BLOCKADE OF CENTRAL NERVOUS-SYSTEM GABAERGIC TONE CAUSES SYMPATHETIC-MEDIATED INCREASES IN CORONARY VASCULAR-RESISTANCE IN CATS

Picrotoxin, an antagonist of GABA produces an increase in coronary vascular resistance, S-T segment elevation, and ventricular arrhythmias after an i.v. injection of 2 mg/kg in chloralose anesthetized cats. To determine whether these responses were due to blockade of CNS GABAergic mechanisms leading to an increase in sympathetic outflow to the coronary vasculature, several types of experiments were performed. Picrotoxin was injected directly into the brain in a dose of 600 .mu.g while coronary blood flow and S-T segment changes were monitored. CNS administration of this agent resulted in a significant increase in coronary vascular resistance, S-T segment elevation, and arrhythmias. Animals were pretreated with the GABA receptor agonist drug, muscimol, prior to central administration of picrotoxin. Pretreatment prevented the usual increase in coronary vascular resistance, S-T segment elevation, and arrhythmias. Animals were subjected to acute bilateral cardiac sympathetic denervation prior to picrotoxin administration. Denervation attenuated the picrotoxin-induced increase in coronary vascular resistance (mean = 11.6 .+-. 2.1% vs. 26.1 .+-. 7.1%, P < 0.05) and elevation in S-T segment (mean = 0.09 .+-. 0.03 mV vs. 0.29 .+-. 0.04 mV, P < 0.05), and prevented arrhythmias. Pretreatment with the .alpha.-receptor blocking agent, phentolamine, produced even more pronounced antagonistic effects. Blockade of CNS GABAergic tone leads to enhanced sympathetic outflow to the coronary vasculature, resulting in an increase in coronary vascular resistance of sufficient intensity of cause S-T segment elevation and arrhythmias.