Characterization of central H2 receptors mediating cardiovascular activity by means of three histamine H2 receptor antagonists: MK-208, BMY-25368, and cimetidine in the rat

Abstract

Stimulation of central histamine H1 and or H2 receptors with histaminergic drugs results in a dose-related pressor response and bradycardia in conscious, freely-moving rats. Two recently developed peripheral histamine H2 antagonists, MK-208 and BMY-26368, as well as cimetidine, were evaluated with respect to their ability to block the cardiovascular actions of central histamine H2 receptors. These drugs do not readily cross the blood brain barrier, therefore, they were administered intracerebroventricularly (i.c.v.). The ability of these agents to attenuate the cardiovascular effects of the H2 agonist impromidine was studied in conscious, freely-moving rats. Blood pressure and heart rate were monitored directly via indwelling carotid catheters, and drugs were administered i.c.v. through permanently implanted cannulae. All of the H2 antagonists tested induced a transient hypertensive response that lasted approximately 15 min. MK-208 (30 μg) partially blocked the central cardiovascular actions of impromidine. Unlike other histaminergic agents, MK-208 produced a tachycardia and a profound hyperactivity which slowly developed into seizures. BMY-25368 and cimetidine failed to antagonize the cardiovascular actions of impromidine. These results demonstrate that cimetidine and BMY-25368, established peripheral H2 antagonists, did not block central H2 receptors, suggesting that central and peripheral H2 receptors may be pharmacologically distinct.