HISTAMINE H(1) RECEPTORS MEDIATE VASODILATION IN GUINEA-PIG ILEUM RESISTANCE VESSELS - CHARACTERIZATION WITH COMPUTER-ASSISTED VIDEOMICROSCOPY AND NEW SELECTIVE AGONISTS

Histamine receptors on guinea-pig ileum submucosal arterioles (outside diameter 40-80 mum) were studied in vitro using a computer-assisted videomicroscopy system (Diamtrak(R)). Histamine receptor agonists investigated in this study were histamine, the H-1 receptor-selective compound, 2-[2-(3-fluorophenyl)-4-imidazolyl]ethanamine (VZ 20), the H-2 receptor-selective compounds, dimaprit, impromidine, (+/-)-N1-[3-(4-fluorophenyl)-3-(pyridin-2-yl)propyl]-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (arpromidine) and (+/-)-N1-[3-(3,4-difluorophenyl)-3-(pyridin-2-yl)propyl]-N2-[3-(1H-imidazol-4-yl)propyl]guanidine (BU-E-75), as well as the H-3 receptor-selective drug, (R)-alpha-methylhistamine ((R)-alpha-MeHA). Applied to vessels at resting tone, the agonists (1 nM-300 muM) did not change arteriolar diameter. Vessels preconstricted by 10 muM noradrenaline showed similar concentration-dependent vasodilations with histamine and VZ 20 (pD2 = 5.38 and 5.36, respectively). This histamine-induced vasodilation was not affected by tetrodotoxin (0.5 muM) or indomethacin (1 muM), but was completely abolished in the presence of 1 muM of the H-1 receptor antagonist, mepyramine. Calculation of the antagonist affinity of mepyramine for the histamine receptors in submucosal arterioles yielded a pA2 of 9.46. In contrast to histamine and VZ 20, the H-2 receptor agonist, dimaprit, and the H-3 receptor agonist, (R)-alpha-MeHA, were ineffective at preconstricted arterioles. The guanidine-type H-2 receptor agonists, impromidine, arpromidine and BU-E-75, produced vasodilation at noradrenaline-preconstricted arterioles (-log EC50 = 4.47, 5.30 and 5.39, respectively) but, in contrast to histamine, were ineffective at arterioles preconstricted by U-46619 (300 nM). The - log EC50 were significantly correlated to antagonist affinities (pA2 values) of the compounds determined at alpha1-adrenoceptors in rat vas deferens and using urapidil as reference alpha-1-receptor antagonist (impromidine = 4.73, arpromidine = 5.66 and BU-E-75 = 6.15; urapidil pA2 = 7.52 and -log EC50 = 6.56 at guinea-pig ileum submucosal arterioles). Thus, vasodilation due to the guanidine-type H-2 receptor agonists in noradrenaline-preconstricted arterioles was due to concomitant alpha1-adrenoceptor antagonism of the compounds. The data suggest that submucosal arterioles in guinea-pig ileum possess only functional histamine H-1 receptors, activation of which dilates the blood vessels.