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 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.


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), Gs alpha (functional reconstitution), and Gi alpha (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 guanylylim-idodiphosphate-stimulated adenylyl cyclase activities as well as beta 1-adrenergic receptors were reduced in SHR. The catalyst and Gs alpha were unchanged, but Gi alpha 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.
Böhm
M
M
Klinik III für Innere Medizin, Universität zu Köln, Germany.
Castellano
M
M
Agabiti-Rosei
E
E
Flesch
M
M
Paul
M
M
Erdmann
E
E
D000262:Adenylyl Cyclases / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D017328:Fosinopril / Q000008:administration & dosage* / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D017328:Fosinopril; D009638:Norepinephrine