Treatment with irbesartan counteracts the functional remodeling of ventricular myocytes from hypertensive rats

Changes in electrophysiological (action potential prolongation, decrease in transient outward current I-to, occurrence of the hyperpolarization-activated current I-f) and contractile properties develop in hypertrophied ventricular myocytes, likely implicated in the increased propensity to arrhythmias. Angiotensin II is a key signal for myocyte hypertrophy; the effect of 8-week treatment with irbesartan, a type 1 angiotensin II receptor (AT(1)) antagonist, on cardiac remodeling was tested. Sixteen-month-old hypertensive rats (SHRs) were treated with irbesartan (20 mg/kg/d) or saline for 8 weeks. At the end of treatment, systolic blood pressure and heart weight to body weight ratio were reduced in irbesartan-treated compared with nontreated SHRs. Electrical and contractile properties were measured in isolated ventricular myocytes, by patch-clamp or video-dimension analysis, respectively. Action potential duration was significantly shorter in irbesartan-treated than in nontreated SHRs (at -60 mV: 119+/-24 ms vs 187+/-20 ms); correspondingly, maximal I-to density was larger in irbesartan-treated than in nontreated SHRs (25.4+/-2.8 pA/pF vs 18.5+/-1.5 pA/pF). Maximal specific conductance of I-f was lower in irbesartan-treated vs nontreated SHRs (24.8+/-3.0 pS/pF vs 35.2+/-4.0 pS/pF). Finally, the relaxation rate of shortening in field-stimulated intact myocytes was significantly faster in irbesartan-treated than in nontreated SHRs (7.3+/-0.5/s vs 5.7+/-0.3/s). Thus, AT(1) blockade with irbesartan, at an oral daily dosage that gave a slight but significant reduction of systolic blood pressure, largely counteracts the development of myocyte hypertropby and associated functional alterations.