In transgenic rats harboring the mouse Ren-2d gene [TG(mREN2)27], downregulation of the myocardial beta-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 beta-adrenergic receptor adenylyl cyclase system. In freshly harvested aortas from transgenic rats, the activity of adenylyl cyclase was reduced significantly (P<.05) in the presence of isoprenaline (10 micromol/L; -28+/-4.5%), guanosine 5'-triphosphate, 5'-guanylylimidodiphosphate [Gpp(NH)p] (100 micromol/L; -29+/-4.7%), and forskolin (100 micromol/L) with (-42+/-6%) and without (-40+/-4.3%) MnCl2. Densities of beta-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 MnCl2 was not different. Affinities and densities of beta-adrenoceptors and amounts of immunochemically detected inhibitory and stimulatory G-protein alpha-subunits were unchanged. Desensitization after incubation with 10 micromol/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 beta-adrenergic adenylyl cyclase system is due to humoral and hemodynamic factors present in vivo rather than to transgenicity itself.