5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor

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Abstract
The mechanism of 5‐hydroxytryptamine (5‐HT)‐induced tachycardia is species‐dependent and is mediated directly or indirectly either by ‘5‐HT1‐like’ (cat), 5‐HT2 (rat, dog) or 5‐HT3 (rabbit) receptors, or by an action similar to tyramine (guinea‐pig). The present investigation is devoted to the analysis of the positive chronotropic effect of 5‐HT in the pentobarbitone‐anaesthetized pig. Intravenous bolus injections of 5‐HT (3, 10 and 30 μg kg−1) in pigs resulted in dose‐dependent increases in heart rate of 24 ± 2, 38 ± 3 and 51 ± 3 beats min−1, respectively (n = 39). Topical application of a high concentration of 5‐HT (150 μg kg−1 in 5 ml) on the right atrium was also followed by tachycardia (38 ± 6 beats min−1, n = 4). A number of drugs which antagonize responses mediated by different 5‐HT receptors ‐ phenoxybenzamine, methiothepin, metergoline, methysergide and mesulergine (‘5‐HT1‐like’ and 5‐HT2 receptors), ketanserin, cyproheptadine, pizotifen and mianserin (5‐HT2 receptors), and MDL 72222 and ICS 205–930 (5‐HT3 receptors) — did not attenuate the chronotropic responses to 5‐HT. The 5‐HT‐induced tachycardia was also not affected by antagonists at α‐ and β‐adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, and calcium channels. Selective inhibitors of 5‐HT‐uptake, indalpine and fluvoxamine, themselves increased porcine heart rate and facilitated 5‐HT‐induced tachycardia both in magnitude and in duration. A number of putative selective agonists at ‘5‐HT1‐like’ receptors or their possible subtypes (5‐carboxamidotryptamine (5‐CT), 8‐hydroxy‐2‐(di‐N,N‐n‐propylamino) tetralin (8‐OH‐DPAT), BEA 1654 and RU 24969), or at 5‐HT3 receptors (2‐methyl‐5‐HT), elicited no or only a weak tachycardiac response in the pig. RU 24969, but not 8‐OH‐DPAT, seemed to potentiate the responses to 5‐HT, whereas 5‐CT slightly inhibited these responses. It was concluded that the tachycardia induced by 5‐HT in the pig does not involve the receptors for some common neurotransmitter substances but may be mediated by a new 5‐HT receptor type that is clearly different from ‘5‐HT1 ‐like’, 5‐HT2 or 5‐HT3 receptors.