Presynaptic modulation of efferent sympathetic and vagal neurotransmission in the canine heart by hypoxia, high K+, low pH, and adenosine. Possible relevance to ischemia-induced denervation.

Abstract

Ischemia in the dog produces denervation of myocardium apical to the ischemic area. To investigate the mechanism(s) of the denervation, we tested the effects of hypoxia and some components of ischemia including high K+, low pH, and adenosine on efferent cardiac autonomic responses. In anesthetized, open-chest dogs, we occluded a diagonal branch of the left anterior descending coronary artery and perfused it with hypoxic Tyrode's solutions (PO2 less than 50 mm Hg). We found that effective refractory period (ERP) shortening induced by bilateral ansae subclaviae stimulation at myocardium basal and apical to the perfusing area did not change during a 20-25 minute period of perfusion with hypoxic normal Tyrode's solution. During perfusion with hypoxic combined Tyrode's solution containing 12 mM K+, pH 6.8, and 10 microM adenosine, ERP shortening at basal sites induced by bilateral ansae subclaviae stimulation remained unchanged but was attenuated at apical sites (16 +/- 1 to 8 +/- 1 msec, mean +/- SEM, n = 35, p less than 0.001), and seven apical sites exhibited denervation (less than or equal to 2-msec shortening). The maximum extracellular K+ concentration of the perfusing area, measured with a K(+)-sensitive electrode, was 5.1 +/- 0.9 mM (N = 3 dogs) during perfusion with normal Tyrode's solution and was 11.8 +/- 0.1 mM (N = 3 dogs) during perfusion with hypoxic combined solution (p = 0.017). In a separate group of dogs, the effects of high K+, low pH, and adenosine in the absence of ischemia were examined. Oxygenated Tyrode's solutions were instilled into the pericardial cavity to superfuse epicardial nerves. The Tyrode's solutions containing high K+ (12 mM), low pH (6.4), or adenosine (10 microM), individually or combined, reduced ERP shortening induced by bilateral ansae subclaviae stimulation in the ventricular intramyocardium to 46%, 55%, 56%, and 33% of each control value obtained during superfusion with normal Tyrode's solution and reduced the magnitude of ERP lengthening induced by bilateral cervical vagal stimulation to 57%, 71%, 61%, and 39%, respectively. ERP responses of the test sites to infused norepinephrine and methacholine, however, remained unaffected by superfusion with combined Tyrode's solution. Thus, high K+, low pH, and adenosine each inhibit efferent sympathetic and vagal neurotransmission presynaptically in the canine heart and may contribute to the development of denervation during early ischemia.