Venance S L, Bennett B M, Pang S C
Department of Anatomy and Cell Biology, Queen's University, Kingston, ON, Canada.
Can J Physiol Pharmacol. 1994 Oct;72(10):1208-14. doi: 10.1139/y94-171.
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 adenylylcyclase/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.
目前仍不清楚自发性高血压大鼠（SHR）血管中明显的生长反应背后的机制。相对于Wistar-Kyoto（WKY）大鼠，SHR主动脉外膜层的成纤维细胞在体外表现出更高的增殖率，这在培养的主动脉平滑肌细胞中也很明显。据信，高血压患者和动物的腺苷酸环化酶/环磷酸腺苷信号转导途径发生了改变，因此对β-肾上腺素能受体激活的反应减弱。本研究考察了β-肾上腺素能受体介导的与直接激活腺苷酸环化酶对培养的主动脉成纤维细胞内细胞内环磷酸腺苷积累及随后DNA合成的影响。我们假设异丙肾上腺素和福斯高林升高环磷酸腺苷水平均可使SHR成纤维细胞的增殖能力恢复正常。福斯高林增加了细胞内环磷酸腺苷水平，并以相同方式抑制了表皮生长因子刺激的胸苷掺入，这表明SHR和WKY外膜成纤维细胞的腺苷酸环化酶活性没有差异。异丙肾上腺素使SHR细胞内环磷酸腺苷水平升高的程度明显大于福斯高林，但相对于福斯高林，其对生长因子诱导的DNA合成的抑制作用较小。这些数据表明，异丙肾上腺素通过激活β-肾上腺素能受体，在外膜成纤维细胞中表现出环磷酸腺苷依赖性和环磷酸腺苷非依赖性作用。异丙肾上腺素的环磷酸腺苷非依赖性作用与环磷酸腺苷预期的作用相反，这可能为体外和体内对β-肾上腺素能受体激活反应减弱提供了解释。
