COX/iNOS dependence for angiotensin-II-induced endothelial dysfunction.

Vascular dysfunction induced by angiotensin-II can result from direct effects on vascular and inflammatory cells and indirect hemodynamic effects. Using isolated and functional cultured aortas, we aimed to identify the effects of angiotensin-II on cyclooxygenase (COX) and inducible nitric oxide synthase (iNOS) and evaluate their impact on vascular reactivity. Aortic rings from mice were incubated overnight in culture medium containing angiotensin-II (100 nmol/L) or vehicle to induce vascular disfunction. Vascular reactivity of cultured arteries was evaluated in a bath chamber. Immunofluorescence staining for COX-1 and COX-2 was performed. Nitric oxide (NO) formation was approached by the levels of nitrite, a NO end product, and using a fluorescent probe (DAF). Oxidative and nitrosative stress were determined by DHE fluorescence and nitrotyrosine staining, respectively. Arteries cultured with angiotensin-II showed impairment of endothelium-dependent relaxation, which was reversed by the AT1 receptor antagonist. Inhibition of COX and iNOS restored vascular relaxation, suggesting a common pathway in which angiotensin-II triggers COX and iNOS, leading to vasoconstrictor receptors activation. Moreover, using selective antagonists, TP and EP were identified as the receptors involved in this response. Endothelium-dependent contractions of angiotensin-II-cultured aortas were blunted by ibuprofen, and increased COX-2 immunostaining was found in the arteries, indicating endothelium release of vasoconstrictor prostanoids. Angiotensin-II induced increased reactive oxygen species and NO production. An iNOS inhibitor prevented NO enhancement and nitrotyrosine accumulation in arteries stimulated with angiotensin-II. These results confirm that angiotensin-II causes vascular inflammation that culminates in endothelial dysfunction in an iNOS and COX codependent manner.

Vascular Inflammation in Hypertension: Targeting Lipid Mediators Unbalance and Nitrosative Stress.

Arterial hypertension is a worldwide public health threat. High Blood Pressure (BP) is commonly associated with endothelial dysfunction, nitric oxide synthases (NOS) unbalance and high peripheral vascular resistance. In addition to those, inflammation has also been designated as one of the major components of BP increase and organ damage in hypertension. This minireview discusses vascular inflammatory triggers of high BP and aims to fill the existing gaps of antiinflammatory therapy of hypertension. Among the reasons discussed, enhanced prostaglandins rather than resolvins lipid mediators, immune cell infiltration and oxidative/nitrosative stress are pivotal players of BP increase within the inflammatory hypothesis. To address these inflammatory targets, this review also proposes new concepts in hypertension treatment with non-steroidal antiinflammatory drugs (NSAIDs), nitric oxide-releasing NSAIDs (NO-NSAIDs) and specialized proresolving mediators (SPM). In this context, the failure of NSAIDs in hypertension treatment seems to be associated with the reduction of endogenous NO bioavailability, which is not necessarily an effect of all drug members of this pharmacological class. For this reason, NO-releasing NSAIDs seem to be safer and more specific therapy to treat vascular inflammation in hypertension than regular NSAIDs.