Relaxin Ameliorates Hypertension and Increases Nitric Oxide Metabolite Excretion in Angiotensin II But Not Nω-Nitro-L-Arginine Methyl Ester Hypertensive Rats

Previous findings suggest a potential therapeutic action of relaxin, the putative vasodilatory signal of normal pregnancy, in some forms of cardiovascular disease. However, the mechanisms underlying the beneficial effects of relaxin have not been fully elucidated. The purpose of this study was to determine whether the vasodilatory effects of relaxin are dependent on activation of NO synthase. We examined the effect of relaxin in male Sprague-Dawley rats given angiotensin II (Ang II; 200 ng/kg per minute SC by minipump), the NO synthase inhibitor N-omega-nitro-L-arginine methyl ester (L-NAME; 1.5 mg/100 g IV followed by 150 mg/L in drinking water), or vehicle for 3 weeks. After 7 days of Ang II or L-NAME, mean arterial pressure was elevated compared with baseline. Relaxin was administered (4 mu g/h, SC by minipump) for the next 2 weeks of Ang II, L-NAME, or vehicle treatment. Two-week relaxin treatment alone slightly reduced mean arterial pressure in normotensive rats. Three weeks of either Ang II or L-NAME treatment alone produced hypertension, albuminuria, mild glomerular sclerosis, reduced nitric oxide metabolite excretion, and increased oxidative stress (excretion of hydrogen peroxide and thiobarbituric acid reactive substances and renal cortex nitrotyrosine abundance). Relaxin reduced mean arterial pressure, albumin excretion, and oxidative stress markers and preserved glomerular structure and nitric oxide metabolite excretion in Ang II-treated rats; however, relaxin did not attenuate these changes in the rats treated with L-NAME. None of the treatments affected protein abundance of neuronal or endothelial NO synthase in the kidney cortex. These data suggest that the vasodilatory effects of relaxin are dependent on a functional NO synthase system and increased NO bioavailability possibly because of a reduction in oxidative stress. (Hypertension. 2011;58:197-204.)