Search

The antagonist effects of indoramin were investigated in rabbit perfused ear artery, common carotid artery, and human perfused temporal artery preparations. Indoramin was a potent competitive antagonist of the constrictor effects of noradrenaline (NA) in all three preparations, pA2 values being 7.77 for the ear artery, 8.20 for the common carotid artery and 7.46 for the human temporal artery. The constrictor actions of serotonin (5-hydroxytryptamine, 5-HT) were competitively antagonized by indoramin. The pA2 values obtained in the rabbit common carotid and human temporal artery (5.92 and 6.25, respectively), were lower than those for NA in the same preparations and lower than that obtained in the rabbit perfused ear artery (7.55). Indoramin was a potent competitive antagonist (pA2:8.31) of histamine-induced vasoconstriction in the rabbit perfused ear artery preparation. These results can be explained on the basis of previous findings that the action of 5-HT in the rabbit ear artery is mediated via an alpha-adrenoceptor, and that the rabbit common carotid artery contains true 5-HT receptors. The findings suggest that specific 5-HT receptors may be present in the human temporal artery and that alpha-adrenoceptor antagonism may be the pharmacological property of most relevance to the efficacy of indoramin in migraine prophylaxis.

1. The current classification of receptors for 5-hydroxytryptamine (5-HT) is based on functional studies, and encompasses three main receptor types. 2. 5-HT1-like receptors mediate inhibition of release of various neurotransmitters from central and peripheral sites, smooth muscle contraction and relaxation (and release of endothelium-derived relaxing factor), tachycardia, a variety of behavioural actions (for example, forepaw treading, hypothermia, hyperphagia, drug discriminative stimulus properties, nociceptive pathway modulation, and anxiolytic, anti-aggressive and prosexual effects), and central neuronal excitatory and inhibitory activity. Selective antagonists for this receptor are not yet available, but the 5-HT2 receptor antagonists methysergide and methiothepin have appreciable affinity for 5-HT1-like receptors, and 5-carboxamidotryptamine is a selective agonist. 3. 5-HT2 receptors mediate smooth muscle contraction, platelet aggregation, increased capillary permeability, some behavioural syndromes (for example, head twitch and wet-dog shakes) and drug discriminative stimulus properties, central neuroexcitatory effects, and some neuroendocrine functions. Ketanserin and cyproheptadine are selective antagonists. 4. 5-HT3 receptors mediate peripheral afferent and efferent neuroexcitatory actions, anxiogenic effects, and modulation of cytotoxic drug-induced emesis, gastric emptying, and dopamine-related mesolimbic hyperactivity. Selective antagonists include cocaine, MDL 72222 and ICS 205-930; 2-methyl-5-HT is a selective agonist.