Effect of sodium nitrite on renal function and sodium and water excretion and brachial and central blood pressure in healthy subjects: a dose-response study.

Sodium nitrite (NaNO2) is converted to nitric oxide (NO) in vivo and has vasodilatory and natriuretic effects. Our aim was to examine the effects of NaNO2 on hemodynamics, sodium excretion, and glomerular filtration rate (GFR). In a single-blinded, placebo-controlled, crossover study, we infused placebo (0.9% NaCl) or 0.58, 1.74, or 3.48 µmol NaNO2·kg-1·h-1 for 2 h in 12 healthy subjects, after 4 days of a standard diet. Subjects were supine and water loaded. We measured brachial and central blood pressure (BP), plasma concentrations of renin, angiotensin II, aldosterone, arginine vasopressin (P-AVP), and plasma nitrite (P-[Formula: see text]), GFR by Cr-EDTA clearance, fractional excretion of sodium (FENa) free water clearance (CH2O), and urinary excretion rate of guanosine 3',5'-cyclic monophosphate (U-cGMP). The highest dose reduced brachial systolic BP (5.6 mmHg, P = 0.003), central systolic BP (5.6 mmHg, P = 0.035), and CH2O (maximum change from 3.79 to 1.27 ml/min, P = 0.031) and increased P-[Formula: see text] (from 0.065 to 0.766 µmol/l, P < 0.001), while reducing U-cGMP (from 444 to 247 pmol/min, P = 0.004). GFR, FENa, P-AVP, and the components in the renin-angiotensin-aldosterone system did not change significantly. In conclusion, intravenous NaNO2 induced a dose-dependent reduction of brachial and central BP. The hemodynamic effect was not mediated by the renin-angiotensin-aldosterone system. NaNO2 infusion resulted in a vasopressin-independent decrease in CH2O and urine output but no change in urinary sodium excretion or GFR. The lack of increase in cGMP accompanying the increase in [Formula: see text] suggests a direct effect of nitrite or nitrate on the renal tubules and vascular bed with little or no systemic conversion to NO.

Effect of tolvaptan on renal handling of water and sodium, GFR and central hemodynamics in autosomal dominant polycystic kidney disease during inhibition of the nitric oxide system: a randomized, placebo-controlled, double blind, crossover study.

BACKGROUND: Tolvaptan slows progression of autosomal dominant polycystic kidney disease (ADPKD) by antagonizing the vasopressin-cAMP axis. Nitric oxide (NO) stimulates natriuresis and diuresis, but its role is unknown during tolvaptan treatment in ADPKD. METHODS: Eighteen patients with ADPKD received tolvaptan 60 mg or placebo in a randomized, placebo-controlled, double blind, crossover study. L-NMMA (L-NG-monomethyl-arginine) was given as a bolus followed by continuous infusion during 60 min. We measured: GFR, urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary excretion of aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensinII (p-AngII), aldosterone (p-Aldo), and central blood pressure (cBP). RESULTS: During tolvaptan with NO-inhibition, a more pronounced decrease was measured in UO, CH2O (61% vs 43%) and FENa (46% vs 41%) after placebo than after tolvaptan; GFR and u-AQP2 decreased to the same extent; p-AVP increased three fold, whereas u-ENaCγ, PRC, p-AngII, and p-Aldo remained unchanged. After NO-inhibition, GFR increased after placebo and remained unchanged after tolvaptan (5% vs -6%). Central diastolic BP (CDBP) increased to a higher level after placebo than tolvaptan. Body weight fell during tolvaptan treatment. CONCLUSIONS: During NO inhibition, tolvaptan antagonized both the antidiuretic and the antinatriuretic effect of L-NMMA, partly via an AVP-dependent mechanism. U-AQP2 was not changed by tolvaptan, presumeably due to a counteracting effect of elevated p-AVP. The reduced GFR during tolvaptan most likely is caused by the reduction in extracellular fluid volume and blood pressure. TRIAL REGISTRATION: Clinical Trial no: NCT02527863 . Registered 18 February 2015.

Effect of tolvaptan on renal water and sodium excretion and blood pressure during nitric oxide inhibition: a dose-response study in healthy subjects.

BACKGROUND: Tolvaptan is a selective vasopressin receptor antagonist. Nitric Oxide (NO) promotes renal water and sodium excretion, but the effect is unknown in the nephron's principal cells. In a dose-response study, we measured the effect of tolvaptan on renal handling of water and sodium and systemic hemodynamics, during baseline and NO-inhibition with L-NMMA (L-NG-monomethyl-arginine). METHODS: In a randomized, placebo-controlled, double blind, cross over study, 15 healthy subjects received tolvaptan 15, 30 and 45 mg or placebo. L-NMMA was given as a bolus followed by continuous infusion during 60 min. We measured urine output (UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP) and central blood pressure (cBP). RESULTS: During baseline, FENa was unchanged. Tolvaptan decreased u-ENaCγ dose-dependently and increased p-AVP threefold, whereas u-AQP2 was unchanged. During tolvaptan with NO-inhibition, UO and CH2O decreased dose-dependently. FENa decreased dose-independently and u-ENaCγ remained unchanged. Central BP increased equally after all treatments. CONCLUSIONS: During baseline, fractional excretion of sodium was unchanged. During tolvaptan with NO-inhibition, renal water excretion was reduced dose dependently, and renal sodium excretion was reduced unrelated to the dose, partly via an AVP dependent mechanism. Thus, tolvaptan antagonized the reduction in renal water and sodium excretion during NO-inhibition. Most likely, the lack of decrease in AQP2 excretion by tolvaptan could be attributed to a counteracting effect of the high level of p-AVP. TRIAL REGISTRATION: Clinical Trial no: NCT02078973 . Registered 1 March 2014.

Effect of vasopressin antagonism on renal handling of sodium and water and central and brachial blood pressure during inhibition of the nitric oxide system in healthy subjects.

BACKGROUND: Tolvaptan is a selective vasopressin receptor antagonist (V2R) that increases free water excretion. We wanted to test the hypotheses that tolvaptan changes both renal handling of water and sodium and systemic hemodynamics during basal conditions and during nitric oxide (NO)-inhibition with L-NG-monomethyl-arginine (L-NMMA). METHODS: Nineteen healthy subjects were enrolled in a randomized, placebo-controlled, double-blind, crossover study of two examination days. Tolvaptan 15 mg or placebo was given in the morning. L-NMMA was given as a bolus followed by continuous infusion during 60 minutes. We measured urine output(UO), free water clearance (CH2O), fractional excretion of sodium (FENa), urinary aquaporin-2 channels (u-AQP2) and epithelial sodium channels (u-ENaCγ), plasma vasopressin (p-AVP), central and brachial blood pressure(cBP, bBP). RESULTS: During baseline conditions, tolvaptan caused a significant increase in UO, CH2O and p-AVP, and FENa was unchanged. During L-NMMA infusion, UO and CH2O decreased more pronounced after tolvaptan than after placebo (-54 vs.-42% and -34 vs.-9% respectively). U-AQP2 decreased during both treatments, whereas u-ENaCγ decreased after placebo and increased after tolvaptan. CBP and bBP were unchanged. CONCLUSION: During baseline conditions, tolvaptan increased renal water excretion. During NO-inhibition, the more pronounced reduction in renal water excretion after tolvaptan indicates that NO promotes water excretion in the principal cells, at least partly, via an AVP-dependent mechanism. The lack of decrease in u-AQP2 by tolvaptan could be explained by a counteracting effect of increased plasma vasopressin. The antagonizing effect of NO-inhibition on u-ENaC suggests that NO interferes with the transport via ENaC by an AVP-dependent mechanism.