Protective Roles for Neuronal Nitric Oxide Synthase (nNOS) and Cyclo‐oxygenase2 (COX2) in the Salt‐Sensitive Female mRen2.Lewis Rat

Abstract

Salt-sensitive hypertension is associated with an increased risk of cardiovascular and renal morbidity. We previously reported that female mRen2.Lewis rats exhibit marked increases in systolic blood pressure (SBP) and proteinuria during a chronic high salt diet. Moreover, high salt upregulated nNOS (2.4 fold) and COX2 (3.3 fold) mRNA levels in renal cortex. Increased immunostaining for nNOS and COX2 was evident in the macula densa and cortical tubules in the high salt group. To assess the influence of these pathways in salt-induced hypertension, nNOS or COX2 inhibitors were chronically administered to female mRen2.Lewis rats under high (HS: 8%) or normal (NS: 1%) salt diets. A three-week treatment with the selective nNOS inhibitor L-VNIO (0.5mg/kg/day) increased both SBP and proteinuria in the HS group (186 + 5 vs. 214 + 8 mmHg, p<0.05; 10.4 + 1.3 vs. 17.5 + 3.5 mg/kg/day), but had no effect in the NS group (145 + 4 vs. 139 + 7 mmHg; 11.6 + 1.9 vs. 9.17 + 2.4 mg/kg/day). The selective COX2 inhibitor NS-398 (1mg/kg/day) also increased blood pressure to a similar extent in the HS group (195 + 5 vs. 227 + 11 mmHg), but exacerbated the proteinuria to a greater degree (88 + 17 mg/kg/day). Western blot analysis revealed reduced COX2 content in the renal cortex (p<0.05) following chronic nNOS inhibition. We conclude that nNOS is protective for hypertension in the salt-sensitive female mRen2.Lewis rat through a positive influence on COX2 expression; however, COX2 exhibits a greater role to ameliorate proteinuria. Support: HL-56973, AHA-0525586.