We determined the effects of continuous cardiac vagal nerve stimulation on atrial contractility and on heart rate in mongrel dogs in which we blocked the muscarinic and beta-adrenergic receptors. Each dog received atropine, 0.5 mg/kg and propranolol, 0.5-1 mg/kg. We stimulated the cardiac vagus nerves in each dog for three separate 5-min periods at frequencies of 0 (control), 20, and 40 Hz (5 ms, 15 V) and measured the changes in atrial contractility and heart rate. Vagal nerve stimulation increased right atrial contractility from the control value by 27% at 20 Hz and by 19% during stimulation at 40 Hz (P < 0.001). Vagal nerve stimulation also increased the heart rate from 114 +/- 5 beats/min during the control period to 146 +/- 10 beats/min (P < 0.01) during stimulation at a frequency of 20 Hz and to 140 +/- 11 beats/min (P < 0.05) during stimulation at 40 Hz. Injection of the vasoactive intestinal peptide (VIP) antagonist, [4Cl-D-Phe6,Leu17]VIP, directly into the dog right coronary artery in concentrations of 0 (control), 2, and 4 micrograms/kg did not influence spontaneous atrial contractility or the heart rate. However, 4 micrograms/kg of the VIP antagonist significantly reduced the augmentation in right atrial contractility and the increase in heart rate during vagal nerve stimulation. Our experiments suggest that cardiac vagal nerve stimulation, during muscarinic and beta-adrenergic receptor blockade, releases VIP or a 'VIP-like substance', that significantly augments atrial contractility and increases heart rate.