Characterization and Function of Histamine Receptors in Corpus Cavernosum

Abstract

Widespread clinical use of H2 antagonists for peptic ulcer disease has been associated with reports of impotence. Histamine is a vasoactive amine which is endogenously produced in many organs including the penis. To date, 3 histamine receptor subtypes (H1, H2 and H3) have been identified. However, the role and function of histamine in the corpus cavernosal physiology are poorly understood. This study evaluates the in vitro functional characteristics of the 3 histamine receptor subtypes in the isolated corpus cavernosal strips from New Zealand White rabbits. The isometric responses to histamine and specific histamine receptor subtype agonists were assessed, following cyclooxygenase (indomethacin, 10(-5) M.), adrenergic (guanethidine, 5 x 10(-6) M.) and cholinergic (atropine, 5 x 10(-6) M.) blockade, at resting tension and after submaximal precontraction with norepinephrine (NE, 2 x 10(-5) M.). Histamine (10(-8) M. to 10(-3) M.) produced concentration-dependent contraction from basal and precontracted states and did not relax precontracted tissue. The H1 agonist, 2-(2-thiazolyl)ethylamine (10(-8) M. to 10(-3) M.), produced a contractile response from both basal and precontracted states, while the corporal tissue did not respond to either dimaprit, an H2 agonist (10(-8) M. to 10(-5) M.) or R(-)-alpha-methyl-histamine, an H3 agonist (10(-8) M. to 10(-5) M.). The response to histamine was progressively attenuated by an H1 antagonist (mepyramine; 10(-8) M. to 10(-5) M.), while neither an H2 antagonist (cimetidine; 10(-4)M.) nor an H3 antagonist (thioperamide; 10(-4)M.) had any inhibitory effects. H1 antagonism enhanced relaxation induced by electrical field stimulation (neurally mediated). Such relaxation increased after preincubation with 10(-6) M. or greater of mepyramine (p < 0.05). This study suggests that the principal histamine receptor subtype that mediates smooth muscle cell contraction in the corpus cavernosum is the H1 subtype. Since histamine H1 receptor antagonism increased NANC neurally mediated corporal relaxation, it possesses potential as an intracavernosal pharmacotherapeutic agent for the treatment of erectile dysfunction. This study, therefore, strongly indicates that H2 receptor antagonists are unlikely to have direct effects on penile erection.