The effect of sodium nitrite infusion on renal function, brachial and central blood pressure during enzyme inhibition by allopurinol, enalapril or acetazolamide in healthy subjects: a randomized, double-blinded, placebo-controlled, crossover study

BACKGROUND: Sodium nitrite (NaNO(2)) causes vasodilation, presumably by enzymatic conversion to nitric oxide (NO). Several enzymes with nitrite reducing capabilities have been discovered in vitro, but their relative importance in vivo has not been investigated. We aimed to examine the effects of NaNO(2) on blood pressure, fractional sodium excretion (FE(Na)), free water clearance (C(H2O)) and GFR, after pre-inhibition of xanthine oxidase, carbonic anhydrase, and angiotensin-converting enzyme. The latter as an approach to upregulate endothelial NO synthase activity. METHODS: In a double-blinded, placebo-controlled, crossover study, 16 healthy subjects were treated, in a randomized order, with placebo, allopurinol 150 mg twice daily (TD), enalapril 5 mg TD, or acetazolamide 250 mg TD. After 4 days of treatment and standardized diet, the subjects were examined at our lab. During intravenous infusion of 240 μg NaNO(2)/kg/hour for 2 h, we measured changes in brachial and central blood pressure (BP), plasma cyclic guanosine monophosphate (P-cGMP), plasma and urine osmolality, GFR by (51)Cr-EDTA clearance, FE(Na) and urinary excretion rate of cGMP (U-cGMP) and nitrite and nitrate (U-NO(x)). Subjects were supine and orally water-loaded throughout the examination day. RESULTS: Irrespective of pretreatment, we observed an increase in FE(Na), heart rate, U-NO(x), and a decrease in C(H2O) and brachial systolic BP during NaNO(2) infusion. P-cGMP and U-cGMP did not change during infusion. We observed a consistent trend towards a reduction in central systolic BP, which was only significant after allopurinol. CONCLUSION: This study showed a robust BP lowering, natriuretic and anti-aquaretic effect of intravenous NaNO(2) regardless of preceding enzyme inhibition. None of the three enzyme inhibitors used convincingly modified the pharmacological effects of NaNO(2). The steady cGMP indicates little or no conversion of nitrite to NO. Thus the effect of NaNO(2) may not be mediated by NO generation. TRIAL REGISTRATION: EU Clinical Trials Register, 2013-003404-39. Registered December 3 2013.