Characteristics of Inhibitory Effects of Serotonin (5-HT)3-Receptor Antagonists, YM060 and YM114 (KAE-393), on the von Bezold-Jarisch Reflex Induced by 2-Methyl-5-HT, Veratridine and Electrical Stimulation of Vagus Nerves in Anesthetized Rats

Abstract

BJR were largely consistent with those against 5-HT-induced BJR. In contrast, higher doses (100 pg/kg, i.v.) of YM060, YM114, ondansetron and granisetron did not inhibit veratridine (150 pg/kg, i.v.)-induced BJR. Atropine (300 pg/kg, i.v.) abolished bradycardia induced by electrical stimulation of vagal efferent nerves, whereas YM060, YM 114, ondansetron and granisetron had no effect at a dose of 1000 ug/kg, i.v. 5-HT (0.625-5.0 pg) injected into the left ventricle also caused a dose-dependent decrease in heart rate, an effect that was abolished by YM060 (0.1 pg/kg, i.v.), atropine (100 pg/kg, i.v.) and vagotomy. These results suggest that YM060 and YM114 are highly potent and selective 5-HT3-receptor antagonists that do not affect veratridine-or electrical stimulation-induced bradycardia in anesthetized rats. They also suggest that 5-HT-induced BJR in anesthetized rats originates from 5-HT3 receptors located on the endings of vagal afferent nerves in the heart. Keywords: 5-HT3-receptor antagonist, von Bezold-Jarisch reflex, Vagus nerve, Veratridine Serotonin (5-HT) is widely distributed and is implicated in a variety of physiological responses. Research into 5-HT-receptor subtypes, especially the 5-HT3 receptor, has advanced in recent years. 5-HT3 receptors are located on central, sensory and autonomic nerves and on the myenteric plexus (1, 2), and have been implicated in anxiety (3, 4), vomiting responses to cancer chemotherapeutic agents (5, 6) and stress-induced gastrointestinal disorders (7).Bolus intravenous injection of 5-HT causes transient bradycardia (the von Bezold-Jarisch reflex; BJR) in many species including rats, cats, dogs and rabbits (8-11). Fozard (12) reported that this reflex in anesthetized rats is mediated through the activation of 5-HT3 receptors located on endings of vagal afferent nerves. Activation of these receptors lead to the stimulation of vagus nerves, resulting in the bradycardia. 5-HT1-and 5-HT2-receptor antagonists had no effects on BJR induced by 5-HT in anesthetized rats (13). BJR in anesthetized rats is therefore frequently utilized as an in vivo system for the evaluation of 5-HT3-receptor blocking effects. Bradycardiac reflex through the stimulation of vagus nerves is evoked not only by activation of 5-HT3 receptors but also by activation of chemoreceptors in the heart and electrical stimulation of vagus nerves. It was reported that veratridine-induced BJR was evoked by ACh released from

Effects of Palonosetron on Perioperative Cardiovascular Complications in Patients Undergoing Noncardiac Surgery With General Anesthesia: A Retrospective Cohort Study

“…In our study, although there was no significant difference in the composite cardiac outcome, the incidence of intraoperative hypotension was lower in the palonosetron exposure group than the nonexposure group. This unexpected effect of palonosetron may be explained by inhibition of the Bezold–Jarisch reflex, which is a cardioinhibitory reflex, including bradycardia, hypotension, and peripheral vasodilation, for which 5‐HT (serotonin) is an important inducing factor via 5‐HT 3 receptors in the intracardiac vagal nerve endings in the setting of decreased blood volume . In previous clinical studies, ondansetron was shown to reduce spinal‐induced hypotension in patients undergoing spinal anesthesia, and granisetron, as another first‐generation 5‐HT 3 receptor antagonist, prevented neural‐mediated hypotension in patients undergoing head‐upright tilt testing .…”

Reduction in spinal-induced hypotension with ondansetron in parturients undergoing caesarean section: A double-blind randomised, placebo-controlled study

“…Blockade of the 5-HT3 receptor antagonizes the BJR induced by serotonin. 8,9 White et al observed that i.v. administration of the 5-HT3 antagonist granisetron 50 lg/kg was efficacious in suppressing bradycardia and hypotension associated with the BJR in a rabbit model.…”

“…3 Owczuk et al observed that intravenous ondansetron attenuated spinal-induced hypotension. 4 Animal studies suggest that 5-HT (serotonin) may be an important factor associated inducing the BJR in the setting of decreased blood volume [5][6][7][8] ; this effect can be blocked at the 5-HT3 receptor. 9 We hypothesized that spinal-induced hypotension and bradycardia could be minimized with the use of intravenous ondansetron, a 5-HT3 receptor antagonist, in non-labouring obstetric patients undergoing caesarean section.…”

A Phase II Trial of the Novel Serotonin Type 3 Receptor Antagonist Ramosetron in Japanese Male and Female Patients with Diarrhea-Predominant Irritable Bowel Syndrome

“…Ramosetron hydrochloride (ramosetron) is a potent and selective synthetic 5-HT 3 receptor antagonist [4, 5]. The results of animal studies have shown that ramosetron inhibited an acceleration of defecation or diarrhea induced by restraint stress [6].…”