Selective histamine H3 receptor agonists, such as R-alpha-methylhistamine, have been shown to inhibit neurogenic sympathetic pressor responses in vivo. The objective of the present study was to test the hypothesis that R-alpha-methylhistamine would evoke an histamine H3 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 pressor response. The depressor response was antagonized by chlorpheniramine (selective histamine H1 receptor antagonist, 3 mg.kg-1, i.v.), but was unaffected by cimetidine (selective histamine H2 receptor antagonist, 3 mg.kg-1, i.v.) or thioperamide (selective histamine H3 receptor antagonist, 3 mg.kg-1, i.v.). The pressor 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 pressor 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 anaesthetized rats inasmuch as the depressor response was antagonized by chlorpheniramine whereas the pressor response was resistant to histamine H1, H2 and H3 receptor antagonists. Combined alpha- and beta-adrenoceptor blockade (with phentolamine and nadolol) produced significant attenuation of the pressor and tachycardic responses to R-alpha-methylhistamine in pithed rats.(ABSTRACT TRUNCATED AT 250 WORDS)