CHARACTERISTICS OF CARDIOVASCULAR REFLEXES ORIGINATING FROM 5‐HT₃ RECEPTORS IN THE HEART AND LUNGS OF UNANAESTHETIZED RABBITS

Abstract

1. When phenylbiguanide (1-PBG) (6.25-400 micrograms) was injected into the left atrium, right atrium or pulmonary artery of unanesthetized rabbits it caused dose-dependent falls of heart rate and arterial pressure, and short-lived hypopnoea or apnoea. The threshold dose was 50-100 micrograms. Maximal falls of heart rate (86-108 beats/min) and arterial pressure (33-35 mmHg) occurred at a dose of 200 micrograms. The latency between injection and onset of the bradycardia was 2.2-2.6 s and did not depend on the route. Cardiac output fell transiently with heart rate, but at the time of the maximal fall of arterial pressure it had returned to normal. All effects were abolished by intrapericardial procaine. The haemodynamic effects were exaggerated by sino-aortic barodenervation. Intrapericardial 1-PBG (200-400 micrograms) was without effect. Injection of 1-PBG (greater than 50-100 micrograms) into the aortic arch caused a variable increase in heart rate and arterial pressure. 2. When both cervical vagus nerves were crushed the depressor effects of atrial 1-PBG were reduced by only 76-84%. 3. The dose-response curves for left atrial and pulmonary artery injection of 1-PBG were shifted successively to the right by intravenous infusion of the 5-HT3 antagonist MDL72222 (0.1 and 1.0 mg/kg). 4. We conclude that in unanesthetized rabbits left atrial 1-PBG selectively excites myocardial afferents, whereas right atrial or pulmonary artery 1-PBG excites afferents that originate close to the pulmonary vasculature. In each case 1-PBG acts through pharmacologically specific 5-HT3 receptors. The afferents run mainly, but not exclusively, in the vagus nerves. The reflex fall of arterial pressure is accounted for almost entirely by a decrease in peripheral resistance.

Phenylbiguanide as electron donor in heterocyclic synthesis

“…Numerous reports have appeared in the literature, describing the cardiovascular reflexes [1][2][3][4][5][6], agonists and antagonists [3][4][5][6][7][8][9], visceral reflexes [10,11], and physiological [12] activity, as well as industrial [13][14][15][16][17] applications of arylbiguanides. Our long-term interest in chemical reactions induced by charge-transfer complexation forms a part of our systematic efforts to obtain new heterocyclic systems [18][19][20][21][22][23][24][25][26][27].…”

Chemosensitive cardiopulmonary afferents and the haemodynamic response to simulated haemorrhage in conscious rabbits

“…In rabbits (Evans et al, 1990a) and rats (Willette et al, 1982) phenylbiguanide-sensitive cardiopulmonary afferents are prominent, whereas they appear to be absent in dogs (Dawes et al, 1952) and man (Jain et al, 1972). On the basis of these pieces of circumstantial evidence we had expected to find that in conscious rabbits the signal that initiates the sympathoinhibitory phase of simulated haemorrhage was conveyed by phenylbiguanide-sensitive cardiac afferents, but we have not been able to demonstrate that this is so.…”

“…The effect of phenylbiguanide is mediated by pharmacologically-specific 5-HT3 receptors (Wright & Angus, 1988;Evans et al, 1990a). The afferents run mainly, though not exclusively, in the vagus nerves.…”

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

“…A number of authors have examined the mechanism of 5-HT-induced BJR. Evans et al (10) reported that intraatrial injection of phenylbiguanide, a 5-HT3-receptor agonist, induced a dose-dependent decrease in heart rate in conscious rabbits and that this response was inhibited by atropine and bilateral vagotomy. Bradycardia induced by intraatrial and intraventricular injections of 5-HT was also inhibited by both atropine and vagotomy in conscious and anesthetized dogs (8).…”

“…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)(9)(10)(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.…”