CARDIOVASCULAR EFFECTS OF R-ALPHA-METHYLHISTAMINE, A SELECTIVE HISTAMINE H-3 RECEPTOR AGONIST, IN RATS - LACK OF INVOLVEMENT OF HISTAMINE H-3 RECEPTORS

Selective histamine H-3 receptor agonists, such as R-alpha-methylhistamine, have been shown to inhibit neurogenic sympathetic presser responses in vivo. The objective of the present study was to test the hypothesis that R-alpha-methylhistamine would evoke an histamine H-3 receptor mediated hypotensive response in an animal with intact sympathetic vascular tone. In pentobarbital anaesthetized rats, administration of R-alpha-methylhistamine (0.1-3 mg.kg(-1), i.v.) had a biphasic effect on arterial pressure, consisting of a transient depressor response followed by a more long-lasting presser response. The depressor response was antagonized by chlorpheniramine (selective histamine H-1 receptor antagonist, 3 mg.kg(-1), i.v.), but was unaffected by cimetidine (selective histamine H-2 receptor antagonist, 3 mg.kg(-1), i.v.) or thioperamide (selective histamine H-3 receptor antagonist, 3 mg.kg(-1), i.v.). The presser response was unaltered by chlorpheniramine, cimetidine or thioperamide. In pithed rats, R-alpha-methylhistamine had a biphasic effect on arterial pressure which was qualitatively similar to that seen in anaesthetized rats with the exception that the presser responses were much greater in magnitude and duration and were accompanied by significant increases in heart rate. On a pharmacological basis, the biphasic response in pithed rats was identical to that seen in anaesthtized rats inasmuch as the depressor response was antagonized by chlorpheniramine whereas the presser response was resistant to histamine H-1, H-2 and H-3 receptor antagonists. Combined alpha- and beta-adrenoceptor blockade (with phentolamine and nadolol) produced significant attenuation of the presser and tachycardic responses to R-alpha-methylhistamine in pithed rats. The presser and tachycardic responses to R-alpha-methylhistamine were significantly blunted in adrenalectomized rats when compared to sham controls. Chemical sympathectomy, with 6-hydroxydopamine pretreatment, attenuated the tachycardic but not the presser responses to R-alpha-methylhistamine. These data suggest that the depressor response to R-alpha-methylhistamine is mediated via agonism of histamine H-1 receptors, whereas the presser response, which is mediated in part by adrenal catecholamines, is not due to activation of either histamine H-1, H-2 or H-3 receptors. No evidence was found for the involvement of histamine H-3 receptors in the cardiovascular effects of R-alpha-methylhistamine.