Abstract 16564: Stimulation of a Nitrate-Nitrite-NO Pathway Reduces Angiotensin II-Mediated Contraction of Renal Microcirculation
BACKGROUND: Reduced NO bioavailability in the kidney increases preglomerular reactivity, which may contribute to hypertension. Inorganic nitrate and nitrite can be reduced in vivo and emerge as substrates for NOS-independent NO generation. Therapeutic effects have been reported in renal disease, hypertension and diabetes. However, underlying mechanisms and potential effects in the kidney are not known. We investigated the hypothesis that nitrite may stimulate NO in the kidney and hence modulate renal microvascular responses.
METHODS: Isolated renal afferent arterioles of mice were used to investigate effects of nitrite on luminal diameter and NO production (DAF-FM). Contractions to Ang II (10-12 to 10-6 M), with or without NOS-inhibition (L-NAME; 10-4 M), were measured with acute nitrite treatment and after chronic nitrate treatment.
RESULTS: Acute treatment with nitrite, applied to the bath (10-9 to 10-4M), increased luminal diameter dose dependently (5±1% at 10-5 M), which was linked to increased NO production (7±1% at 10-5 M). Ang II constricted arterioles with a maximal response of 31±3%. Simultaneous nitrite treatment (10-5 M) attenuated the Ang II response (17±4%). L-NAME enhanced Ang II-mediated contraction (56±4%), and nitrite attenuated this response (25±2%). Mechanistically, nitrite-mediated attenuation of Ang II+L-NAME-induced contraction was abolished with a NO scavenger (cPTIO; 66±2%), a guanylyl cyclase inhibitor (ODQ; 58±4%), and with a xanthine oxidase inhibitor (oxypurinol; 63±3%). To test the effects of nitrite in a model with oxidative stress and NO-deficiency associated with enhanced preglomerular reactivity, we used SOD1-knockout mice. Nitrite attenuated the abnormally strong Ang II-mediated contraction in SOD1-knockouts from 89±5 to 48±6%. Chronic treatment with inorganic nitrate (10 mM, drinking water) for one week increased nitrite levels and attenuated the response to L-NAME+Ang II (32±2%).
CONCLUSION: Stimulation of a nitrate-nitrite-NO pathway attenuates Ang II-mediated contraction in the renal microcirculation. This novel function of these inorganic anions in the kidney may contribute to their therapeutic effects in renal and cardiovascular disease when NOS function is compromised.
- © 2011 by American Heart Association, Inc.