Role of Na+/H+ exchanger in acetylcholine-mediated pulmonary artery contraction of spontaneously hypertensive rats

Compared to sympathetic nervous system, the role of parasympathetic innervation on tone development, especially under diseased conditions, of the pulmonary artery is relatively unknown. In this study, the contractile effect of acetylcholine and the type(s) of muscarinic (M) receptor involved in the pulmonary artery (1st intralobar branch; endothelium-denuded, under resting tension) of the normotensive Wistar-Kyoto (WKY) and age-matched (male, 22-26 weeks old) Spontaneously hypertensive rats (SHR) were investigated. Cumulative administration of acetylcholine (greater than or equal to0.1 muM) caused a concentration-dependent increase in tension (antagonised by p-fluoro-hexahydro-siladifenidol and 4-diphenylacetoxy-N-methylpiperidine, both are selective muscarinic M-3 receptor antagonists) and the magnitude of maximum contraction (expressed as % of 50 mM [K+](o)-induced contraction) was markedly enhanced in the presence of neostigmine (10 muM, an anticholinesterase) (acetylcholine 30 muM, SHR: 72% vs. 35%; WKY: 32% vs. 20%). In SHR only, acetylcholine-elicited contraction was suppressed by 1-[beta-[3-(4-Methoxyphenyl)-propoxyl]-4-methoxyphenethyl]-1H-imidazole (SKF 96365, 1 muM), amiloride (500 muM), ethylisopropyl-amiloride (EIPA, 10 muM), 2-[2-[4-(4-Nitrobenzyloxy)phenyl]ethyl]isothiourea (KB-R 7943, 5 muM), 2,4-dichlorobenzamil (10 muM), and an equal molar substitution of [Na+](o), (less than or equal to30 mM) with choline or N-methyl-D-glucamine. In nominally [Ca2+](o)-free, EGTA (0.5 mM)-containing Krebs' solution, acetylcholine (greater than or equal to3 muM) only elicited a small contraction. In conclusion, muscarinic M-3 receptor activation is responsible for the pulmonary artery contraction induced by acetylcholine, with a greater magnitude observed in SHR. The exaggerated contraction in SHR is probably due to an influx of [Na+](o), through the Na+/H+ exchanger and the store-operated channels (SOC) into smooth muscle cells. Elevation of cytosolic [Na+](i) subsequently leads to an influx of [Ca2+](o) through the reverse mode of the Na+/Ca2+ exchanger seems to play a permissive role in mediating the exaggerated contractile response of acetylcholine recorded in the SHR. (C) 2003 Elsevier Science B.V. All rights reserved.