Dose-Dependent Dissociation of ACE-Inhibitor Effects on Blood Pressure, Cardiac Hypertrophy, and β-Adrenergic Signal Transduction

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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 guanylylimidodiphosphate-stimulated adenylyl cyclase activities as well as β 1 -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.