Acute effects of phenoxybenzamine on alpha-adrenoceptor responses in vivo and in vitro: relation of in vivo pressor responses to the number of specific adrenoceptor binding sites.
Pressor responses to intravenous phenylephrine, an adrenoceptor agonist, and to the alpha 2-adrenoceptor-selective agonist guanabenz were examined in conscious rabbits 30 min after treatment with a range of doses of phenoxybenzamine (10(-5) to 5 mg/kg). The maximum number of specific prazosin- and clonidine-binding sites in the spleen of rabbits sacrificed 30 min after receiving phenoxybenzamine were measured using radioligand binding techniques. Treatment with phenoxybenzamine resulted in a dose-dependent reduction in the maximum pressor response to both phenylephrine and guanabenz, although phenoxybenzamine was a more potent antagonist at postsynaptic alpha 1- than at postsynaptic alpha 2-adrenoceptors. Phenoxybenzamine treatment also caused a dose-dependent reduction in specific [3H]prazosin and [3H]clonidine binding. The maximum in vivo pressor response to guanabenz was observed only when all specific clonidine-binding sites were present. There was a close correlation between in vitro receptor number and in vivo pressor responses for alpha 2-adrenoceptor stimulation but not for alpha 1-adrenoceptor-mediated responses. The maximum pressor response to phenylephrine could be obtained in rabbits in which the number of specific prazosin-binding sites was reduced by 60%. These experiments provide an approach to relating in vitro receptor number to in vivo responses.
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001794:Blood Pressure / Q000187:drug effects*; D003000:Clonidine / Q000378:metabolism; D006143:Guanabenz / Q000494:pharmacology; D008297:Male; D010643:Phenoxybenzamine / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism; D011817:Rabbits; D011869:Radioligand Assay
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D010643:Phenoxybenzamine; D010656:Phenylephrine; D006143:Guanabenz; D003000:Clonidine; D011224:Prazosin