Gender specific generation of nitroxyl (HNO) from rat endothelium

Nitric oxide (NO) has long been accepted as the majority biological mediator underlying the critically important vasodilator function of the vascular endothelium yet there is growing evidence that the protonated one-electron reduction species of NO, nitroxyl (HNO), may also have biological activity. In this study we examined if there was a gender variation in the production of HNO from the endothelium of isolated segments of rat aorta. By use of recognized pharmacological inhibitors, we found that when the endothelium was stimulated by acetylcholine vascular relaxation was mediated entirely via NO in tissue from both males and females. The vasorelaxation induced by basal (non-stimulated) endothelium from females was also mediated entirely by NO. However, in contrast, the influence of basally active endothelium in males was mediated by both NO and HNO. The generation of HNO in males was dependent on endothelial nitric oxide synthase and relaxation was mediated via activation of soluble guanylate cyclase. We believe that this is the first evidence of a gender variation in the production of HNO and this may have important implications for our understanding of disparity in the development of cardiovascular disease between the sexes.