1. Desensitization of the myocardial beta-
adrenergic signal transduction pathway is an important mechanism which is involved in the progression of hypertensive
heart disease. The aim of the present study was to evaluate the differential effects of chronic
pharmacotherapy with an
angiotensin converting enzyme (
ACE)-inhibitor, an AT1-receptor antagonist and a direct
vasodilator on blood pressure,
cardiac hypertrophy and the beta-
adrenergic signal transduction. Therefore, transgenic TG(mREN2)27 (TG) rats overexpressing the mouse
renin gene were used. This strain is characterized by the development of fulminant
hypertension with
cardiac hypertrophy. 2. Seven week old heterozygous TG(mREN2)27 rats were treated for 11 weeks with the AT1-receptor antagonist
losartan (10 mg kg[-1]), the
ACE-inhibitor quinapril (15 mg kg[-1]) and the direct
vasodilator hydralazine (30 mg kg[-1]). Untreated TG and normotensive Sprague-Dawley rats (SD) served as controls. 3. TG(mREN2)27-rats were characterized by arterial
hypertension (TG 194+/-3.2 mmHg vs SD 136+/-2.9 mmHg systolic blood pressure), increased left ventricular weights (TG 4.3+/-0.3 vs SD 3.0+/-0.1 mg g(-1)
body weight), decreased myocardial
neuropeptide Y (NPY) concentrations (TG 1143+/-108 vs SD 1953+/-134 pg g(-1) wet weight), reduced beta-
adrenoceptor densities (TG 51.1+/-1.9 vs SD 63.4+/-3.7 fmol mg[-1]) as assessed by [125I]-
cyanopindolol binding studies, and increased Gi(alpha)-activities (TG 4151+/-181 vs SD 3169+/-130 densitometric units) as assessed by
pertussis toxin catalyzed [32P]-ADP-ribosylation. Downregulation of beta-
adrenoceptors and increased Gi(alpha) were accompanied by significantly reduced
isoprenaline-,
Gpp(NH)p- and
forskolin-stimulated
adenylyl cyclase activity. Catalyst activity as determined by
forskolin plus Mn2+ co-stimulation of
adenylyl cyclase did not differ between TG(mREN2)27- and SD control-rats. 4.
Losartan and
quinapril significantly restored systolic blood pressures, left ventricular weights, beta-
adrenoceptor densities, myocardial
neuropeptide Y-concentrations,
adenylyl cyclase activities and Gi(alpha)-activities towards the values in Sprague-Dawley-controls. No differences were observed between the effects of
quinapril- and
losartan-treatment. In contrast,
hydralazine had only minor effects on blood pressure reduction, regression of
left ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5. In conclusion, direct vasodilatation is not able to overcome the pathophysiological alterations in TG caused by transgene overexpression. In contrast,
ACE-inhibitors and AT1-receptor antagonists, which inhibit the renin angiotensin system, equally exert beneficial effects on blood pressure, myocardial
hypertrophy and neuroeffector mechanisms. Modulation of the sympathetic tone and resensitization of the beta-
adrenergic signal transduction system may contribute to the special effectiveness of these drugs in the treatment of the hypertensive
cardiomyopathy.