(Circulation. 1995;92:3006-3013.)
© 1995 American Heart Association, Inc.
Articles |
Dose-Dependent Dissociation of ACE-Inhibitor Effects on Blood Pressure, Cardiac Hypertrophy, and ß-Adrenergic Signal Transduction
From the Klinik III für Innere Medizin, Universität zu Köln, Germany (M.B., M.F., E.E.); Scienze Mediche, Universitá degli Studi di Brescia, Italy (M.C., E.A.R.); and the Freie Universität Berlin, Berlin, Germany (M.P.).
Correspondence to Michael Böhm, Klinik III für Innere Medizin, Universität zu Köln, Joseph-Stelzmann Str 9, 50924 Köln, Germany.
Background Dose-dependent effects of ACE inhibitors on blood pressure, cardiac hypertrophy, and ß-adrenergic signal transduction were examined in an animal model with ß-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 ß-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,
ß-adrenergic receptors (radioligand binding),
Gs
(functional reconstitution), and Gi
(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 ß1-adrenergic receptors were reduced in SHR.
The catalyst and Gs were unchanged, but
Gi and norepinephrine concentrations were
increased. Both LD and HD treatments restored ß-adrenergic
alteration.
Conclusions LD treatment with ACE inhibitors restored ß-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.
Key Words: angiotensin • enzymes • blood pressure • hypertrophy • receptors, adrenergic, beta
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