Differential antagonism of the initial fast and secondary slow contractile responses of the rat isolated aorta to 5-hydroxytryptamine by mianserin and ketanserin.

1 The rat isolated aorta is contracted by 5-hydroxytryptamine (5-HT) with an initial fast and secondary slow response. The secondary slow responses were greater than the initial fast. The effects of antagonists (prazosin, idazoxan, phentolamine, dihydroergotamine, methysergide, cyproheptadine, mianserin and ketanserin) on these initial fast and secondary slow contractile responses to 5-HT were studied. 2 Prazosin and idazoxan at 10(-7)M had no effect on responses to 5-HT. Thus all concentrations of 5-HT contract the aorta by stimulating receptors distinct from alpha-adrenoreceptors. 3 Phentolamine, dihydroergotamine, methysergide and cyproheptadine had similar inhibitory effects on the initial fast and secondary slow responses to 5-HT. Phentolamine at 10(-6)M caused parallel, whereas dihydroergotamine (10(-9)-10(-8)M), methysergide (10(-9)-10(-8)M) and cyproheptadine (3 X 10(-11)-10(-8)M) caused non-parallel rightward shifts of the concentration-response curves. 4 Mianserin and ketanserin had greater inhibitory effects on the initial fast than secondary slow responses. Mianserin (10(-9)-10(-7)M) caused a non-parallel and parallel rightward shift of the concentration-response curves to the initial fast and secondary slow responses to 5-HT, respectively. Ketanserin (10(-8)-10(-7)M) produced non-parallel rightward shifts of the concentration-response curves. 5 One possible explanation of these results is that the rat aorta has no spare 5-HT2 receptors and that in inhibiting responses to 5-HT: (a) phentolamine is a competitive antagonist, (b) mianserin and ketanserin are slowly dissociating antagonists, and (c) dihydroergotamine, methysergide and cyproheptadine are irreversible antagonists. Furthermore, the competitive and irreversible antagonists have similar effects on initial fast and secondary slow responses to 5-HT, whereas the slow dissociating antagonists (mianserin and ketanserin) have a greater inhibitory effect on the initial fast than secondary slow response.