Intravenous injection of an H3-agonist, (R)-alpha-methylhistamine, dose-dependently caused a transient fall in mean arterial pressure of guinea-pigs. This pressor response was not reduced by combined mepyramine/cimetidine (up to 1 mg kg-1), atropine or propranolol, but was attenuated by either a selective H3-antagonist, thioperamide, or a competitive inhibitor of nitric oxide synthesis, NG-monomethyl L-arginine. The reduction by the inhibitor of nitric oxide synthesis was reversed by L- but not D-arginine. Histamine activated the H3-sites since its depressor response (obtained with mepyramine and cimetidine) was similar to that of (R)-alpha-methylhistamine. Our data indicate that H3-sites could exist in the cardiovascular system of guinea-pigs and that their stimulation might be mediated through the L-arginine/nitric oxide pathway.