1. When phenylbiguanide (1-PBG) (6.25–400 μg) was injected into the left atrium, right atrium or pulmonary artery of unanaesthetized rabbits it caused dose-dependent falls of heart rate and arterial pressure, and short-lived hypopnoea or apnoea. The threshold dose was 50–100 μg. Maximal falls of heart rate (86–108 beats/min) and arterial pressure (33–35 mmHg) occurred at a dose of 200 μg. 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 μg) was without effect. Injection of 1-PBG (>50–100 μg) 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 unanaesthetized 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.