EFFECTS OF ANGIOTENSIN-II TYPE-1 RECEPTOR BLOCKADE AND ANGIOTENSIN-CONVERTING ENZYME-INHIBITION ON CARDIAC BETA-ADRENERGIC SIGNAL-TRANSDUCTION

Inhibition of the renin-angiotensin system has been shown to improve s ymptoms and prognosis in heart failure. We compared the effects of inh ibition of angiotensin-converting enzyme or blockade of angiotensin II type 1 (AT(1)) receptors in a model with renin-induced hypertension t hat is known to exhibit similar changes in sympathetic activation and beta-adrenergic desensitization, as observed in heart failure. Treatme nt with captopril (100 mg/kg of leed) or the AT(1)-antagonist Bay 10-6 734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2(d) gene [TG(mREN2)27]. Neuropeptide Y and angiotensin I I levels, adenylyl cyclase activity, beta-adrenergic receptors, G(s al pha), and G(i alpha) were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial ang iotensin II concentrations. Isoprenaline- and guanylylimidodiphosphate -stimulated adenylyl cyclase activities and beta-adrenergic receptor d ensity were reduced, whereas the catalyst and G(s alpha)-function were unchanged. G(i alpha) protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ven tricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroef fector defects are similarly reversed by angiotensin-converting enzyme inhibition or AT(1) antagonism. The data support the concept that pha rmacological interventions in the myocardial renin-angiotensin system significantly reverse local sympathetic neuroeffector defects. This co uld be important for the beneficial effects of these agents.