15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and cyanopindolol

1. The alpha(1)-adrenoceptor antagonist properties of the beta-adrenoceptor nonconventional partial agonist, CGP 12177A, was investigated in functional assays in rat aorta and in radioligand binding assays in rat cerebral cortical membranes. In addition, binding affinities of other beta-adrenoceptor ligands were measured to investigate any correlation between alpha(1)-adrenoceptor affinity and relaxant potency in phenylephrine-constricted rings. 2. In functional studies, CGP 12177A produced parallel rightward shifts of the phenylephrine CRC with no reduction in the maximum responses. Schild regression analysis gave a straight line with a slope of 0.95 (95% CL: 0.87-1.04), suggesting reversible competitive antagonism, and gave a pK(B) value of 5.26. In contrast, CGP 12177A (

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adrenergic alpha-1 Receptor Antagonists; Adrenergic beta-Antagonists; Alprenolol; Animals; Aorta, Thoracic; Binding Sites; Bupranolol; Cell Membrane; Cerebral Cortex; Dose-Response Relationship, Drug; Ethanolamines; Imidazoles; Male; Muscle, Smooth, Vascular; Phenylephrine; Pindolol; Prazosin; Propanolamines; Propranolol; Radioligand Assay; Rats; Rats, Wistar; Receptors, Adrenergic, alpha-1; Receptors, Adrenergic, beta-3; Tritium; United Kingdom; Vasoconstriction

5-Hydroxytryptamine (5-HT) evoked potent contractile responses in phenoxybenzamine-treated ring segments of rat caudal artery, partially contracted with U46619. Responses were mimicked by 5-HT1-selective agonists with the potency order: RU24969 > 5-carboxamidotryptamine > 5-HT = CP-93,129 >> sumatriptan. 8-Hydroxy-N,N-dipropylaminotetralin was virtually inactive. Responses were unaffected by spiperone (0.1 microM) and mesulergine (1.0 microM), but were antagonized competitively by (+/-)-cyanopindolol affording agonist-independent pKB estimates of 8.4 to 8.9. The pharmacological profile of this receptor is consistent with that of the 5-HT1B subtype. Since the 5-HT1B receptor is the rodent homologue of the 5-HT1D beta subtype, it might be anticipated that 5-HT1D beta receptors will be found to mediate vasoconstrictor responses in non-rodent species.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Arteries; Ergolines; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Pindolol; Prostaglandin Endoperoxides, Synthetic; Rats; Rats, Wistar; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Spiperone; Vasoconstrictor Agents