Prostaglandin synthesis elicited by adrenergic stimuli is mediated via alpha-2C and alpha-1A adrenergic receptors in cultured smooth muscle cells of rabbit aorta.
This study was performed to characterize the subtype of adrenergic receptor(s) (AR) involved in prostacyclin synthesis [measured as 6-keto-prostaglandin (PG)F1 alpha] elicited by AR agonists in cultured vascular smooth muscle cells of rabbit aorta. Both alpha-1 and alpha-2 AR agonists enhanced 6-keto-PGF1 alpha synthesis in a dose-dependent manner with the following order of potency: norepinephrine greater than BHT 933 greater than UK 14304 greater than xylazine greater than phenylephrine greater than or equal to methoxamine greater than cirazoline. Isoproterenol and oxymetazoline did not alter 6-keto-PGF1 alpha synthesis. Methoxamine-induced 6-keto-PGF1 alpha synthesis was not reduced by the alpha-2 AR antagonist rauwolscine. The affinities of AR antagonists (PA2 value) in inhibiting methoxamine-induced 6-keto-PGF1 alpha synthesis were of the following order: prazosin greater than WB 4101 greater than corynanthine greater than yohimbine. Administration of WB 4101 and the irreversible alpha-1B AR antagonist chloroethylclonidine reduced norepinephrine (in the presence of rauwolscine, 10(-8) M)- or methoxamine-induced 6-keto-PGF1 alpha synthesis; WB 4101 was more potent than chloroethylclonidine. UK 14304-induced 6-keto-PGF1 alpha synthesis was not reduced by chloroethylclonidine or BRL 44408, a selective alpha-2A AR antagonist, but it was inhibited by other alpha AR antagonists. The affinities of AR antagonists (PA2 values) in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis were of the following order: rauwolscine greater than yohimbine greater than BAM 1303 greater than BRL 41992 greater than WB 4101 greater than ARC 239 greater than or equal to prazosin greater than SKF 104078 greater than or equal to corynanthine. The order of affinity of alpha-2 AR antagonists in inhibiting UK 14304-induced 6-keto-PGF1 alpha synthesis in vascular smooth muscle cells was similar to that derived from radioligand binding studies in opossum kidney cell line receptors classified as alpha-2C receptors. These data suggest that 6-keto-PGF1 alpha synthesis elicited by adrenergic stimuli in cultured vascular smooth muscle cells of rabbit aorta is mediated primarily via alpha-2C and to a lesser extent alpha-1A receptors.
Nebigil
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Department of Pharmacology, College of Medicine, University of Tennessee, Memphis.
Malik
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KU
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis*; D000316:Adrenergic alpha-Agonists / Q000378:metabolism / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D013379:Substrate Specificity
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D015121:6-Ketoprostaglandin F1 alpha