N-004 INORGANIC NITRITE ATTENUATES ANGIOTENSIN II INDUCED CONTRACTION OF THE RENAL MICROCIRCULATION VIA XANTHINE OXIDASE-DEPENDENT NO PRODUCTION

Abstract

Background Reduced nitric oxide (NO) bioavailability in the kidney increases reactivity of preglomerular vessels, and may contribute to hypertension. Inorganic nitrite is emerging as a substrate for NOS-independent generation of NO, and physiological and therapeutic effects have been demonstrated in renal and cardiovascular disease. Today the influence of nitrite on renal microvascular function is not known. Methods Isolated and perfused renal afferent arterioles of mice (C57BL/6J) were used to investigate the effects of nitrite (10−9 to 10−4 mol/L, each dose applied for 2 min) on the luminal diameter. Effects of nitrite (10−5 mol/L) on NO production (using DAF-FM), and isotonic contractions to Ang II (10−12 to 10−6 mol/L, each dose applied for 2 min) were measured with or without simultaneous NOS-inhibition with L-NAME (10−4 mol/L). Results Nitrite increased luminal diameter in a dose dependent manner (6 ± 1% at 10−4 mol/L). Nitrite at 10−5 mol/L, applied for 15 min, dilated arterioles (6 ± 2%) and was associated with an increase in NO production (7 ± 1%). Ang II constricted arterioles in a concentration-dependent manner with a maximal response of 31 ± 3%. Simultaneous nitrite treatment (10−5 mol/L) attenuated the contractile response to Ang II (17 ± 4%). Simultaneous treatment with L-NAME enhanced Ang II-mediated contraction (56 ± 4%), and nitrite attenuated the response (25 ± 2%). The nitrite-mediated attenuation on Ang II+L-NAME-induced contraction was abolished by the NO scavenger cPTIO (66 ± 2%), the guanylyl cyclase inhibitor ODQ (58 ± 4%), as well as the xanthine oxidase inhibitor oxypurinol (63 ± 3%). Conclusion Inorganic nitrite undergoes xanthine oxidase-mediated reduction to NO in the microcirculation of the kidney, and attenuates Ang II mediated contraction. This novel function of nitrite in regulating preglomerular resistance may contribute to the reported effects in cardiovascular health and disease.