ISOPROTERENOL EXERTS CYCLIC-AMP INDEPENDENT EFFECTS ON DNA-SYNTHESIS IN CULTURED ADVENTITIAL FIBROBLASTS FROM SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS
Sl. Venance et al., ISOPROTERENOL EXERTS CYCLIC-AMP INDEPENDENT EFFECTS ON DNA-SYNTHESIS IN CULTURED ADVENTITIAL FIBROBLASTS FROM SPONTANEOUSLY HYPERTENSIVE AND WISTAR-KYOTO RATS, Canadian journal of physiology and pharmacology, 72(10), 1994, pp. 1208-1214
Understanding the mechanism behind the growth response evident in the
vasculature of the spontaneously hypertensive rat (SHR) remains elusiv
e. Fibroblasts from the aortic adventitial layer of the SHR manifest t
he heightened proliferative rate in vitro relative to Wistar-Kyoto (WK
Y) rats that is conspicuous in cultured aortic smooth muscle cells. Th
e adenylyl-cyclase/cyclic AMP signal transduction pathway is believed
to be altered in hypertensive people and animals such that responses t
o 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 subseque
nt DNA synthesis in cultured aortic fibroblasts. We hypothesized that
elevation of cyclic AMP levels by both isoproterenol and forskolin wou
ld normalize the proliferative capacity of SHR fibroblasts. Forskolin
increased intracellular cyclic AMP levels and inhibited epidermal grow
th factor stimulated thymidine incorporation in an equivalent manner i
n 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 forsk
olin, and yet, relative to forskolin, attenuated growth factor induced
DNA synthesis to a lesser extent. These data suggest that isoproteren
ol, via beta-adrenoceptor activation, exhibits both cyclic AMP depende
nt and cyclic AMP independent effects in adventitial fibroblasts. The
cyclic AMP independent effects of isoproterenol oppose the expected ob
servations due to cyclic AMP and may offer an explanation to the blunt
ed responses to beta-adrenoceptor activation evident both in vitro and
in vivo.