Regulation of Vascular Tone by Endothelium-Derived Contracting Factor (EDCF)

Abstract

Our purpose was to identify endothelium-derived contracting factor produced by acetylcholine stimulation in the aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The rings of the thoracic aorta were obtained from age-matched SHR and WKY rats, and changes in isometric tension were recorded. The relaxant responses to acetylcholine in the aortic rings from SHR were significantly weaker than those from WKY rats. The relaxant responses to acetylcholine were significantly enhanced by pretreatment with a cyclooxygenase inhibitor (indomethacin) or the thromboxane A2/prostaglandin H2 receptor antagonist (ONO-3708) in aortic rings from both SHR and WKY rats. A thromboxane A2 synthetase inhibitor (OKY-046) did not affect the acetylcholine-induced relaxation in the aortic rings from either SHR or WKY rats. When these rings were pretreated with an inhibitor of nitric oxide production (N-nitroarginine methylester), the relaxant response induced by acetylcholine was completely inhibitied. In the organ bath solution, prostaglandin E2 and 6-keto-prostaglandin F1α concentrations increased after acetylcholine stimulation, but prostaglandin F2α and thromboxane B2 concentrations did not. Exogenous prostaglandin H2, a stable analogue of thromboxane A2, and prostaglandin F2α induced contractions of the SHR rings at a lower concentration than prostaglandin E2, prostaglandin D2, and prostaglandin I2. These contractile responses to various prostaglandins were markedly inhibited by pretreatment with ONO-3708. A prostacyclin sinthetase inhibitor did not affect the relaxant responses to acetylcholine in the SHR rings. These results show that endothelium-derived contracting factor is produced and released by acetylcholine stimulation the aorta of not only SHR but also in WKY rats, and suggest that prostaglandin H2, a precursor of the released prostaglandins, is a strong candidate for being endothelium-derived contracting factor produced by acetylcholine stimulation. It was also suggested that in the rat aorta treated by acetylcholine, the vascular tonus is regulated by two factors, prostaglandin H2 (EDCF) and nitric oxide (endothelium-derived relaxing factor).