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

Abstract

1. 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. 2. Intravenous bolus injections of 5-HT (3, 10 and 30 micrograms 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 micrograms kg-1 in 5 ml) on the right atrium was also followed by tachycardia (38 +/- 6 beats min-1, n = 4). 3. 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. 4. The 5-HT-induced tachycardia was also not affected by antagonists at alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, and calcium channels. 5. 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. 6. A number of putative selective agonists at '5-HT1-like' receptors or their possible subtypes (5- carboxamidotryptamine (5-CT), 8-hydroxy-24di-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. 7. 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.