The Effect of Sodium Nitrite on Renal Function and Blood Pressure in Hypertensive Versus Healthy Subjects

Study Overview
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Brief Summary
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The purpose of this study is to investigate how the effect of infused sodium nitrite differs in hypertensives compared to healthy age and sex matched controls. 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.

Detailed Description
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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 a wrist born device. Hypothesis: Sodium nitrite infusion increases the urinary sodium excretion and glomerular filtration rate (GFR) 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 The hemodynamic and renal effects is more pronounced in hypertensives as compared to healthy controls. 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: 15 hypertensive subjects and 15 healthy, age and sex matched controls is recruited. Each subject will attend to two 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 sodium nitrite. During the two examination days each subject receives both treatments in random order. Perspectives: 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 Infusion on Renal Variables, Peripheral and Central Blood Pressure in Hypertensive Versus Normotensive Subjects in a Randomised, Placebo Controlled, Cross Over, Case-control Study

Conditions
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Hypertension

Intervention / Treatment
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* Drug: Sodium nitrite
* Drug: Sodium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (subjects with hypertension): BMI 18.5-30.0 Ambulatory daytime blood pressure >135 mmHg systolic and/or >85 mmHg diastolic Women of childbearing potential must use safe contraception Exclusion Criteria (subjects with hypertension): Tobacco smoking, medicine or substance abuse Weekly consumption of more than 14 units (12 g alcohol per unit) for women and 21 units for men Pregnancy or nursing Neoplasia Clinically significant heart, lung, liver, kidney, metabolic or neurologic disease Albuminuria > 300 mg/L Renography with signs of renal artery stenosis or hydronephrosis Clinically signs of secondary hypertension Clinically significant hypokalemia Clinically significant anemia Estimated glomerular filtration rate (eGFR) < 60 ml/min Clinically significant findings in screening blood samples, urine sample or ECG Persistent office blood pressure > 170/105 mmHg on the maximum dose of amlodipine (10 mg daily) Unacceptable symptoms of elevated blood pressure Unacceptable side effects of amlodipine Inclusion Criteria (healthy normotensive subjects): BMI 18.5-30.0 Women of childbearing potential must use safe contraception Exclusion Criteria (healthy normotensive subjects): Tobacco smoking, medicine or substance abuse Weekly consumption of more than 14 units (12 g alcohol per unit) for women and 21 units for men Medical treatment 2 weeks prior to each examination day, except for contraception Pregnancy or nursing Neoplasia Clinically significant heart, lung, liver, kidney, metabolic or neurologic disease Clinically significant albuminuria Clinically significant anemia Estimated glomerular filtration rate (eGFR) < 60 ml/min Clinically significant findings in screening blood samples, urine sample or ECG Ambulatory daytime blood pressure >135/85 mmHg Blood donation within 1 month of the first examination day

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 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: Sodium nitrite<br>Sodium nitrite, 240 micrograms/kg/hour for 2 hours | Drug: Sodium nitrite<br>* Sodium nitrite, 240 micrograms/kg/hour for 2 hours<br>* Other names: NaNO2;|
| Placebo Comparator: Placebo<br>Sodium chloride, isotonic 0.9%, 25 ml/hour for 2 hours | Drug: Sodium chloride<br>* Sodium chloride, isotonic 0.9%, 25 ml/hour for 2 hours<br>* Other names: NaCl;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fractional urinary sodium excretion (FENa) |  | 1 day | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peripheral (brachial) blood pressure | Measured by oscillometric sphygmomanometer | 1 day | 
| Central aortic systolic blood pressure (CASP) | Measured by tonometric pulse wave analysis. Device BPro from HealthSTATS international, Singapore | 1 day | 
| Plasma concentration of nitrite and nitrate (NOx) |  | 1 day | 
| Urinary excretion of nitrite and nitrate (NOx) |  | 1 day | 
| Glomerular filtration rate |  | 1 day | 
| Proximal sodium transport (Estimated by lithium clearance) | Estimated by lithium clearance | 1 day | 
| Free water clearance |  | 1 day | 
| Urinary excretion of cyclic guanosine monophosphate (cGMP) |  | 1 day | 
| Urinary excretion of epithelial sodium channels (ENaC) |  | 1 day | 
| Urinary excretion of aquaporin 2 water channels (AQP2) |  | 1 day | 
| Plasma concentration of renin (PRC) |  | 1 day | 
| Plasma concentration of angiotensin II (ANG2) |  | 1 day | 
| Plasma concentration of aldosterone |  | 1 day | 
| Plasma concentration of atrial natriuretic peptide (ANP) |  | 1 day | 
| Plasma concentration of brain natriuretic peptide (BNP) |  | 1 day | 
| Plasma concentration of cyclic guanosine monophosphate (cGMP) |  | 1 day | 
| Plasma concentration of endothelin |  | 1 day | 
| Plasma concentration of vasopressin (AVP, ADH) |  | 1 day |