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. approximately 800 microm) of the normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) (male, 22-26 weeks old). In phenylephrine (1 microM) pre-contracted preparations, histamine and 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl) heptanecarboxamide (HTMT, a histamine H(1) receptor agonist) elicited a concentration-dependent relaxation, with a smaller magnitude recorded in SHR. Application of 10 microM S-[4-(N,N-dimethylamino)-butyl]isothiourea (SKF 91488, a selective histamine N-methyl-transferase inhibitor), but not aminoguanidine (100 microM, 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 microM, 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 microM each). A similar further contraction (clobenpropit-sensitive) was observed with imetit (a histamine H(3)/H(4) receptor agonist) (> or =3 microM). Under resting tension, imetit (> or =0.3 microM) caused a clobenpropit (10 nM)- and prazosin (1 microM)-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.
Lau
Wing Hung
WH
Department of Pharmacology, Faculty of Medicine, The Chinese University of Hong Kong, Room 409B, Basic Medical Sciences Building, Shatin, N.T., Hong Kong SAR, PR China.
Kwan
Yiu Wa
YW
Au
Alice Lai Shan
AL
Cheung
Wui Hang
WH
D000818:Animals; D004305:Dose-Response Relationship, Drug; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology*; D006973:Hypertension / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D011968:Receptors, Histamine / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D011968:Receptors, Histamine; D006632:Histamine