Characterization of putative 5‐HT7 receptors mediating tachycardia in the cat

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Abstract
It has been suggested that the tachycardic response to 5‐hydroxytryptamine (5‐HT) in the spinal‐transected cat is mediated by ‘5‐HT1‐like’ receptors since this effect, being mimicked by 5‐carboxamidotryptamine (5‐CT), is not modified by ketanserin or MDL 72222, but it is blocked by methiothepin, methysergide or mesulergine. The present study was set out to reanalyse this suggestion in terms of the IUPHAR 5‐HT receptor classification schemes proposed in 1994 and 1996. Intravenous (i.v.) bolus injections of the tryptamine derivatives, 5‐CT (0.01, 0.03, 0.1, 0.3, 1, 3, 10 and 30μgkg−1), 5‐HT (3, 10 and 30μgkg−1) and 5‐methoxytryptamine (3, 10 and 30μgkg−1) as well as the atypical antipsychotic drug, clozapine (1000 and 3000μgkg−1) resulted in dose‐dependent increases in heart rate, with a rank order of agonist potency of 5‐CT >>5‐HT >5‐methoxytryptamine >>clozapine. The tachycardic effects of 5‐HT and 5‐methoxytryptamine were dose‐dependently antagonized by i.v. administration of lisuride (30 and 100μgkg−1), ergotamine (100 and 300μgkg−1) or mesulergine (100, 300 and 1000μgkg−1); the highest doses of these antagonists used also blocked the tachycardic effects of 5‐CT. Clozapine (1000 and 3000μgkg−1) did not affect the 5‐HT‐induced 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 (300μgkg−1) and mesulergine (300 and 1000μgkg−1) also attenuated the tachycardic effects of isoprenaline. 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 0.3mlkg−1), the 5‐HT1B/1D receptor antagonist, GR127935 (500μgkg−1) or the 5‐HT3/4 receptor antagonist, tropisetron (3000μgkg−1). Intravenous injections of the 5‐HT1 receptor agonists, sumatriptan (30, 100 and 300μgkg−1) and indorenate (300 and 1000μgkg−1) or the 5‐HT4 receptor (partial) agonist cisapride (300 and 1000μgkg−1) were devoid of effects on feline heart rate per se and failed to modify significantly 5‐HT‐induced tachycardic responses. Based upon the above rank order of agonist potency, the failure of sumatriptan, indorenate or cisapride to produce cardioacceleration and the blockade by a series of drugs showing high affinity for the cloned 5‐ht7 receptor, the present results indicate that the 5‐HT receptor mediating tachycardia in the cat is operationally similar to other putative 5‐HT7 receptors mediating vascular and non‐vascular responses (e.g. relaxation of the rabbit femoral vein, canine external carotid and coronary arteries, rat systemic vasculature and guinea‐pig ileum). Since these responses represent functional correlates of the 5‐ht7 gene product, the 5‐HT7 receptor appellation is reinforced. Therefore, the present experimental model, which is not complicated by the presence of other 5‐HT receptors, can be utilized to characterize and develop new drugs with potential agonist and antagonist properties at functional 5‐HT7 receptors.