The present study demonstrates changes in the ET-receptor expression pattern in favor of the ETA receptor in human end-stage heart failure. Furthermore, activation of the cardiac ET system with increased tissue ET-1 concentrations in the failing myocardium is observed. This is more likely due to decreased clearance than to increased synthesis, because ppET-1 gene expression and ECE activity are unchanged.

1 The aim of the present study was to evaluate the effects of 17,B-oestradiol in human myocardium. The effects of 17#f-oestradiol, progesterone and testosterone on force of contraction were investigated in electrically driven isolated atrial trabeculae and ventricular papillary muscles from human hearts in the presence and absence of Bay K 8644, a calcium channel agonist. In addition, the effects of 17,Boestradiol, progesterone and testosterone on binding of [3H]-PN 200 110 were assessed in membranes prepared from human ventricular myocardium.2 17/-Oestradiol elicited a negative inotropic effect in atrial (ICm: 7.1 ktmol 1-', confidence interval 3.8 to 13.4, n = 3) and ventricular preparations (IC50: 4.6 ,mol 1-', confidence interval 2.2 to 9.4, n = 3) as compared with solvent controls. There was no significant difference (P> 0.05) of IC50 values in the absence and presence of isoprenaline (0.01 umol 1-') in atrial (IC50: 10.8 imol I-1, confidence interval 9.1 to 12.9, n = 6) and ventricular preparations (IC50: 9.4 umol 1-1, confidence interval 7.3 to 11.9, n = 8). Testosterone, progesterone at 30 umol I1-and the solvent control had no significant effect on the concentration-response curves to Bay K 8644.

Abstract-In transgenic rats harboring the mouse Ren-2 d gene [TG(mREN2)27], downregulation of the myocardial ␤-adrenergic receptor adenylyl cyclase system has been demonstrated previously. Because a reduced vasodilatory reactivity may significantly contribute to hypertension in this model of an activated tissue renin-angiotensin system, the present study investigated alterations of the vascular ␤-adrenergic receptor adenylyl cyclase system. In freshly harvested aortas from transgenic rats, the activity of adenylyl cyclase was reduced significantly (PϽ.05) in the presence of isoprenaline (10 mol/L; Ϫ28Ϯ4.5%), guanosine 5Ј-triphosphate, 5Ј-guanylylimidodiphosphate [Gpp(NH)p] (100 mol/L; Ϫ29Ϯ4.7%), and forskolin (100 mol/L) with (Ϫ42Ϯ6%) and without (Ϫ40Ϯ4.3%) MnCl 2 . Densities of ␤-adrenoceptors were similar in both strains. In situ hybridization demonstrated the expression of the transgene in aortic smooth muscle cells. These data indicate a reduced catalyst function as a major contributing factor involved in the maintenance of high blood pressure in TG(mREN2)27. However, in cultivated aortic smooth muscle cells, cAMP production after stimulation with isoprenaline, forskolin, and Gpp(NH)p in the presence or absence of MnCl 2 was not different. Affinities and densities of ␤-adrenoceptors and amounts of immunochemically detected inhibitory and stimulatory G-protein ␣-subunits were unchanged. Desensitization after incubation with 10 mol/L isoprenaline for 72 hours was identical in smooth muscle cells from both strains. Cell cultivation and isoprenaline treatment had no effect on transgene expression. We concluded that in transgenic rats the downregulation of the aortic ␤-adrenergic adenylyl cyclase system is due to humoral and hemodynamic factors present in vivo rather than to transgenicity itself. (Hypertension. 1998;31:1157-1165.) Key Words: renin-angiotensin system Ⅲ adenyl cyclase Ⅲ receptors, adrenergic Ⅲ muscle, smooth, vascular Ⅲ rats, transgenic P rimary hypertension is thought to be influenced by genetic and environmental factors. Animal models with genetic forms of hypertension can serve as tools to understand genotype-phenotype interactions in this disease. Significant genetic heterogeneity has been demonstrated in polygenic inbred rats.1 Recently, a transgenic rat model overexpressing a mouse renin gene (mouse Ren-2 d ) was generated.2 It has been characterized by fulminant hypertension and cardiac hypertrophy, low renal and plasma renin activities, and low circulating levels of angiotensin II, thus reflecting an activated tissue RAS.3,4 TG(mREN2)27-rats may represent an appropriate model for studying the impact of a single candidate gene on the development of hypertension. In hypertrophied hearts from this strain, our laboratory demonstrated desensitization of the ␤-adrenergic receptor adenylyl cyclase system, ie, downregulation of ␤ 1 -adrenoceptors, reduced expression of G i ␣-subunits, and reduced positive inotropic responses to isoprenaline. The activity of the catalyst of adenylyl cyclase was only...

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