DOSE-DEPENDENT DISSOCIATION OF ACE-INHIBITOR EFFECTS ON BLOOD-PRESSURE, CARDIAC-HYPERTROPHY, AND BETA-ADRENERGIC SIGNAL-TRANSDUCTION

Background Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and beta-adrenergic signal transduction were exa mined in an animal model with beta-adrenergic desensitization: which h as been identified in failing hearts and in hypertensive cardiac hyper trophy. It is unknown whether beneficial ACE-inhibitor effects are due to an unloading of the failing heart or a reduction of neuroendocrine activation with beta-adrenergic resensitization. Methods and Results Low-dose (LD, 1 mg/kg) and high-dose (HD, 25 mg/kg) fosinopril treatme nt was performed in spontaneously hypertensive rats (SHR) and control (WKY) rats. Myocardial norepinephrine concentrations, adenylyl cyclase activity, beta-adrenergic receptors (radioligand binding), G(s alpha) (functional reconstitution), and G(i alpha) (pertussis toxin labeling ) were determined. Ventricular weights and blood pressures were measur ed. HD but not LD reduced blood pressure and left ventricular weights in SHR, Isoprenaline- and guanylylim-idodiphosphate-stimulate adenylyl cyclase activities as well as beta(1)-adrenergic receptors were reduc ed in SHR. The catalyst and G(i alpha) were unchanged, but G(s alpha) and norepinephrine concentrations were increased. Both LD and HD treat ments restored beta-adrenergic alteration. Conclusions LD treatment wi th ACE inhibitors restored beta-adrenergic signal transduction defects independently of regression of cardiac hypertrophy. This could contri bute to the effects of ACE inhibitors in patients, who are often treat ed with nonhypotensive doses.