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

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.

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