Vagal nerve stimulation during muscarinic and beta-adrenergic blockade causes significant coronary artery dilation

Abstract

Vasoactive intestinal peptide (VIP) is present in post-ganglionic vagal nerve fibers in the coronary arteries and right ventricle but no significant amounts are found in the left ventricle. We determined the effects of VIP, released endogenously from cardiac vagal nerves, on the circumflex mean coronary artery pressure and on right and left ventricular (RV and LV) contractility (d P/d t max) and relaxation (d P/d t min). In 20 anesthetized, open chest mongrel dogs, the cervical vagus nerves and cardiac sympathetic ansa subclaviae were isolated and transected. Electrodes were applied to the cardiac segments of the right and left vagus nerves for subsequent stimulation. The muscarinic and β-adrenergic receptors were blocked with atropine and propranolol, respectively. The heart rate was controlled by either producing atrioventricular node block in 10 dogs and pacing the ventricles (series 1) or by right atrial pacing in 10 separate dogs (series 2). Coronary artery blood flow was controlled by perfusing the circumflex coronary artery in each dog with femoral arterial blood at a controlled flow rate. Coronary artery pressure, ventricular and aortic pressures and d P/d t were continuously measured. Experiments were performed prior to and after the administration of [4Cl-D-Phe 6,Leu 17]VIP, a sensitive and selective VIP antagonist. Vagal nerve stimulation at 20 Hz (0.5 ms, 20 V) for 5 min significantly decreased the circumflex mean coronary artery pressure by 17% from the control value of 95±2 mmHg in series 1 and by 13% from the control value of 109±2 mmHg in series 2 (both p<0.005). Aortic, LV and RV systolic and end-diastolic pressures, LV d P/d t max and d P/d t min, and the EKG did not change. In contrast, RV d P/d t max and d P/d t min increased by 22% ( p<0.04) and 23% ( p<0.02), respectively, in series 1 and by 26% ( p<0.02) and 33% ( p<0.01), respectively, in series 2. The VIP antagonist, [4Cl-D-Phe 6,Leu 17]VIP, directly injected into the left circumflex coronary artery, had no effect on coronary, aortic or ventricular pressures, ventricular d P/d t or the EKG. However, 20 Hz vagal stimulation in the presence of the VIP antagonist did not decrease circumflex mean coronary artery pressure. In addition, vagal stimulation, in the presence of the VIP antagonist, had no effect on LV pressures or d P/d t but increased RV d P/d t max and d P/d t min. RV d P/d t max increased by 16% ( p<0.01) and RV d P/d t min increased by 22% ( p<0.04), respectively, in series 1 and by 27 and 24%, respectively, in series 2 (both p<0.01). Vagal nerve stimulation during muscarinic and β-adrenergic blockade releases VIP or a `VIP-like' substance that significantly decreases circumflex coronary artery vascular resistance and increases RV d P/d t max and d P/d t min.