Nebigil C, Malik K U
Department of Pharmacology, College of Medicine, University of Tennessee, Memphis.
J Pharmacol Exp Ther. 1992 Dec;263(3):987-96.
Prostaglandin (PG) synthesis elicited by adrenergic transmitter in the vascular smooth muscle cells (VSMC) of rabbit aorta is primarily mediated through activation of alpha-2C and alpha-1A adrenergic receptors (ARs). We have now investigated and compared the signal transduction mechanisms involved in alpha-2C and alpha-1A AR-stimulated prostacyclin (PGI2) production, measured as 6-keto-PGF1 alpha, in vascular smooth muscle cells. Norepinephrine, methoxamine (an alpha-1 AR agonist) and UK-14304 (an alpha-2 AR agonist) enhanced 6-keto-PGF1 alpha production. UK-14304 and norepinephrine (in the presence of propranolol), but not methoxamine, reduced basal adenosine 2':3'-cyclic monophosphate (cyclic AMP) as well as forskolin- and isoproterenol-stimulated cyclic AMP accumulation. Forskolin and isoproterenol did not alter basal 6-keto-PGF1 alpha production and alpha AR agonist-induced 6-keto-PGF1 alpha production. Alpha-2C and alpha-1A AR-stimulated 6-keto-PGF1 alpha production was independent of cyclic AMP levels in vascular smooth muscle cells. Both alpha-2C and alpha-1A AR-stimulated 6-keto-PGF1 alpha production required extracellular Ca++. Pertussis toxin prevented inhibition of cyclic AMP accumulation and reduced 6-keto-PGF1 alpha production in response to AR agonists. Guanosine 5'-O-(3-thiotriphosphate) potentiated 6-keto-PGF1 alpha production induced by norepinephrine and UK-14304 but not by methoxamine, whereas at a higher Mg++ concentration (4 mM), guanosine 5'-O-(3-thiotriphosphate) potentiated 6-keto-PGF1 alpha production by all three agonists. In contrast, the effect of UK-14304 on cyclic AMP was prevented in the presence of 4 mM Mg++. These data suggest that the pertussis toxin-sensitive G protein(s) mediated the stimulation of PG synthesis by alpha-1A and alpha-2C AR activation and the decrease in cyclic AMP accumulation by alpha-2C AR activation.
肾上腺素能递质在兔主动脉血管平滑肌细胞（VSMC）中引发的前列腺素（PG）合成主要通过α-2C和α-1A肾上腺素能受体（ARs）的激活介导。我们现在研究并比较了血管平滑肌细胞中α-2C和α-1A AR刺激前列环素（PGI2）生成（以6-酮-PGF1α衡量）所涉及的信号转导机制。去甲肾上腺素、甲氧明（一种α-1 AR激动剂）和UK-14304（一种α-2 AR激动剂）增强了6-酮-PGF1α的生成。UK-14304和去甲肾上腺素（在普萘洛尔存在下），而非甲氧明，降低了基础腺苷2':3'-环磷酸（环磷酸腺苷）以及福斯高林和异丙肾上腺素刺激的环磷酸腺苷积累。福斯高林和异丙肾上腺素未改变基础6-酮-PGF1α生成以及α AR激动剂诱导的6-酮-PGF1α生成。α-2C和α-1A AR刺激的6-酮-PGF1α生成与血管平滑肌细胞中的环磷酸腺苷水平无关。α-2C和α-1A AR刺激的6-酮-PGF1α生成均需要细胞外Ca++。百日咳毒素可防止环磷酸腺苷积累的抑制，并降低对AR激动剂反应的6-酮-PGF1α生成。鸟苷5'-O-(3-硫代三磷酸)增强了去甲肾上腺素和UK-14304诱导的6-酮-PGF1α生成，但未增强甲氧明诱导的生成，而在较高Mg++浓度（4 mM）下，鸟苷5'-O-(3-硫代三磷酸)增强了所有三种激动剂诱导的6-酮-PGF1α生成。相反，在4 mM Mg++存在下，UK-14304对环磷酸腺苷的作用被阻止。这些数据表明，百日咳毒素敏感的G蛋白介导了α-1A和α-2C AR激活对PG合成的刺激以及α-2C AR激活对环磷酸腺苷积累的减少。
