Hydroxyl Radical—a Mediator of Acetylcholine-induced Vascular Relaxation

Abstract

It is well known that acetylcholine (Ach)-induced vasodilation is mediated through the release of the endothelium-derived relaxing factor (EDRF), nitric oxide (NO·). It has been suggested that NO interacts with superoxide anion (O −2) to generate peroxynitrite which at physiological pH gives rise to peroxynitrous acid that rapidly decomposes to hydroxyl radical (·OH) and nitrogen dioxide. ·OH relaxes isolated aorta. It was hypothesized that Ach-induced vascular relaxation is mediated by ·OH derived from interaction of NO and O −2. To test this hypothesis we investigated the effect of Ach on norepinephrine (NE)-precontracted isolated rabbit aortic preparations in the absence or presence of scavengers of O −2[superoxide dismutase (SOD)] and of ·OH [dimethylthiourea (DMTU) or mannitol]. ·OH and Ach produced relaxation of NE-precontracted preparations in a concentration-dependent manner. Relaxation produced by ·OH generating system was prevented by mannitol, a ·OH scavenger suggesting that relaxation is due to ·OH. SOD, DMTU, mannitol or combination of SOD and DMTU markedly reduced the Ach-induced relaxation. Glyburide (an ATP-sensitive K +channel blocker) was ineffective in blocking the Ach-induced remaining relaxation in the presence of SOD and DMTU. These results suggest that ·OH formed from interaction of O −2and NO· is the mediator of Ach-induced vascular relaxation. Thus while EDRF is NO·, its mechanism of action involves ·OH.