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

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

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.

Study Overview

• Status: Unknown
• Conditions: Hypertension
• Intervention / Treatment: Drug: Sodium nitrite; Drug: Sodium chloride

Detailed Description

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:

1. Sodium nitrite infusion increases the urinary sodium excretion and glomerular filtration rate (GFR)
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. 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

1. Renal handling of nitrite, nitrate, sodium and water
2. Plasma concentrations of vasoactive hormones
3. 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.

• Study Type: Interventional
• Enrollment (Anticipated): 30
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Jeppe B Rosenbaek, MD; Phone Number: +4578436585; Email: jepros@rm.dk
• Study Contact Backup: Name: Erling B Pedersen, MD, DMSc; Phone Number: +4578436840; Email: ebp@dadlnet.dk

Study Locations

• Denmark
  • Holstebro, Denmark, 7500
    • Recruiting
    • Department of Medical Research and Medicine, Holstebro Regional Hospital
    • Contact: Jeppe B Rosenbaek, MD; Phone Number: +4578436585; Email: jepros@rm.dk
    • Sub-Investigator: Jeppe B Rosenbaek, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 68 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sodium nitrite; Sodium nitrite, 240 micrograms/kg/hour for 2 hours	Drug: Sodium nitrite; Sodium nitrite, 240 micrograms/kg/hour for 2 hours; Other Names: NaNO2
Placebo Comparator: Placebo; Sodium chloride, isotonic 0.9%, 25 ml/hour for 2 hours	Drug: Sodium chloride; Sodium chloride, isotonic 0.9%, 25 ml/hour for 2 hours; Other Names: NaCl

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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

Collaborators and Investigators

• Sponsor: Erling Bjerregaard Pedersen
• Investigators: Principal Investigator: Erling B Pedersen, MD, DMSc, Holstebro Regional Hospital

Publications and helpful links

General Publications

• Rosenbaek JB, Hornstrup BG, Jorgensen AN, Mortensen J, Pedersen EB, Bech JN. Effects of sodium nitrite on renal function and blood pressure in hypertensive vs. healthy study participants: a randomized, placebo-controlled, crossover study. J Hypertens. 2018 Mar;36(3):666-679. doi: 10.1097/HJH.0000000000001598.

Study record dates

Study Major Dates

• Study Start: May 1, 2015
• Primary Completion (Anticipated): October 1, 2016
• Study Completion (Anticipated): October 1, 2016

Study Registration Dates

• First Submitted: February 18, 2015
• First Submitted That Met QC Criteria: August 17, 2015
• First Posted (Estimate): August 19, 2015

Study Record Updates

• Last Update Posted (Estimate): August 19, 2015
• Last Update Submitted That Met QC Criteria: August 17, 2015
• Last Verified: February 1, 2015

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Hypertension
• Other Study ID Numbers: JBR-1-2014