CHARACTERIZATION OF PUTATIVE 5-HT7 RECEPTORS MEDIATING TACHYCARDIA INTHE CAT

1 It has been suggested that the tachycardic response to 5-hydroxytryp tamine (5-HT) in the spinal-transected cat is mediated by '5-HT1-like' receptors since this effect, being mimicked by 5-carboxamidotryptamin e (5-CT), is not modified by ketanserin or MDL 72222, but it is blocke d by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5-HT recep tor classification schemes proposed in 1994 and 1996. 2 Intravenous (i .v.) bolus injections of the tryptamine derivatives, 5-CT (0.01,0.03, 0.1, 0.3, 1, 3, 10 and 30 mu g kg(-1)), 5-HT (3, 10 and 30 mu g kg(-1) ) and 5-methoxytryptamine (3, 10 and 30 mu g kg(-1)) as well as the at ypical antipsychotic drug, clozapine (1000 and 3000 mu g kg(-1)) resul ted in dose-dependent increases in heart rate, with a rank order of ag onist potency of 5-CT much greater than 5-HT > 5-methoxytryptamine muc h greater than clozapine. 3 The tachycardic effects of 5-HT and 5-meth oxytryptamine were dose-dependently antagonized by i.v. administration of lisuride (30 and 100 mu g kg(-1)), ergotamine (100 and 300 mu g kg (-1)) or mesulergine (100, 300 and 1000 mu g kg(-1)); the highest dose s of these antagonists used also blocked the tachycardic effects of 5- CT. Clozapine (1000 and 3000 mu g kg(-1)) did not affect the 5-HT-indu ced tachycardia, but attenuated, with its highest dose, the responses to 5-methoxytryptamine and 5-CT. However, these doses of clozapine as well as the high doses of ergotamine (300 mu g kg(-1)) and mesulergine (300 and 1000 pg kg(-1)) also attenuated the tachycardic effects of i soprenaline. In contrast, 5-HT-, 5-methoxytryptamine- and 5-CT-induced tachycardia were not significantly modified after i.v. administration of physiological saline (0.1 and 0.3 mi kg(-1)), the 5-HT1B/1D recept or antagonist, GR127935 (500 mu g kg(-1)) or the 5-HT3/4 receptor anta gonist, tropisetron (3000 mu g kg(-1)). 4 Intravenous injections of th e 5-HT1 receptor agonists, sumatriptan (30, 100 and 300 mu g kg(-1)) a nd indorenate (300 and 1000 mu g kg(-1)) or the 5-HT4 receptor (partia l) agonist cisapride (300 and 1000 mu g kg(-1)) were devoid of effects on feline heart rate per se and failed to modify significantly 5-HT-i nduced tachycardic responses. 5 Based upon the above rank order of ago nist potency, the failure of sumatriptan, indorenate or cisapride to p roduce cardioacceleration and the blockade by a series of drugs showin g high affinity for the cloned 5-ht(7) receptor, the present results i ndicate that the 5-HT receptor mediating tachycardia in the cat is ope rationally similar to other putative 5-HT7 receptors mediating vascula r and non-vascular responses (e.g., relaxation of the rabbit femoral v ein, canine external carotid and coronary arteries, rat systemic vascu lature and guinea-pig ileum). Since these responses represent function al correlates of the 5-ht(7) gene product, the 5-HT7 receptor appellat ion is reinforced. Therefore, the present experimental model, which is not complicated by the presence of other 5-HT receptors, can be utili zed to characterize and develop new drugs with potential agonist and a ntagonist properties at functional 5-HT7 receptors.