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C Nebigil and KU Malik
Department of Pharmacology, College of Medicine, University of Tennessee, Memphis.
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.
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