Peroxynitrite is Involved in the Dysfunction of Vasorelaxation in SHR/NDmcr-cp Rats, Spontaneously Hypertensive Obese Rats

Abstract

SHR/NDmcr-cp (SHR-cp) rats display typical symptoms and features of the metabolic syndrome. We previously reported that endothelium-dependent relaxation decreases in the thoracic aortas of SHR-cp rats, despite increased nitric oxide (NO) production from the endothelium. In the present study, to search for the reasons for this contradiction, we investigated whether vascular abnormality could be reduced by treatment of SHR-cp rats with antihypertensive drugs; a calcium channel blocker (amlodipine), an alpha 2 and imidazoline receptor agonist (moxonidine), and an angiotensin II type 1 (AT1) receptor antagonist (telmisartan). Telmisartan but not amlodipine and moxonidine ameliorated the impairment of relaxation in response to acetylcholine and the increased protein expression of endothelium NO synthase in thoracic aortas. All three drugs significantly lowered the blood pressure. Telmisartan decreased the serum levels of lipid peroxide and 8-hydroxy-2'-deoxyguanosine, oxidative stress markers, and also the aortic levels of the protein expression of gp91, a component of NADPH oxidase, and 3-nitrotyrosine, a biomarker of peroxynitrite. These findings suggest that NADPH oxidase-derived superoxide, probably produced due to stimulation of AT1 receptors, reacts with NO to form peroxynitrite, and consequently decreases active NO, leading to attenuation of endothelium-dependent relaxation. Angiotensin receptor antagonists may be effective for preventing endothelial dysfunction in metabolic syndrome.

Reactive oxygen species and vascular biology: implications in human hypertension

“…13 Almost all experimental models of hypertension display some form of oxidative excess. [14][15][16][17][18][19][20] As inhibition of ROS-generating enzymes, anti-oxidants and ROS scavengers reduce blood pressure, whereas pro-oxidants increase blood pressure, it has been suggested that ROS are causally associated with hypertension, at least in animal models.…”

Reactive Oxygen Species, Vascular Noxs, and Hypertension: Focus on Translational and Clinical Research

“…Most experimental models of hypertension exhibit some degree of oxidative stress (48,67,93,95,236). Moreover, mice with reduced antioxidant enzyme systems and those deficient in NADPH oxidase have higher blood pressures than those with intact systems.…”

The Effects of Antihypertensive Agents in Metabolic Syndrome – Benefits Beyond Blood Pressure Control

“…Similar brachial BP and CAP reductions were achieved with valsartan plus HCTZ versus amlodipine; however, valsartan plus HCTZ provided a greater reduction in arterial stiffness (estimated by aortic PWV) [97]. Reductions in central SBP were greater with fosinopril plus HCTZ than with indapamide or amlodipine; this correlated with 24-hour and nighttime SBP reductions, but not with seated cuff SBP [98].…”