Cardiovascular effects of the beta-carboline FG 7142 in borderline hypertensive rats

The hypothesis that acute and chronic administration of the benzodiazepine inverse agonist FG 7142 (N-methyl-beta-carboline-3-carboxamide) produces cardiovascular changes similar to those seen during acute and chronic episodes of stress was studied using conscious, unrestrained borderline hypertensive rats (BHR). Chronic intraperitoneal administration of FG 7142 (10 mg/kg; 5 days/week for 8 weeks) failed to alter resting mean arterial pressure or heart rate compared to maturation and vehicle controls. However, chronic administration of FG 7142 prevented the hypertension associated with a high salt diet. Similarly, acute intravenous (i.v.) administration of FG 7142 (10 mg/kg) in BHR rendered hypertensive with a high-salt diet produced a significant reduction in resting mean arterial pressure as well as marked increases in heart rate. Pretreatment with the benzodiazepine receptor antagonist flumazenil (RO 15-1788, 10 mg/kg, i.v.) blocked the tachycardic response but had no effect on the hypotensive effect of FG 7142 administered i.v. in BHR with salt-induced hypertension. Acute administration of FG 7142 (0.1-10 mg/kg, i.v.) in normal BHR produced no significant changes in resting mean arterial pressure and dose-related increases in heart rate. These experiments indicate that, in conscious unrestrained BHR, FG 7142 can elicit changes in heart rate but not the changes in arterial pressure typically associated with stress or anxiety. Therefore, it appears that FG 7142 is of limited use as a pharmacological tool for investigating the cardiovascular effects of acute or chronic stress in BHR.