EFFECTS OF QUINAPRIL, LOSARTAN AND HYDRALAZINE ON CARDIAC-HYPERTROPHYAND BETA-ADRENERGIC NEUROEFFECTOR MECHANISMS IN TRANSGENIC (MREN2)27 RATS

1 Desensitization of the myocardial beta-adrenergic signal transductio n pathway is an important mechanism which is involved in the progressi on of hypertensive heart disease. The aim of the present study was to evaluate the differential effects of chronic pharmacotherapy with an a ngiotensin converting enzyme (ACE)-inhibitor, an AT(1)-receptor antago nist and a direct vasodilator on blood pressure, cardiac hypertrophy a nd the beta-adrenergic signal transduction. Therefore, transgenic TG(m REN2)27 (TG) rats overexpressing the mouse renin gene were used. This strain is characterized by the development of fulminant hypertension w ith cardiac hypertrophy. 2 Seven week old heterozygous TG(mREN2)27 rat s were treated for 11 weeks with the AT(1)-receptor antagonist losarta n (10 mg kg(-1)), the ACE-inhibitor quinapril (15 mg kg(-1)) and the d irect vasodilator hydralazine (30 mg kg(-1)). Untreated TG and normote nsive 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), decr eased myocardial neuropeptide Y (NPY) concentrations (TG 1143 +/- 108 vs SD 1953 +/- 134 pg g(-1) wet weight), reduced beta-adrenoceptor den sities (TG 51.1 +/- 1.9 vs SD 63.4 +/- 3.7 fmol mg(-1)) as assessed by [I-125]-cyanopindolol binding studies, and increased G(i alpha)-activ ities (TG 4151 +/- 181 vs SD 3169 +/- 130 densitometric units) as asse ssed by pertussis toxin catalyzed [P-32]-ADP-ribosylation. Downregulat ion of beta-adrenoceptors and increased G(i alpha) were accompanied by significantly reduced isoprenaline-, Gpp(NH)p- and forskolin-stimulat ed adenylyl cyclase activity. Catalyst activity as determined by forsk olin plus Mn2+ co-stimulation of adenylyl cyclase did not differ betwe en TG(mREN2)27- and SD control-rats. 4 Losartan and quinapril signific antly restored systolic blood pressures, left ventricular weights, bet a-adrenoceptor densities, myocardial neuropeptide Y-concentrations, ad enylyl cyclase activities and G(i 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 lef t ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5 In conclusion, direct vasodilatation is not able to overcome the patho physiological alterations in TG caused by transgene overexpression. In contrast, ACE-inhibitors and AT(1)-receptor antagonists, which inhibi t the renin angiotensin system, equally exert beneficial effects on bl ood pressure, myocardial hypertrophy and neuroeffector mechanisms. Mod ulation of the sympathetic tone and resensitization of the beta-adrene rgic signal transduction system may contribute to the special effectiv eness of these drugs in the treatment of the hypertensive cardiomyopat hy.