Iwasaki H, Eguchi S, Shichiri M, Marumo F, Hirata Y
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Eur J Pharmacol. 1998 Jul 3;352(1):131-4. doi: 10.1016/s0014-2999(98)00413-0.
Adrenomedullin activates receptor-mediated adenylate cyclase to cause vasorelaxation. To elucidate whether desensitization of adenylate cyclase coupled to vascular adrenomedullin receptors occurs, we studied the adenylate cyclase activity after treatment with rat adrenomedullin in cultured rat aortic vascular smooth muscle cells. Cyclic AMP (cAMP) generation induced by adrenomedullin was markedly decreased by pretreatment with adrenomedullin: a maximal reduction (approximately 80%) was induced after 2 h and persisted during 24 h. Desensitization was independent of protein kinase A, protein kinase C, protein tyrosine kinase or receptor sequestration, because pretreatment with either isoproterenol, forskolin, tetradecanoylphorbol acetate, cytochalasin D, or colchicine did not affect the adrenomedullin-stimulated cAMP response. Furthermore, preincubation with inhibitors for these protein kinases prior to pretreatment with adrenomedullin failed to affect the adrenomedullin-induced decrease in cAMP response following the second stimulation with adrenomedullin. The present results provide the evidence for the existence of desensitization of adenylate cyclase coupled to vascular adrenomedullin receptors.
肾上腺髓质素激活受体介导的腺苷酸环化酶以引起血管舒张。为了阐明与血管肾上腺髓质素受体偶联的腺苷酸环化酶是否会发生脱敏，我们在培养的大鼠主动脉血管平滑肌细胞中用大鼠肾上腺髓质素处理后研究了腺苷酸环化酶活性。用肾上腺髓质素预处理可使肾上腺髓质素诱导的环磷酸腺苷（cAMP）生成明显减少：2小时后诱导最大减少（约80%），并在24小时内持续存在。脱敏与蛋白激酶A、蛋白激酶C、蛋白酪氨酸激酶或受体隔离无关，因为用异丙肾上腺素、福斯可林、十四酰佛波醇乙酸酯、细胞松弛素D或秋水仙碱预处理均不影响肾上腺髓质素刺激的cAMP反应。此外，在肾上腺髓质素预处理之前用这些蛋白激酶的抑制剂预孵育，未能影响第二次用肾上腺髓质素刺激后肾上腺髓质素诱导的cAMP反应降低。目前的结果为与血管肾上腺髓质素受体偶联的腺苷酸环化酶存在脱敏提供了证据。
