ISOPROTERENOL EXERTS CYCLIC-AMP INDEPENDENT EFFECTS ON DNA-SYNTHESIS IN CULTURED ADVENTITIAL FIBROBLASTS FROM SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS

Understanding the mechanism behind the growth response evident in the vasculature of the spontaneously hypertensive rat (SHR) remains elusive. Fibroblasts from the aortic adventitial layer of the SHR manifest the heightened proliferative rate in vitro relative to Wistar-Kyoto (WKY) rats that is conspicuous in cultured aortic smooth muscle cells. The adenylyl-cyclase/cyclic AMP signal transduction pathway is believed to be altered in hypertensive people and animals such that responses to beta-adrenoceptor activation are blunted. The present study examined the effects of beta-adrenoceptor-mediated versus direct activation of adenylylcyclase on intracellular cyclic AMP accumulation and subsequent DNA synthesis in cultured aortic fibroblasts. We hypothesized that elevation of cyclic AMP levels by both isoproterenol and forskolin would normalize the proliferative capacity of SHR fibroblasts. Forskolin increased intracellular cyclic AMP levels and inhibited epidermal growth factor stimulated thymidine incorporation in an equivalent manner in both SHR and WKY adventitial fibroblasts, implying that there is no difference in adenylylcyclase activity. Isoproterenol elevated cyclic AMP levels to a significantly greater degree in the SHR than did forskolin, and yet, relative to forskolin, attenuated growth factor induced DNA synthesis to a lesser extent. These data suggest that isoproterenol, via beta-adrenoceptor activation, exhibits both cyclic AMP dependent and cyclic AMP independent effects in adventitial fibroblasts. The cyclic AMP independent effects of isoproterenol oppose the expected observations due to cyclic AMP and may offer an explanation to the blunted responses to beta-adrenoceptor activation evident both in vitro and in vivo.