Alterations in endothelial nitric oxide synthase activity and their relevance to blood pressure.

Among all physiologic functions of nitric oxide (NO) known so far, NO-dependent regulation of vascular tone is one of the most important. Under physiological conditions vascular NO is mainly generated by endothelial NO-synthase (eNOS), the major isoform of NOS in the cardiovascular system. NO produced in vascular endothelial cells displays complex physiologic activities considered to be vasoprotective. Of those, the initially detected vasodilation was most rigorously investigated. Increasing the activity of eNOS by genetic approaches in mouse models, non-pharmacologic interventions such as exercise training and treatment with a variety of drugs, for example ACE-inhibitors, reduces blood pressure. Conversely, several experimental and clinical conditions reducing the activity of eNOS and/or initiating the development of endothelial dysfunction show the opposite effect. While robust evidence suggest that endothelial dysfunction occurs in overt hypertension, it is still a matter of debate whether endothelial dysfunction might be an underlying cause of essential hypertension. Therefore, investigations using transgenic mice expressing mutant eNOS enzymes as well as clinical studies demonstrating an association of hypertension with some loss-of-function alleles in the promoter and in exon 7 of the eNOS gene were highlighted in this review. It is concluded that present experimental and clinical data strongly support the view that endothelial dysfunction contributes to the well-known genetic causes of hypertension and should be considered as a pre-hypertensive treatment option.