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

Healthy Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02078908
• Other study ID #: JBR-1-2013
• Secondary ID: 2013-002211-10
• Status: Completed
• Phase: Phase 1
• First received: September 19, 2013
• Last updated: October 8, 2014
• Start date: September 2013
• Est. completion date: June 2014

Study information

• Verified date: October 2014
• Source: Regional Hospital Holstebro
• Contact: n/a
• Is FDA regulated: No
• Health authority: Denmark: Danish Health and Medicines AuthorityDenmark: The Regional Committee on Biomedical Research EthicsDenmark: Danish Dataprotection Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12
• Est. completion date: June 2014
• Est. primary completion date: June 2014
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 40 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Crossover Assignment, Masking: Single Blind (Subject), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Healthy

Intervention

Drug:
• Sodium nitrite, 40 micrograms/kg/hour
Continuous 2 hour infusion of sodium nitrite, 40 micrograms/kg/hour
• Sodium nitrite, 120 micrograms/kg/hour
Continuous 2 hour infusion of sodium nitrite, 120 micrograms/kg/hour
• Sodium nitrite, 240 micrograms/kg/hour
Continuous 2 hour infusion of sodium nitrite, 240 micrograms/kg/hour
• Placebo
Continuous 2 hour infusion of sodium chloride, 25 ml/hour

Locations

Country	Name	City	State
Denmark	Department of Medical Research, Regional Hospital Holstebro	Holstebro

Sponsors (1)

Lead Sponsor	Collaborator
Erling Bjerregaard Pedersen

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Fractional urinary sodium excretion		One day	No
Secondary	Nitrite clearance		One day	No
Secondary	Nitrate clearance		One day	No
Secondary	Glomerular filtration rate	Measured by determent renal clearance of 51Cr-EDTA (51-chrome ethylenediaminetetraacetic acid) using constant infusing technique	One day	No
Secondary	Proximal sodium transport	Proximal sodium transport is estimated by lithium clearance	One day	No
Secondary	Free water clearance		One day	No
Secondary	Urinary excretion of cyclic guanosine monophosphate (cGMP)		One day	No
Secondary	Urinary excretion of epithelial sodium channels (ENaC)		One day	No
Secondary	Urinary excretion of water channels (aquaporin-2)		One day	No
Secondary	Plasma concentration of renin		One day	No
Secondary	Plasma concentration of angiotensin 2		One day	No
Secondary	Plasma concentration of aldosterone		One day	No
Secondary	Plasma concentration of atrial natriuretic peptide (ANP)		One day	No
Secondary	Plasma concentration of brain natriuretic peptide (BNP)		One day	No
Secondary	Plasma concentration of cyclic guanosine monophosphate (cGMP)		One day	No
Secondary	Plasma concentration of endothelin		One day	No
Secondary	Plasma concentration of vasopressin (AVP, ADH)		One day	No
Secondary	Peripheral (brachial) blood pressure	Measured by oscillometric sphygmomanometer, Omron 705IT, Omron Matsusaka CO. Ltd.	One day	Yes
Secondary	Central aortic systolic blood pressure (CASP)	Estimated by tonometric pulse wave analysis. Device: BPro from HealthSTATS International, Singapore	One day	No