Further analysis of the inhibitory effects of dihydroergotamine, cyproheptadine and ketanserin on the responses of the rat aorta to 5-hydroxytryptamine.
1. The aim of the present study was to analyse the inhibitory effects of dihydroergotamine, cyproheptadine and ketanserin on the rat aorta contractile responses to 5-HT. Initially phenoxybenzamine treatment was used to determine whether spare receptors exist at the maximum responses to 5-HT. Then the reversibility of the inhibitory effects of phentolamine, dihydroergotamine, cyproheptadine and ketanserin against the fast and slow response of the rat aorta to 5-HT were determined. 2. Phenoxybenzamine caused non-parallel rightward shifts of the 5-HT concentration-response curves with reduced maximal responses. The KA values for 5-HT to produce fast and slow responses were 2-5 x 10(-5) M. These KA values are much higher than those previously reported for 5-HT at 5-HT2-receptors and suggest that the 5-HT2-receptor of the rat aorta is 'atypical'. The rat aorta has spare 5-HT-receptors for the maximal fast and slow responses to 5-HT. 3. Phentolamine, dihydroergotamine, cyproheptadine and ketanserin inhibited the fast and slow responses to 5-HT. Phentolamine and ketanserin and the higher concentrations of dihydroergotamine and cyproheptadine tested had greater inhibitory effects on the fast than slow 5-HT responses possibly because the fast 5-HT response did not always reach equilibrium in the presence of antagonists. 4. The inhibitory effects on 5-HT responses of phentolamine at 10(-6)-10(-5) M were readily reversible, those of cyproheptadine at 10(-9)-10(-8) M and ketanserin at 10(-8) M were slowly reversible and those of dihydroergotamine at 10(-9)-10(-8) M were irreversible by washing in drug-free Krebs. 5. The inhibitory effects of phentolamine and ketanserin were not altered by increasing the treatment time whereas some of the effects of cyproheptadine and the effects of dihydroergotamine on responses to 5-HT were increased by prolonging the contact time with the antagonist from 75 to 150 min. 6. The present study shows that at the rat aorta 5-HT2-receptor, phentolamine is a competitive readily reversible, cyproheptadine and ketanserin are competitive slowly reversible and dihydroergotamine is a competitive irreversible antagonist.
Doggrell
S A
SA
Department of Pharmacology, School of Medicine, University of Auckland, New Zealand.
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D003533:Cyproheptadine / Q000494:pharmacology*; D004087:Dihydroergotamine / Q000494:pharmacology*; D066298:In Vitro Techniques; D007650:Ketanserin / Q000494:pharmacology*; D008297:Male; D010643:Phenoxybenzamine / 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*
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D010643:Phenoxybenzamine; D003533:Cyproheptadine; D012701:Serotonin; D004087:Dihydroergotamine; D007650:Ketanserin