Bradykinin regulates captopril-induced upregulation of beta-adrenergic receptor in cultured neonatal rat cardiomyocytes.

The aim of this study was to elucidate the role of bradykinin in mediating captopril-induced upregulation of beta-adrenergic receptor (beta-AR). The density of beta-AR on the surface of cardiac myocytes was measured by binding assay using [(3)H]CGP-12177. Treatment of cultured neonatal rat cardiomyocytes with captopril resulted in a time-dependent elevation of bradykinin concentration in the culture medium. The increased bradykinin concentration was significant at 2, 3 and 6 h, but not at 12 h after exposure to captopril. This time-dependent effect of captopril on enhancement of bradykinin levels paralleled that of beta-AR upregulation. Exogenously applied bradykinin increased beta-AR density by 22, 30 and 35% at 0.01, 0.1 and 1 microm concentrations, respectively. Myocytes treated with 1 microm bradykinin responded to isoproterenol (ISP) in a dose-dependent manner, as demonstrated by acceleration of spontaneous beating frequency. These beating acceleration effects of bradykinin were abolished by Hoe 140. Stimulation of bradykinin B2 receptor by exogenously added bradykinin for 6 h was sufficient to produce beta-AR up-regulation to a level similar to that seen after 24 h. Our results indicate that bradykinin potentiation by ACE inhibitors regulates, at least in part, captopril-induced beta-AR up-regulation.