The antihypertensive effects of sodium nitrite are not associated with circulating angiotensin converting enzyme inhibition

• Sodium nitrite exerts antihypertensive effects by mechanisms not entirely known.
• The effects of sodium nitrite may be due to nitrite-derived nitric oxide formation.
• Nitric oxide inhibits the angiotensin converting enzyme (ACE).
• We demonstrated that nitrite does not inhibit circulating ACE in vivo or in vitro.
• Antihypertensive effects of nitrite are not mediated inhibition of circulating ACE.

Nitrite-derived nitric oxide (NO) formation exerts antihypertensive effects. Because NO inhibits angiotensin converting enzyme (ACE) activity, we carried a comprehensive series of experiments in rats to test the hypothesis that sodium nitrite exerts antihypertensive effects by inhibiting ACE. We examined whether sodium nitrite (15 mg/kg; or vehicle; by gavage): (I) attenuates the pressor responses to angiotensin I at doses of 0.03, 0.1, 0.3, 1, 3, and 10 μg/kg intravenously; (II) attenuates the acute hypertension induced by L-NAME (100 mg/kg; or vehicle; by gavage); (III) attenuates the chronic hypertension induced by L-NAME (1 g/L in drinking water; or vehicle) administered for 6 weeks; (IV) attenuates the hypertension in the 2 kidney-1 clip (2K1C) chronic hypertension model. Blood samples were collected at the end of each study and plasma angiotensin converting enzyme (ACE) activity was measured with a fluorimetric assay using Hippuryl-His-Leu as substrate. ACE inhibitors were used as positive controls. Plasma nitrite concentrations were measured by ozone-based reductive chemiluminescence. The in vitro effects of sodium nitrite (0, 1, 3, 10, 30, 100 μmol/L) on plasma ACE activity were also determined. We found that sodium nitrite did not affect the pressor responses to angiotensin I. Moreover, while sodium nitrite exerted significant antihypertensive effects in acute and chronic hypertension models, no significant effects on plasma ACE activity were found. In vitro experiments showed no effects of sodium nitrite on plasma ACE activity. This is the first study to demonstrate that the acute and chronic antihypertensive effects of sodium nitrite are not associated with significant inhibition of circulating ACE activity.

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