title: Unsurmountable antagonism to 5-hydroxytryptamine in rat kidney results from pseudoirreversible inhibition rather than multiple receptors or allosteric receptor modulation.
abstract: Experiments were conducted in the isolated perfused rat kidney to determine the mechanism of unsurmountable antagonism by metergoline toward the vasoconstrictor response to 5-hydroxytryptamine (5-HT). Three possible mechanisms were investigated: 1) multiple receptors for 5-HT; 2) pseudoirreversible inhibition; and 3) allosteric modulation of 5-HT receptors. Metergoline and six other 5-HT antagonists acted as potent unsurmountable antagonists, only (-)-propranolol acted competitively (pA2 = 6.5). Multiple receptors for 5-HT were ruled out as the mechanism of unsurmountable antagonism because 5-HT and four 5-HT analogs gave similar pA2 values with (-)-propranolol. In addition, the KA value for 5-HT (185 nM) and the order and relativity of agonist potency suggest the presence of a single 5-HT2 receptor. Pseudoirreversible inhibition, over allosteric modulation of the 5-HT2 receptor, is suggested from experiments in which reversal of metergoline-induced inhibition by (-)-propranolol (studied in the presence of metergoline) was matched, in magnitude, by wash-out of metergoline. (-)-Propranolol is suggested to mimic wash-out by occupying and protecting receptors from which metergoline has dissociated. This is accomplished by virtue of its faster kinetics, on-off the 5-HT receptor, allowing restoration of 5-HT responses via a competitive interaction. Pseudoirreversible antagonism, over allosteric receptor modulation, offers an explanation that does not involve the postulation of allosteric effector sites or changes in the state of the 5-HT2 receptor.
authors.affiliation: Department of Pharmacology, University of Houston, Texas.
authors.forename: R A
authors.initials: RA
authors.lastname: Bond
authors.forename: A G
authors.initials: AG
authors.lastname: Ornstein
authors.forename: D E
authors.initials: DE
authors.lastname: Clarke
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007668:Kidney / Q000187:drug effects*; D008297:Male; D008711:Metergoline / Q000494:pharmacology; D010477:Perfusion; D010643:Phenoxybenzamine / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011985:Receptors, Serotonin / Q000187:drug effects*; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D010643:Phenoxybenzamine; D008711:Metergoline; D012701:Serotonin; D011433:Propranolol