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The Effect of Sodium Nitrite on Renal Function and Blood Pressure in Healthy Humans. A Dose-response Study

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ClinicalTrials.gov Identifier: NCT02078908
Recruitment Status : Completed
First Posted : March 5, 2014
Last Update Posted : October 9, 2014
Sponsor:
Information provided by (Responsible Party):
Erling Bjerregaard Pedersen, Regional Hospital Holstebro

Brief 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.

Condition or disease Intervention/treatment Phase
Healthy Drug: Sodium nitrite, 40 micrograms/kg/hour Drug: Sodium nitrite, 120 micrograms/kg/hour Drug: Sodium nitrite, 240 micrograms/kg/hour Drug: Placebo Phase 1

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Official Title: The Effect of Sodium Nitrite on Renal Variables, Brachial and Central Blood Pressure in Healthy Humans. A Randomized, Cross Over, Placebo Controlled Dose-response Study
Study Start Date : September 2013
Actual Primary Completion Date : June 2014
Actual Study Completion Date : June 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 40 micrograms sodium nitrite
Continuous 2 hour infusion of sodium nitrite, 40 micrograms/kg/hour
Drug: Sodium nitrite, 40 micrograms/kg/hour
Continuous 2 hour infusion of sodium nitrite, 40 micrograms/kg/hour
Other Names:
  • NaNO2
  • ATC V03AB08
  • EV substance code: SUB15308MIG
  • CAS15 number: 7632-00-0

Active Comparator: 120 micrograms sodium nitrite
Continuous 2 hour infusion of sodium nitrite, 120 micrograms/kg/hour
Drug: Sodium nitrite, 120 micrograms/kg/hour
Continuous 2 hour infusion of sodium nitrite, 120 micrograms/kg/hour
Other Names:
  • NaNO2
  • ATC V03AB08
  • EV substance code: SUB15308MIG
  • CAS15 number: 7632-00-0

Active Comparator: 240 micrograms sodium nitrite
Continuous 2 hour infusion of sodium nitrite, 240 micrograms/kg/hour
Drug: Sodium nitrite, 240 micrograms/kg/hour
Continuous 2 hour infusion of sodium nitrite, 240 micrograms/kg/hour
Other Names:
  • NaNO2
  • ATC V03AB08
  • EV substance code: SUB15308MIG
  • CAS15 number: 7632-00-0

Placebo Comparator: Placebo
Continuous 2 hour infusion of sodium chloride, 25 ml/hour
Drug: Placebo
Continuous 2 hour infusion of sodium chloride, 25 ml/hour
Other Name: Sodium chloride




Primary Outcome Measures :
  1. Fractional urinary sodium excretion [ Time Frame: One day ]

Secondary Outcome Measures :
  1. Nitrite clearance [ Time Frame: One day ]
  2. Nitrate clearance [ Time Frame: One day ]
  3. Glomerular filtration rate [ Time Frame: One day ]
    Measured by determent renal clearance of 51Cr-EDTA (51-chrome ethylenediaminetetraacetic acid) using constant infusing technique

  4. Proximal sodium transport [ Time Frame: One day ]
    Proximal sodium transport is estimated by lithium clearance

  5. Free water clearance [ Time Frame: One day ]
  6. Urinary excretion of cyclic guanosine monophosphate (cGMP) [ Time Frame: One day ]
  7. Urinary excretion of epithelial sodium channels (ENaC) [ Time Frame: One day ]
  8. Urinary excretion of water channels (aquaporin-2) [ Time Frame: One day ]
  9. Plasma concentration of renin [ Time Frame: One day ]
  10. Plasma concentration of angiotensin 2 [ Time Frame: One day ]
  11. Plasma concentration of aldosterone [ Time Frame: One day ]
  12. Plasma concentration of atrial natriuretic peptide (ANP) [ Time Frame: One day ]
  13. Plasma concentration of brain natriuretic peptide (BNP) [ Time Frame: One day ]
  14. Plasma concentration of cyclic guanosine monophosphate (cGMP) [ Time Frame: One day ]
  15. Plasma concentration of endothelin [ Time Frame: One day ]
  16. Plasma concentration of vasopressin (AVP, ADH) [ Time Frame: One day ]
  17. Peripheral (brachial) blood pressure [ Time Frame: One day ]
    Measured by oscillometric sphygmomanometer, Omron 705IT, Omron Matsusaka CO. Ltd.

  18. Central aortic systolic blood pressure (CASP) [ Time Frame: One day ]
    Estimated by tonometric pulse wave analysis. Device: BPro from HealthSTATS International, Singapore



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 40 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • BMI 18,5-30 kg/m2
  • Women must use safe contraception

Exclusion Criteria:

  • Tobacco smoking, medicine or substance abuse
  • Weekly consumption of more than 21 standard drinks of alcohol for men and 14 standard drinks of alcohol for women (1 danish standard drink equals 12 grams of alcohol)
  • Medical treatment in the last 2 weeks except for contraception
  • Pregnancy or nursing
  • Diabetes mellitus
  • estimated glomerular filtration rate (eGFR) < 60 ml/min
  • neoplasm
  • clinically significant heart, lung, liver, kidney, metabolic og neurologic disease
  • clinically significant findings in screening blood samples, urine sample or ECG
  • Office blood pressure > 140/90 mmHg
  • Blood donation within 1 month of the first day of investigation

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02078908


Locations
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Denmark
Department of Medical Research, Regional Hospital Holstebro
Holstebro, Denmark, 7500
Sponsors and Collaborators
Erling Bjerregaard Pedersen
Investigators
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Principal Investigator: Jesper N Bech, MD, PhD Regional Hospital Holstebro

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Responsible Party: Erling Bjerregaard Pedersen, Chief physician, PhD, Regional Hospital Holstebro
ClinicalTrials.gov Identifier: NCT02078908     History of Changes
Other Study ID Numbers: JBR-1-2013
2013-002211-10 ( EudraCT Number )
First Posted: March 5, 2014    Key Record Dates
Last Update Posted: October 9, 2014
Last Verified: October 2014

Keywords provided by Erling Bjerregaard Pedersen, Regional Hospital Holstebro:
Central blood pressure
Peripheral (brachial) blood pressure
Renal variables
Vasoactive hormones
Pharmacology
Pharmacokinetics