Clinical trial NCT02078908: The Effect of Sodium Nitrite on Renal Function and Blood Pressure in Healthy Humans. A Dose-response Study
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Central blood pressure
Peripheral (brachial) blood pressure
Renal variables
Vasoactive hormones
Pharmacology
Pharmacokinetics
Lead sponsor: Regional Hospital Holstebro
Sponsor class: OTHER
First posted: 2014-03-05
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Maximum age (years): 40
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Fractional urinary sodium excretion
timeFrame: One day
Secondary outcomes:
measure: Nitrite clearance
timeFrame: One day
measure: Nitrate clearance
timeFrame: One day
measure: Glomerular filtration rate
timeFrame: One day
measure: Proximal sodium transport
timeFrame: One day
measure: Free water clearance
timeFrame: One day
measure: Urinary excretion of cyclic guanosine monophosphate (cGMP)
timeFrame: One day
measure: Urinary excretion of epithelial sodium channels (ENaC)
timeFrame: One day
measure: Urinary excretion of water channels (aquaporin-2)
timeFrame: One day
measure: Plasma concentration of renin
timeFrame: One day
measure: Plasma concentration of angiotensin 2
timeFrame: One day
measure: Plasma concentration of aldosterone
timeFrame: One day
measure: Plasma concentration of atrial natriuretic peptide (ANP)
timeFrame: One day
measure: Plasma concentration of brain natriuretic peptide (BNP)
timeFrame: One day
measure: Plasma concentration of cyclic guanosine monophosphate (cGMP)
timeFrame: One day
measure: Plasma concentration of endothelin
timeFrame: One day
measure: Plasma concentration of vasopressin (AVP, ADH)
timeFrame: One day
measure: Peripheral (brachial) blood pressure
timeFrame: One day
measure: Central aortic systolic blood pressure (CASP)
timeFrame: One day
Other outcomes:
Locations:
city: Holstebro
country: Denmark
facility: Department of Medical Research, Regional Hospital Holstebro
Study officials:
affiliation: Regional Hospital Holstebro
name: Jesper N Bech, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: