Background: Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and β-adrenergic signal transduction were examined in an animal model with β-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 β-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, β-adrenergic receptors (radioligand binding), G(sα) (functional reconstitution), and G(iα) (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 guanylyimidodiphosphate- stimulated adenylyl cyclase activities as well as β1-adrenergic receptors were reduced in SHR. The catalyst and G(sα) were unchanged, but G(iα) and norepinephrine concentrations were increased. Both LD and HD treatments restored β-adrenergic alteration. Conclusions: LD treatment with ACE inhibitors restored β-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.
Dose-dependent dissociation of ACE-inhibitor effects on blood pressure, cardiac hypertrophy, and β-adrenergic signal transduction
Castellano M.;
1995-01-01
Abstract
Background: Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and β-adrenergic signal transduction were examined in an animal model with β-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 β-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, β-adrenergic receptors (radioligand binding), G(sα) (functional reconstitution), and G(iα) (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 guanylyimidodiphosphate- stimulated adenylyl cyclase activities as well as β1-adrenergic receptors were reduced in SHR. The catalyst and G(sα) were unchanged, but G(iα) and norepinephrine concentrations were increased. Both LD and HD treatments restored β-adrenergic alteration. Conclusions: LD treatment with ACE inhibitors restored β-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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
