Vasoactive intestinal polypeptide (VIP) is a neuropeptide released from the vagus, which in contrast to acetylcholine has a long-acting positive chronotropic effect on the heart. The aim of this study, in the anaesthetized dog, was to examine the effects of VIP and a VIP antagonist when injected into the sinus node artery of a vagally intact heart in sinus arrhythmia. The response was compared to that produced by noradrenaline (NAD) infusion and stimulation of the sympathetic nerves to the heart. Mean +/- S.D. of 30 R-R intervals was used to describe mean heart rate interval and heart rate variability. VIP, a VIP antagonist, NAD and sympathetic nerve stimulation all caused increases in heart rate without significant increases in blood pressure. However, only VIP caused an increase in heart rate variability; VIP antagonism and NAD caused a decrease and sympathetic nerve stimulation had no effect. These results suggest that VIP and acetylcholine when released from the vagus act synergistically to increase sinus arrhythmia. (C) 2001 Elsevier Science Ltd. All rights reserved.