Species difference in the 5-hydroxytryptamine3 receptor associated with the von Bezold-Jarisch reflex

Species differences in the 5-hydroxytryptamine (5-HT)3 receptor among anesthetized rats, mice, rabbits, ferrets, dogs and guinea-pigs were examined in the transient bradycardia induced by i.v. injection of 5-HT (the von Bezold-Jarisch reflex). We also investigated the mechanism of the 5-HT-induced bradycardia in these species. 5-Hydroxytryptamine and the selective 5-HT3 receptor agonists, 2-methyl-5-HT and m-chlorophenylbiguanide, dosedependently decreased heart rate in all species. In anesthetized rats, mice, ferrets and guinea-pigs, 2-methyl-5-HT and m-chlorophenylbiguanide behaved as full agonists against the 5-HT3 receptor, whereas their agonistic action in rabbits was partial. On the basis of ED50 values, there was no marked species difference in the potency of 5-HT3 receptor agonists. In contrast, the blocking activities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), granisetron and ondansetron, were markedly weaker in anesthetized guinea-pigs than in the other species. With regard to the mechanism of the 5-HT-induced bradycardia, YM060, atropine or vagotomy completely inhibited the 5-HT-induced bradycardia in anesthetized rats and mice. In guinea-pigs, in contrast, higher doses of YM060 and atropine or vagotomy inhibited this reflex by approximately 80%. Although the YM060-resistant part of the 5-HT-induced bradycardia in guinea-pigs was affected by neither 5-HT2 receptor antagonists nor 5-HT4 receptor antagonists, it was completely abolished by methysergide, a 5-HT1-like and 5-HT2 receptor antagonist. These results suggest that there is a species difference in the 5-HT3 receptor between guinea-pigs and other species in the von Bezold-Jarisch reflex system. They also suggest that the 5-HT-induced bradycardia in anesthetized rats and mice is evoked by acetylcholine released through activation of 5-HT3 receptors on the vagus nerve, while that in guinea-pigs is, at least in part, mediated through 5-HT1-like receptors in addition to 5-HT3 receptors.