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.

Contribution of cyclooxygenase-1-dependent prostacyclin synthesis to bradykinin-induced dermal extravasation.

BACKGROUND: Non-allergic angioedema is a potentially life-threatening condition caused by accumulation of bradykinin and subsequent activation of bradykinin type 2 receptors (B2). Since COX activity plays a pivotal role in B2 signaling, the aim of this study was to determine which prostaglandins are the key mediators and which COX, COX-1 or COX-2, is predominantly involved. METHODS: We used Miles assays to assess the effects of inhibitors of COX, 5-lipoxygenase, epoxyeicosatrienoic acid generation, cytosolic phospholipase A2α and a variety of prostaglandin receptor antagonists on bradykinin-induced dermal extravasation in C57BL/6 and COX-1-deficient mice (COX-1-/-). In addition, the prostacyclin metabolite 6-keto-PGF1α was quantified by ELISA in subcutaneous tissue from C57BL/6 and human dermal microvascular endothelial cells. In the latter, 6-keto-PGF1α was also quantified and identified by LC-MS/MS. RESULTS: Unspecific COX inhibition by ibuprofen and diclofenac significantly reduced B2-mediated dermal extravasation in C57BL/6 but not COX-1-/-. Likewise, inhibition of cytosolic phospholipase A2α showed similar effects. Furthermore, extravasation in COX-1-/- was generally lower than in C57BL/6. Of the prostaglandin antagonists used, only the prostacyclin receptor antagonist RO1138452 showed a significant reduction of dermal extravasation. Moreover, 6-keto-PGF1α concentrations were increased after bradykinin treatment in subcutaneous tissue from C57BL/6 as well as in human dermal microvascular endothelial cells and this increase was abolished by diclofenac. CONCLUSION: Our findings suggest that COX-1-dependent prostacyclin production is critically involved in dermal extravasation after activation of B2 in small dermal blood vessels. Targeting prostacyclin production and/or signaling appears to be a suitable option for acute treatment of non-allergic angioedema.