Characterization of cardiac H3 receptor expression and function

Abstract

Histamine H3 receptors (H3R) modulate the release of neurotransmitters and are hypothesized to play a role in cognition, sleep, and weight regulation thus providing an attractive drug target. Although expressed primarily in the CNS, it is known that this receptor can modulate neurotransmitter release at peripheral tissues including the heart. Using quantitative RT‐PCR, we demonstrate that H3R mRNA is expressed in canine Purkinje fibers although at a lower level than seen in brain. No H3R mRNA was detected in canine ventricle. Exposing isolated canine Purkinje fibers to increasing concentrations (0.01–1.0μM) of the H3R agonist R‐α‐methylhistamine (RAMH) did not affect the action potential duration determined from electrophysiological recordings of stimulated fibers (2 sec basic cycle length). In in vivo rat studies, i.v. infusion of RAMH (10 mg/kg) produced little changes in mean arterial pressure (MAP), heart rate (HR), cardiac contractility (dP/dt), and peripheral vascular resistance whereas 30 mg/kg RAMH caused large increases in MAP (10%), HR (36%), and dP/dt (62%) relative to vehicle treated rats. In a rat myocardial ischemia/reperfusion model involving occlusion of the main coronary artery, RAMH (3 mg/kg, i.v.) failed to reduce infarct size when infused 10 min prior to and during the duration (3 hr) of reperfusion. These results suggest that although H3R mRNA is present in Purkinje fibers, H3R agonists such as RAMH have no direct modulatory effects on Purkinje fiber function. However, RAMH can induce marked changes in cardiac function at high doses whereas lower doses do not appear to protect against reperfusion injury. Additional studies utilizing more potent and selective H3R agonists may be warranted to further elucidate the role of H3Rs in cardiac function.