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

Study Overview
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Brief Summary
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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 increases urinary sodium excretion and renal filtration rate lowers blood pressure, central as well as peripheral affects vasoactive hormones it is possible to establish a dose that affects the renal function with only minor effect on the blood pressure.

Detailed Description
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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: Sodium nitrite infusion increases the urinary sodium excretion and glomerular filtration rate (GFR) in a dose related manner. Sodium nitrite infusion increases plasma levels of nitrite, nitrate, NO and cyclic guanosine monophosphate (cGMP) Sodium nitrite infusion lowers the peripheral and central blood pressure Renal clearance of nitrite is constant and not dose dependent Sodium nitrite infusion affects vasoactive hormones 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 Renal handling of nitrite, nitrate, sodium and water Plasma concentrations of vasoactive hormones 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.

Official Title
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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

Conditions
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Healthy

Intervention / Treatment
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* Drug: Sodium nitrite, 40 micrograms/kg/hour
* Drug: Sodium nitrite, 120 micrograms/kg/hour
* Drug: Sodium nitrite, 240 micrograms/kg/hour
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 40 micrograms sodium nitrite<br>Continuous 2 hour infusion of sodium nitrite, 40 micrograms/kg/hour | Drug: Sodium nitrite, 40 micrograms/kg/hour<br>* Continuous 2 hour infusion of sodium nitrite, 40 micrograms/kg/hour<br>* Other names: CAS15 number: 7632-00-0;|
| Active Comparator: 120 micrograms sodium nitrite<br>Continuous 2 hour infusion of sodium nitrite, 120 micrograms/kg/hour | Drug: Sodium nitrite, 120 micrograms/kg/hour<br>* Continuous 2 hour infusion of sodium nitrite, 120 micrograms/kg/hour<br>* Other names: CAS15 number: 7632-00-0;|
| Active Comparator: 240 micrograms sodium nitrite<br>Continuous 2 hour infusion of sodium nitrite, 240 micrograms/kg/hour | Drug: Sodium nitrite, 240 micrograms/kg/hour<br>* Continuous 2 hour infusion of sodium nitrite, 240 micrograms/kg/hour<br>* Other names: CAS15 number: 7632-00-0;|
| Placebo Comparator: Placebo<br>Continuous 2 hour infusion of sodium chloride, 25 ml/hour | Drug: Placebo<br>* Continuous 2 hour infusion of sodium chloride, 25 ml/hour<br>* Other names: Sodium chloride;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fractional urinary sodium excretion |  | One day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nitrite clearance |  | One day | 
| Nitrate clearance |  | One day | 
| Glomerular filtration rate | Measured by determent renal clearance of 51Cr-EDTA (51-chrome ethylenediaminetetraacetic acid) using constant infusing technique | One day | 
| Proximal sodium transport | Proximal sodium transport is estimated by lithium clearance | One day | 
| Free water clearance |  | One day | 
| Urinary excretion of cyclic guanosine monophosphate (cGMP) |  | One day | 
| Urinary excretion of epithelial sodium channels (ENaC) |  | One day | 
| Urinary excretion of water channels (aquaporin-2) |  | One day | 
| Plasma concentration of renin |  | One day | 
| Plasma concentration of angiotensin 2 |  | One day | 
| Plasma concentration of aldosterone |  | One day | 
| Plasma concentration of atrial natriuretic peptide (ANP) |  | One day | 
| Plasma concentration of brain natriuretic peptide (BNP) |  | One day | 
| Plasma concentration of cyclic guanosine monophosphate (cGMP) |  | One day | 
| Plasma concentration of endothelin |  | One day | 
| Plasma concentration of vasopressin (AVP, ADH) |  | One day | 
| Peripheral (brachial) blood pressure | Measured by oscillometric sphygmomanometer, Omron 705IT, Omron Matsusaka CO. Ltd. | One day | 
| Central aortic systolic blood pressure (CASP) | Estimated by tonometric pulse wave analysis. Device: BPro from HealthSTATS International, Singapore | One day | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Central blood pressure, Peripheral (brachial) blood pressure, Renal variables, Vasoactive hormones, Pharmacology, Pharmacokinetics