The Effect of Orally Administrated Nitrate on Renal Parameters and Systemic Haemodynamics

Study Overview
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Brief Summary
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Treatment with nitrate has shown to lower blood pressure in both healthy subjects and hypertensive patients.Beside this nitrate have also shown to decrease arterial stiffness and improve endothelial function.But the effect of nitrate on renal blood flow, kidney function, water and salt balance and vasoactive hormones is still unclear. Therefore, the purpose of this study is to investigate the effect of orally administered nitrate on these parameters. This will be done in a double-blinded, placebo-controlled, crossover study. 20 healthy subjects will be treated, in a randomized order, with both potassium nitrate and placebo separated by at least 4 weeks wash-out.

Detailed Description
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Inorganic nitrate reduces blood pressure and improves endothelial function in both healthy subjects and hypertensive patients. This effect is thought to be caused through bioconversion to nitric oxide. Thus improving risk factors of cardiovascular decease by increasing vasodilatation, salt regulation and vasoactive hormones.The purpose of this study is to investigate the effect of inorganic nitrate on kidney function, hormones and circulation, which is still unknown. The effect of 4 days treatment with 24 mmol potassium nitrate capsules on heart rate, blood pressure, vasoactive hormones and urinary excretion of sodium and water will be measured in a randomized, placebo controlled, double blinded, crossover study in 20 healthy subjects. Each subject attends 2x2 examination days at least 4 weeks apart. The examination days are divided into 8 clearance periods of 30 min. each. The first 3 are baseline periods and in period 4 1 Liter of saline is administered to detect any difference in renal parameters after NaCl load. If inorganic nitrate supplementation is found to lower blood pressure in addition to favorable renal effects, it could lead to changes in the general treatment of high blood pressure and cardiovascular disease.

Official Title
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The Effect of Orally Administrated Nitrate on Renal Parameters and Systemic Haemodynamics, in a Randomized, Placebo Controlled, Crossed Over Study on Healthy Subjects.

Conditions
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Hypertension

Intervention / Treatment
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* Other: isotonic saline 9%
* Dietary Supplement: Potassium nitrate
* Dietary Supplement: Potassium chloride


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-64 years BMI 18,5-30 Normotensive Women must use contraception Exclusion Criteria: Tobacco smoking (Non-smokers in more than 3 months can be included) Medicine- or drug abuse Alcohol abuse >7 units for women >14 units for men Medical treatment (over the counter medication will evaluated whether or not it is grounds for exclusion) within 2 weeks before the trail period starts except contraception. Pregnancy or nursing Neoplastic disorders Significant clinical signs of heart-, lung-, liver-, kidney-, endocrine- or brain disorders Clinically significant abnormal findings in screening blood samples, urine sample or ECG - Donation of blood within 1 month of the first day of investigation. Allergy against compounds in investigational medicine

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 64 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: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: double-blinded, placebo-controlled, crossover study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Potassium Nitrate<br>4 days treatment with 24 mmol potassium nitrate capsules | Other: isotonic saline 9%<br>* 1 Liter of Isotonic saline administered I.V.<br>* Other names: Sodium Chloride 9%;Dietary Supplement: Potassium nitrate<br>* 24 mmol of Potassium nitrate is the active comparator substance, that is ingested every morning for 4 days before and on the examination day.<br>|
| Placebo Comparator: Potassium Chloride<br>4 days treatment 24 mmol potassium chloride capsules | Other: isotonic saline 9%<br>* 1 Liter of Isotonic saline administered I.V.<br>* Other names: Sodium Chloride 9%;Dietary Supplement: Potassium chloride<br>* 24 mmol of Potassium nitrate is the placebo substance, that is ingested every morning for 4 days before and on the examination day.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Glomerular filtration rate (GFR) | mL/minute | analysed right after each examination day. (day 1) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Brachial blood pressure (BP) | mmhg | analysed right after each examination day. (day 1) | 
| central blood pressure (cSBP) | mmhg | analysed right after each examination day. (day 1) | 
| Heart rate | beats pr. min. | analysed right after each examination day. (day 1) | 
| Pulse wave velocity (PWV) | measured via Mobilograph | analysed right after each examination day. (day 1) | 
| Total vascular resistance (TVR) | measured via Mobilograph | analysed right after each examination day. (day 1) | 
| Augmentation index (Aix@75) | measured via Mobilograph | analysed right after each examination day. (day 1) | 
| Urinary excretions of aquaporin-2 (u-AQP2) | ng/mmol crea | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| Urinary excretions of epithelial sodium channels (u-ENaCγ) | ng/mmol crea | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| Urinary excretions of Na-Cl cotransporter (u-NCC). | ng/mmol crea | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma concentration of renin (PRC) | pg/mL | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma concentration of angiotensin II (p-AngII) | pg/mL | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma concentration of aldosterone (p-Aldo) | pmol/L | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma concentration of arginine vasopressin (p-AVP) | pg/mL | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma concentration of atrial natriuretic peptide (p-ANP) | pmol/L | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma concentration of brain natriuretic peptide (p-BNP). | pmol/L | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma and urine levels of Nitrate (NO3) | μmol/L | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma and urine levels of nitrite (NO2) | μmol/L | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| plasma and urine levels of cyclic guanosine monophosphate (cGMP). | pmol/mL | Centrifuged and hereafter frozen. Analyzed during the following 12 months. | 
| Creatinine clearance (CrCl) | mL/minute | analysed right after each examination day. (day 1) | 
| Urinary excretion rate of sodium (U-Na) | mmol/min | analysed right after each examination day. (day 1) | 
| Urinary excretion rate of potassium(U-K) | mmol/min | analysed right after each examination day. (day 1) | 
| Free water clearance (CH2O) | mL/minute | analysed right after each examination day. (day 1) | 
| Fractional excretion of sodium (FENa) | calculated into % | analysed right after each examination day. (day 1) | 
| Fractional excretion of potassium (FEK) | calculated into % | analysed right after each examination day. (day 1) | 
| Urinary excretion rate of albumin (UAER) | µg/min | analysed right after each examination day. (day 1) |