Dose-dependent dissociation of ACE-inhibitor effects on blood pressure, cardiac hypertrophy, and beta-adrenergic signal transduction
Böhm, M.; Castellano, M.; Agabiti-Rosei, E.; Flesch, M.; Paul, M.; Erdmann, E.
Circulation 92(10): 3006-3013
1995
ISSN/ISBN: 0009-7322 PMID: 7586271 Document Number: 444461
Background Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and beta-adrenergic signal transduction were examined in an animal model with beta-adrenergic desensitization, which has been identified in failing hearts and in hypertensive cardiac hypertrophy. 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 treatment was performed in spontaneously hypertensive rats (SHR) and control (WKY) rats. Myocardial norepinephrine concentrations, adenylyl cyclase activity, beta-adrenergic receptors (radioligand binding), G-salpha (functional reconstitution), and G-ialpha (pertussis toxin labeling) were determined. Ventricular weights and blood pressures were measured. HD but not LD reduced blood pressure and left ventricular weights in SHR. Isoprenaline- and guanylylimidodiphosphate-stimulated adenylyl cyclase activities as well as beta-1-adrenergic receptors were reduced in SHR. The catalyst and G-salpha were unchanged, but G-ialpha and norepinephrine concentrations were increased. Both LD and HD treatments restored beta-adrenergic alteration. Conclusions: LD treatment with ACE inhibitors restored beta-adrenergic signal transduction defects independently of regression of cardiac hypertrophy. This could contribute to the effects of ACE inhibitors in patients, who are often treated with nonhypotensive doses.