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NO produced by NO synthase type 3 (NOS3) in medullary thick ascending limbs (mTHALs) inhibits Cl(-) reabsorption. Acutely, angiotensin II stimulates thick ascending limb NO production. In endothelial cells, NO inhibits NOS3 expression. Therefore, we hypothesized that angiotensin II decreases NOS3 expression via NO in mTHALs. After 24 hours, 10 and 100 nmol/L of angiotensin II decreased NOS3 expression by 23+/-9% (n=6; P&lt;0.05) and 50+/-5% (n=7; P&lt;0.001), respectively, in primary cultures of rat mTHALs. NO synthase inhibition by 4 mmol/L of N(G)-nitro-L-arginine methyl ester hydrochloride prevented angiotensin II from decreasing NOS3 expression (Delta=-5+/-8%; n=5). In the presence of N(G)-nitro-L-arginine methyl ester hydrochloride, the addition of exogenous NO (1 micromol/L spermine NONOate) restored the angiotensin II-induced decreases in NOS3 expression (-22+/-6%; n=7; P&lt;0.013). In addition, NO scavenging with 10 micromol/L of carboxy-PTIO abolished the effect of angiotensin II in NOS3 expression (Delta=-1+/-8% versus carboxy-PTIO alone; n=6). Angiotensin II increases superoxide, and superoxide scavenges NO. Thus, we tested whether scavenging superoxide enhances the angiotensin II-induced reduction in NOS3 expression. Surprisingly, treatment with 100 micromol/L of Tempol, a superoxide dismutase mimetic, blocked the angiotensin II-induced decrease in NOS3 expression (Delta=-3+/-7%; n=6). This effect was not because of increased hydrogen peroxide. We concluded that angiotensin II-induced decreases in NOS3 expression in mTHALs require both NO and superoxide. Decreased NOS3 expression by angiotensin II in mTHALs could contribute to increased salt retention observed in angiotensin II-induced hypertension.

Angiotensin II Decreases Nitric Oxide Synthase 3 Expression via Nitric Oxide and Superoxide in the Thick Ascending Limb