Increases in coronary vascular resistance initiated by blockade of CNS GABAergic tone occurs in the hindbrain.

The purpose of this study was to determine the site of action in the CNS responsible for producing picrotoxin-induced sympathetic mediated increase in coronary vascular resistance. To do this, picrotoxin, was administered either into the lateral cerebral ventricle, with the perfusion restricted to the forebrain, or into the fourth ventricle, to perfuse only the hindbrain and spinal cord, in chloralose-anesthetized cats, while monitoring coronary blood flow from the anterior descending branch of the left coronary artery, arterial pressure, heart rate and electrocardiogram (ECG). There was no difference between administration into the forebrain and hind-brain in terms of changes in coronary vascular resistance, ECG, arterial pressure and sinus rate when 600 micrograms of picrotoxin was used. Administration into either area elicited significant increases in coronary vascular resistance, arterial pressure and sinus rate, as well as changes in the ST segment and occasional ventricular tachyarrhythmias. However, a separation of effects was noted between the forebrain and the hindbrain when 200 micrograms of picrotoxin was administered. Administration of this dose into the forebrain did not significantly alter coronary vascular resistance or the ST segment, although significant increases in arterial pressure and sinus rate occurred in these animals. In contrast, administration of this dose into the hindbrain elicited significant increases in coronary vascular resistance, ST segment, arterial pressure and sinus rate. These results indicate that the most sensitive site for eliciting picrotoxin-induced increase in coronary vascular lies in the hindbrain.

Coronary spasm produced by picrotoxin in cats.

Picrotoxin (2 mg/kg i.v.) was administered to 6 vagotomized chloralose-anesthetized cats while monitoring coronary blood flow (electromagnetic flow probe), blood pressure and ECG. Coronary constriction occurred in each animal as measured by an increase in coronary vascular resistance (CVR) (mean = 25.2 +/- 7.5%, P less than 0.05) followed by ST segment elevation (0.30 +/- 0.06 mV, P less than 0.05). Pretreatment with phentolamine prevented the increase in CVR and the elevation in ST segment. These results demonstrate that picrotoxin produces alpha-receptor mediated coronary spasm.

Effects of phencyclidine, d-amphetamine and pentobarbital on schedule-controlled behavior in rats.

The effects of phencyclidine, d-amphetamine, and pentobarbital on responding maintained under a multiple fixed-interval (FI) 3-min fixed-ratio (FR) 30 schedule of food presentation were studied in rats. Phencyclidine (0.32-7.5 mg/kg) had a biphasic effect on overall response rate in both components; response rate increased and then decreased as the dose was increased. The FR was slightly more sensitive to the rate-decreasing effects of phencyclidine than the FI. The effects of d-amphetamine (0.1-7.5 mg/kg) on overall response rate were qualitatively similar to those of phencyclidine. The FI tended to be slightly more sensitive than the FR to the rate-increasing effects of d-amphetamine. Pentobarbital (1-18 mg/kg) produced little or no rate-increasing effects in the FR at low doses and decreased FR response rate at higher doses. In the FI, pentobarbital produced small increases in overall rate at intermediate doses while decreasing response rate at higher doses. The FR tended to be more sensitive than the FI to the rate-decreasing effects of pentobarbital. Unlike d-amphetamine and pentobarbital, phencyclidine produced smaller rate-increasing effects when the dose-effect curves were redetermined. Within the FI, the effects of phencyclidine and d-amphetamine on response rate were generally independent of the control rate of responding.

Blockade of central nervous system GABAergic tone causes sympathetic-mediated increases in coronary vascular resistance in cats.

Picrotoxin, an antagonist of gamma-aminobutyric acid, produces an increase in coronary vascular resistance, S-T segment elevation, and ventricular arrhythmias after an intravenous injection of 2 mg/kg in chloralose-anesthetized cats. To determine whether these responses were due to blockade of central nervous system GABAergic mechanisms leading to an increase in sympathetic outflow to the coronary vasculature, several types of experiments were performed. First, picrotoxin was injected directly into the brain in a dose of 600 micrograms while coronary blood flow and S-T segment changes were monitored. Central nervous system administration of this agent resulted in a significant increase in coronary vascular resistance, S-T segment elevation, and arrhythmias. Second, animals were pretreated with the gamma-aminobutyric acid 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. Third, 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 less than 0.05) and elevation in S-T segment (mean = 0.09 +/- 0.03 mV vs. 0.29 +/- 0.04 mV, P less than 0.05), and prevented arrhythmias. Pretreatment with the alpha-receptor blocking agent, phentolamine, produced even more pronounced antagonistic effects. These results suggest that blockade of central nervous system GABAergic tone leads to enhanced sympathetic outflow to the coronary vasculature, resulting in an increase in coronary vascular resistance of sufficient intensity to cause S-T segment elevation and arrhythmias.

Central gamma-aminobutyric acid involvement in blood pressure control.

The role of gamma-aminobutyric acid (GABA) in central nervous system (CNS) control of arterial blood pressure has been studied by testing the effects of drugs that either counteract or enhance CNS GABAergic mechanisms while monitoring the arterial pressure of normotensive and hypertensive animals. Drugs that antagonize the effects of GABA (either directly by blocking GABA-mediated responses or indirectly by inhibiting GABA synthesis) cause an increase in arterial pressure. This effect occurs in the forebrain and leads to an increase in sympathetic outflow to the vasculature, including the coronary vessels. GABA and drugs that stimulate GABA receptors (either directly or indirectly by inhibiting GABA metabolism, competing with an endogenous inhibitor of GABA, or activating a GABA chloride ionophore) cause a decrease in arterial pressure. This effect is, in some cases, associated with respiratory depression, and it occurs in the hindbrain, especially at the intermediate area on the ventral surface of the medulla. Hypertensive animals appear to be more sensitive to the hypotensive action of these agents. These results suggest that CNS GABA may have an important role in controlling blood pressure.