An in vitro study of histamine on the pulmonary artery of the Wistar-Kyoto and spontaneously hypertensive rats

The vascular response to most neurotransmitters of different vascular beds is altered under hypertensive condition. The modulatory effect of genetic pulmonary arterial hypertension on histamine responses is not known. The present study was undertaken to evaluate the modulatory effect of enzymatic degradation (via histamine N-methyl-transferase and diamine oxidase) on the vascular response of histamine, and the subtype(s) of histamine receptor present in the pulmonary artery (first branch, O.D. similar to 800 mum) of the normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) (male, 22-26 weeks old). In phenylephrine (1 muM) pre-contracted preparations, histamine and 6-[2-(4-imidazolyl)ethylamino]-N-(4-tiifluoromethylphenyl) heptanecarboxamide (HTMT, a histamine H-1 receptor agonist) elicited a concentration-dependent relaxation, with a smaller magnitude recorded in SHR. Application of 10 muM S-[4-(N,N-dimethylamino)-butyl]isothiourea (SKF 91488, a selective histamine N-methyl-transferase inhibitor), but not aminoguanidine (100 muM, a diamine oxidase inhibitor), significantly attenuated histamine-induced relaxation. Clobenpropit (1 nM, a potent histamine H-3 receptor antagonist) "antagonised" the suppressive effect of SKF 91488 and histamine-evoked relaxation was restored. Endothelial denudation reduced histamine- and abolished HTMT-elicited relaxation. Dimaprit (a histamine H-2 receptor agonist) caused an endothelium-independent, cis-N-(2-phenylcyclopentyl)azacyclotridec-1-en-2-amine (MDL 12330A, 10 muM, an adenylate cyclase inhibitor)-sensitive, concentration-dependent relaxation, with a similar magnitude in both strains of rat. Histamine-evoked relaxation was reversed into a further contraction (clobenpropit (10 nM)-sensitive) (with a greater magnitude occurred in the WKY rat) after blocking the histamine H-1 and H-2 receptors with diphenhydramine plus cimetidine (30 muM each). A similar further contraction (clobenpropit-sensitive) was observed with imetit (a histamine H-3/H-4 receptor agonist) (greater than or equal to 3 muM). Under resting tension, imetit (greater than or equal to 0.3 muM) caused a clobenpropit (10 nM)- and prazosin (1 muM)-sensitive, concentration-dependent contraction, with a greater contraction in the WKY rats. Our results suggest that inhibition of histamine catabolism using SKF 91488 (histamine N-methyl-transferase inhibitor) resulted in a reduction of histamine-mediated relaxation that was due to the activation of the clobenpropit-sensitive, histamine H-3/H-4 receptor and the release of catecholamine. In addition, activation of histamine H-1 and H-2 receptors resulted in relaxation whereas histamine H-3/H-4 receptor activation by imetit yielded a prazosin-sensitive contraction of the pulmonary artery. (C) 2003 Elsevier Science B.V. All rights reserved.