Relaxation Response of Histamine in the Pulmonary Artery of the Wistar‐Kyoto and Spontaneously Hypertensive Rats

Abstract

Mast cells are thought of primarily in the context of allergic disorders and certain acute inflammatory responses. Recent studies suggest, however, that mast cells are also implicated in the expression of a wide variety of biologic responses such as pulmonary vascular disease. In this study, we evaluated the pulmonary arterial relaxation effect, in vitro, of histamine and the receptor subtype(s) involved in the normotensive Wistar-Kyoto (WKY) and age-matched Spontaneously hypertensive rats (SHR) (male, age: 14–22 weeks). Isometric tension change of phenylephrine (1 μM) pre-contracted pulmonary artery in response to histamine and histaminergic agonists challenge was recorded and compared. Histamine (with 10 μM SKF 91488, a histamine N-methyl-transferase inhibitor) caused a concentration-dependent relaxation (endothelium-dependent and -independent) of both strains of rats. However, the magnitude of relaxation response observed in SHR was smaller and it is corresponded to a diminished H1-receptor-mediated (competitively inhibited by diphenhydramine), endothelium-dependent (L-NAME (20 μM)-sensitive) relaxation. The endothelium-independent (H2- and H3-receptors, suppressed by cimetidine and clobenpropit respectively) component was indistinguishable between both strains of rats. Unlike histamine, dimaprit (a H2-receptor agonist) consistently produced a similar degree of relaxation in the WKY and SHR. Under the SKF 91488-free or clobenpropit (1 nM, a H3-receptor blocker)-containing conditions, histamine-evoked relaxation was significantly enhanced in both the WKY and SHR. No potentiation was observed with tetrodotoxin (100 nM) present. Imetit (a H3-receptor agonist) failed to produce relaxation and a further contraction was observed in both strains of rats. The magnitude of imetit-induced contraction was greater in the WKY than in SHR. Imetit-evoked contraction was reduced in he presence of tetrodotoxin (100 nM) and clobenpropit (3 nM). Application of SQ 22536 (100 μM), L-NAME (50 μM), ouabain (10 μM), iberiotoxin (100 nM), glibenclamide (3 μM) and apamin (500 nM) failed to modify the endothelium-independent relaxation of histamine. A supplementation of L-arginine (500 μM) significantly potentiated histamine-evoked relaxation in the WKY and SHR. In conclusion, multiple histaminergic (H1-, H2- and H3-) receptors are present in rat pulmonary artery. A reduced histamine-induced relaxation in SHR is due to the diminished H1-receptor-mediated, endothelium-dependent relaxation. The endothelium-independent (H2- and H3-receptors) component of histamine-induced relaxation, however, was not modified by hypertension.