Inhibition of COX-2 prevents hypertension and proteinuria associated with a decrease of 8-iso-PGF2α formation in l-NAME-treated rats

Publisher Website
Google Scholar
Abstract
Background The inhibition of nitric oxide (NO) exerts injurious effects on the cardiovascular system by several mechanisms, such as the activation of the renin–angiotensin system, oxidative stress, and inflammatory cytokines. We examined whether COX-2, an inducible isoform of cyclooxygenase, is associated with the pathogenesis observed in Nω-nitro-l-arginine methyl ester (l-NAME)-induced hypertensive rats. Methods Three groups of 8-week-old male Sprague–Dawley rats were studied (n = 6 in each group): group 1, untreated controls; group 2, treated with l-NAME (1 g/l for 3 weeks, p.o.); and group 3, l-NAME co-treated with COX-2 inhibitor NS-398 (5 mg/kg per day, i.p.). The l-NAME-induced expression of COX-2 mRNA and protein was semi-quantified in the kidneys and the thoracic aorta. Urinary excretion of the prostaglandin 6-keto PGF1α, thromboxane B2 (TXB2), and prostaglandin E2 (PGE2) was measured in the three groups. Moreover, urinary excretion of 8-iso-PGF2α, a potent vasoconstricting arachidonic acid metabolite acting through thromboxane A (TXA) receptor activation, proposed recently as a marker of oxidative stress, was also measured. Results l-NAME induced significant increases in systolic blood pressure (P< 0.01), urinary protein (P< 0.05), and renal excretion of 8-iso-PGF2α (P< 0.01), compared with the control. In l-NAME-treated rats, the levels of COX-2 mRNA and protein were more than 50% higher in the kidneys (P< 0.05), and six-fold higher in the thoracic aorta (P< 0.01) than in control rats. NS-398 significantly ameliorated an increase in systolic blood pressure (P< 0.01) and urinary protein (P< 0.05) induced by l-NAME. Conclusions These data indicate that an increase in COX-2 expression might have a hypertensive effect, partly associated with 8-iso-PGF2α formation in l-NAME-treated rats.