RECEPTORS FOR 5‐HYDROXYTRYPTAMINE AND NORADRENALINE IN RABBIT ISOLATED EAR ARTERY AND AORTA

Abstract

1 5-Hydroxytryptamine (5-HT) is thought to be implicated in the vascular disturbances of the external carotid artery bed associated with migraine. As part of a study of the pharmacology of some 5-HT antagonists used in the treatment of migraine we have examined the interactions of these drugs with 5-HT and noradrenaline in rabbit isolated ear artery and aortic strip. The results provide new information on the distribution of 5-HT-receptors and α-receptors in these preparations. 2 In the aorta, 5-HT and noradrenaline were of similar potency in producing contractions. Methysergide produced very small contractions and was about 1000 times less potent than the other two agonists. 3 In the ear artery noradrenaline produced monophasic vasoconstrictor responses, whereas 5-HT and methysergide produced prolonged biphasic responses. 5-HT was about 700 times less potent and methysergide about 4500 times less potent than noradrenaline. Methysergide was a better agonist in the ear artery than in the aorta. Biphasic responses to 5-HT and methysergide were also obtained in ear arteries from reserpine-treated rabbits indicating that neither agonist was acting by releasing endogenous noradrenaline. 4 Pizotifen, cyproheptadine and phentolamine had no agonistic actions in either the aorta or ear artery. 5 In the aorta methysergide, pizotifen and cyproheptadine were potent antagonists of 5-HT and much weaker antagonists of noradrenaline. Phentolamine possessed the opposite profile of selectivity. These results show that there are distinct receptors for 5-HT and noradrenaline in rabbit aorta. 6 In the ear artery the pA₂ values for each of the four antagonists were virtually identical against 5-HT and noradrenaline and similar to those obtained on α-adrenoceptors in the aorta. We conclude that 5-HT and noradrenaline act directly at α-receptors to produce vasoconstriction in the ear artery and that this preparation does not contain specific 5-HT-receptors. 7 This insight into the distribution of 5-HT-receptors and α-receptors allows interpretation of the various actions of methysergide. In the aorta, methysergide was a potent antagonist at 5-HT-receptors and a weak partial agonist at α-receptors. In the ear artery, methysergide was a partial agonist at α-receptors; it was only a weak antagonist of 5-HT because this preparation does not contain specific 5-HT-receptors. 8 The cross-reactivity demonstrated throughout these experiments indicates that 5-HT-receptors and α-receptors, although distinct entities, have features in common. 9 These results are discussed in relation to the mode of action of methysergide, pizotifen and cyproheptadine in the treatment of migraine.