We studied neuroeffector defects in hypertrophied myocardium of hypertensive transgenic rats harboring the mouse Ren-2' 1 gene. In transgenic rats, epinephrine and neuropeptide Y concentrations were reduced. A heterologous desensitization of adenylyl cyclase was observed, which was accompanied by a downregulation of 0,-adrenergic receptors, an increase of inhibitory G protein a-subunits, and a mildly depressed catalyst activity of adenylyl cyclase, whereas the bioactivity of stimulatory G protein a-subunits and /3 2 -adrenergic receptors was unchanged. Desensitization of adenylyl H ypertension is well known to produce cardiac hypertrophy as an adaptive mechanism to reduce wall stress, when an increased pressure load is imposed on the myocardium. 1 The cardiac hypertrophy process has been regarded as a precursor of heart failure, 2 and in the Framingham study the prevalence of hypertension was highest in those individuals who developed heart failure. 3 However, it is still unresolved which factors predispose or accelerate the progression from cardiac hypertrophy to cardiac failure. In heart failure, several neurohormonal mechanisms are activated, among which are the circulating and tissue renin-angiotensin systems (RAS) 4 and the sympathetic nervous system. 5 The functional consequence is an increase in peripheral vascular resistance. In addition, several alterations of neuroeffector mechanisms have been observed. Besides an activation of the RAS, the activation of cardiac sympathetic nerves in patients with heart failure is followed by an increased release of norepinephrine from the heart, 6 leading to reduced myocardial norepinephrine and neuropeptide Y concentrations. 7 This neurohumoral stimulation resulting from activation of cardiac sympathetic nerves leads to a desensitization of the adenylyl cyclase caused by a downregulation of j3-adrenergic receptors 8 -10 and an increase of the inhibitory guanine nucleotide binding proteins (G i(V ) in the heart."-' 3 However, the unanswered questions are which signals trigger the sympathetic activation and whether these neuroeffector effects are specific for cardiac failure Received April 8, 1994; accepted in revised form August 10, 1994.From the Klinik III fiir Innere Medizin der Universitat zu Koln (Germany) (M.B., MM, B.S., E.E.); Max Delbruck Zentrum fur Molekulare Medizin Berlin (Germany) (M.P., D.G.); and Cattedra di Medicina Interna, University of Brescia (Italy) (M.C.).Correspondence to PD Dr Michael Bohm, Klinik III fiir Innere Medizin der Universitat zu Koln, Joseph-Stelzmann-Str 9, 50924 Koln, FRG.© 1994 American Heart Association, Inc.cyclase was accompanied by a reduced positive inotropic response to isoproterenol, whereas the effect of Ca 2+ was unchanged. We conclude that sympathetic neuroeffector defects occur in transgenic rats similar to those observed in human failing myocardium. These alterations occur in the stage of hypertrophy and could contribute to contractile dysfunction in later stages. (Hypertension. 1994;24:653-662.) Key Words • ...