The Effect of Sodium Nitrite on Renal Function and Blood Pressure in Healthy Humans. A Dose-response Study
Condition: Healthy
Study type: Interventional
Phase: Phase 1

Summary: 
      The purpose of this study is to investigate the effect of different doses of sodium nitrite
      infusion in 12 healthy subjects. The effects on renal handling of nitrite, nitrate, sodium
      and water, plasma concentrations of vasoactive hormones, peripheral (brachial) and central
      blood pressure will be evaluated.

      Hypothesis

      Sodium nitrite infusion

        1. increases urinary sodium excretion and renal filtration rate

        2. lowers blood pressure, central as well as peripheral

        3. affects vasoactive hormones

        4. it is possible to establish a dose that affects the renal function with only minor
           effect on the blood pressure.
    

Detailed description: 
      Background:

      Nitric oxide (NO) is an important vasodilating molecule with a very complex biochemistry and
      metabolism. NO is classically synthesized from L-arginin by endothelial nitric oxide synthase
      (eNOS) located in the endothelial cell lining. Several chronic cardiovascular diseases such
      as hypertension, chronic kidney disease and diabetes are accompanied by endothelial
      dysfunction and hence diminished synthesis of NO. NO is a very reactive molecule and direct
      investigation of its function are limited and it has mainly been investigated by inhibition
      of eNOS. Recent research has shown that sodium nitrite is readily converted to NO by enzymes
      in vivo. The effects of sodium nitrite on renal variables, vasoactive hormones and central
      blood pressure are previously unexamined. It is now possible to achieve serial estimations of
      the central aortic systolic pressure (CASP) by newly designed wrist born device.

      Hypothesis:

        1. Sodium nitrite infusion increases the urinary sodium excretion and glomerular filtration
           rate (GFR) in a dose related manner.

        2. Sodium nitrite infusion increases plasma levels of nitrite, nitrate, NO and cyclic
           guanosine monophosphate (cGMP)

        3. Sodium nitrite infusion lowers the peripheral and central blood pressure

        4. Renal clearance of nitrite is constant and not dose dependent

        5. Sodium nitrite infusion affects vasoactive hormones

        6. It is possible to establish a dose that affects the renal variables with only minor
           effect on the blood pressure.

      Purpose:

      The purpose of this study is to investigate the effects of sodium nitrite infusion on

        1. Renal handling of nitrite, nitrate, sodium and water

        2. Plasma concentrations of vasoactive hormones

        3. Peripheral (brachial) blood pressure and CASP

      Design:

      12 healthy subjects are recruited in this randomised, cross over, placebo controlled,
      single-blinded study. Each subject will attend to four examination days. Four days prior to
      each examination day subjects are given a standardized diet with a low level of nitrate and
      nitrite. On the evening before the examination day the subjects take a single dose of lithium
      carbonate 300 mg in order to measure lithium clearance. On the examination days subjects are
      receiving a two hour infusion of either placebo (isotonic sodium chloride) or one of three
      doses of sodium nitrite. During the four examination days each subject receives all
      treatments in random order.

      Perspectives:

      Knowledge regarding hemodynamic and renal dose-response relationship is essential, in order
      to carry out future planned studies of the nitrite-NO system, in hypertensive subjects and
      during simultaneous modulation of various enzyme systems, involved in the conversion of
      nitrite to NO. Increasing knowledge about the nitrite-NO system can contribute to changing
      the clinical practise of diagnostics and treatment of cardiovascular diseases.
    

Intervention name(s): Sodium nitrite, 40 micrograms/kg/hour; Sodium nitrite, 120 micrograms/kg/hour; Sodium nitrite, 240 micrograms/kg/hour; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Continuous 2 hour infusion of sodium nitrite, 40 micrograms/kg/hour; Continuous 2 hour infusion of sodium nitrite, 120 micrograms/kg/hour; Continuous 2 hour infusion of sodium nitrite, 240 micrograms/kg/hour; Continuous 2 hour infusion of sodium chloride, 25 ml/hour
Other intervention name(s): NaNO2; ATC V03AB08; EV substance code: SUB15308MIG; CAS15 number: 7632-00-0; NaNO2; ATC V03AB08; EV substance code: SUB15308MIG; CAS15 number: 7632-00-0; NaNO2; ATC V03AB08; EV substance code: SUB15308MIG; CAS15 number: 7632-00-0; Sodium chloride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Single (Participant)
Primary purpose: Basic Science
Keywords: Central blood pressure; Peripheral (brachial) blood pressure; Renal variables; Vasoactive hormones; Pharmacology; Pharmacokinetics