impaired excitation-contraction coupling mechanisms. These alterations may be arrhythmogenic in myocardial hypertrophy and failure. Angiotensin II, through stimulation of AT1-receptors, play an important role in the progression of myocardial hypertrophy. We tested the effect of an 8-week treatment with irbesartan (IRBE), an AT1-antagonist, on electrophysiologicremodeling and contractility of left VMs from old hypertensive rats (SHR). 16-month-old SHR were given IRBE (20 mg/Kg/day n=10) or saline (CTR, n=11) for 8 weeks in tap water. Electrical activity (APD, If, Ito) or shortening were measured (1,2). Membrane capacitance, an index of cell hypertrophy, was significantly reduced in IRBE vs. CTR (241±11 vs. 281±11 pF, p<0.01). APD was shorter in IRBE vs. CTR (119±24 vs. 187±20 ms, p<0.05), due to Ito restoration. Oppositely, If density was significantly lower in IRBE than in CTR. VMs plated on laminin-covered dishes were electrically stimulated (0.8 Hz), in the absence or presence of isoprenaline (ISO). While basal peak shortening was similar in the two groups, relaxation rate (RR) was significantly slower in CTR (5.7±0.3 s-1) than in IRBE (7.3±0.5 s-1) (p<0.05). This difference persisted in 5 nM ISO, which significantly speeded up RR in IRBE (8.9±0.6 s-1) but not in CTR (5.9±0.4 s-1). Thus, AT1 blockade with IRBE reduces the development of electrophysiological alterations and impairment of calcium handling in hypertrophied myocytes; this effect may decrease the propensity to arrhythmias in this setting.