Further analysis of the inhibitory effects of dihydroergotamine, cyproheptadine and ketanserin on the responses of the rat aorta to 5‐hydroxytryptamine

Abstract

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.

Responsiveness, affinity constants and receptor reserves for serotonin on aortae of aged normotensive and hypertensive rats

“…Spiperone (Cohen et al 1982) and ketanserin, which are selective 5-HT 2A -receptor antagonists, but not the selective α 1 -and α 2 -adrenoceptor antagonists, prazosin and idazoxan (Doggrell 1987), are potent inhibitors of the rat aorta serotonergic response. However, the rat aorta 5-HT 2A -receptors may be atypical as the affinity constants (K A ) for serotonin are 10-100-fold greater (Doggrell 1992(Doggrell , 1995, and this study) than those previously reported for serotonin at 5-HT 2A -receptors. K A values for serotonin in the order of 1-8i10 − 7  have been obtained at the 5-HT 2A -receptors of the rabbit aorta (Clancy & Maayani 1985 ;Leff et al 1987), calf coronary and pulmonary artery (Frenken & Kaumann 1987) and rat kidney vasculature (Bond et al 1989).…”