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 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). 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 α- and β-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-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. 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.