L-arginine Treatment in Mild Hypertension (LAHN)

September 4, 2016 updated by: Meir Medical Center

Efficacy of L-arginine Treatment on Blood Pressure Control Patients With Stage 1 Hypertension

Essential Hypertension is characterized by endothelial dysfunction due to reduced nitric oxide (NO) bioavailability. Impairment in nitric oxide-mediated vasodilatation in human brachial, coronary, and renal arteries has been demonstrated in patients with essential hypertension. Administration of L-arginine, a NO substrate yeld controversial results.

The purpose of the present study, double blind and matched for age, sex and body mass index (BMI), is to assess the efficacy of L-arginine treatment on blood pressure (BP) control and arterial stiffness in patients with stage1 hypertension.

Study Overview

Status

Unknown

Conditions

Detailed Description

Scientific background

Essential Hypertension is characterized by endothelial dysfunction with impaired vasorelaxation.

Reduced nitric oxide bioavailability, which is considered a hallmark of endothelial dysfunction, plays an important role in mediating blood pressure elevation. Accumulating evidence demonstrates a critical role of nitric oxide in blood pressure regulation. Released from the endothelial cells, nitric oxide increases 30,50-cyclic-guanosine monophosphate (cGMP) production and subsequent cGMP-dependent protein kinase (PKG) activation in the underneath vascular smooth muscle cells (VSMCs), resulting in vasodilatation. The investigators and others have shown that inhibition of NO synthesis increase blood pressure in normal pregnant rats and different animal models. In vivo studies confirmed an essential role of nitric oxide in vasorelaxation of large human arteries. Impairment in nitric oxide-mediated vasodilatation in brachial, coronary, and renal arteries has been demonstrated in patients with essential hypertension.

Several mechanisms have been found responsible for nitric oxide deficiency in hypertension. One of them is deficit of the NO substrate, L-arginine. L-arginine transport is impaired in hypertensive and normotensive patients with a genetic background of essential hypertension, and the offspring of essential hypertensive patients are characterized by a reduced response to acetylcholine linked to a defect in the nitric oxide pathway. These data represent the link between L-arginine and the onset of essential hypertension. The Km of endothelial nitric oxide synthase for L-arginine is about 3mmol/l, but the concentration of plasma L-arginine rarely falls below 60mmol/l in pathological conditions. An elevation in asymmetric dimethylarginine (ADMA, an endogenous NO competitive inhibitor) levels may explain this 'L-arginine paradox'. The administration of excess exogenous L-arginine displaces the competitive inhibitor, improves intracellular transport of this amino acid, and restores NO production to physiological levels. In fact L-arginine supplementation improved endothelial dysfunction in hypertension.

Administration of L arginine in humans have not shown uniform blood pressure responses. A meta-analysis published in 2011 was able to find only 11 articles dealing with l-arginine administration and blood pressure. The population studies were heterogeneous. Compared with placebo, oral L-arginine intervention was associated with an average net change ranging from -23.0 to 2.8 mm Hg for SBP and from -11.0 to 1.0 mm Hg for diastolic BP. Most trials showed an intervention-related trend toward BP reductions, but only a few reached statistical significance.

Endothelial dysfunction leads to an increase in arterial stiffness, a known marker that increases cardiovascular morbidity and mortality. Arterial stiffness can be measured by non invasive methodology, e.g.; measuring carotid-femoral pulse wave velocity, augmentation index, aortic pulse pressure and aortic systolic blood pressure.

Whether administration of l-arginine improved arterial stiffness in patients with mild hypertension it is not known.

Arginoline is a dietary supplement that contains L-arginine at a concentration of 5 g/L. It is possible to dilute with water or take chilled. It is produced by Pharmayeda, an Israeli industry.

Clinical observational studies [personal communication] have shown that at a dose of 60 ml\day [10 gr of l-arginine] flow mediated vasodilation improves, suggesting an increase in nitric oxide function.

Methods

Office Blood Pressure (OBP) measurement:

OBP will be measured with a Suntech 247 digital automated device. BP will be determined 3 times at one min. interval each. The mean of the second and third measurements will be noted as the OBP of the visit.

ABPM:

24 hours ABPM will be performed with an Oscar 2 ABPM device of SunTech Medical. The Oscar 2 ABPM device is clinically validated to all 3 internationally recognized protocols (British Heart Society, American Society of Hypertension and the Association for the Advancement of Medical Instrumentation).

Blood pressure is measured in a 20 min. interval at day time and a 30 min. interval at night time. The patients are requested to fill a diary with their activities during the ABPM study, including their subjective evaluation of the sleeping quality.

Measurement of arterial stiffness:

The SphygmoCor X-CEL System (AtCor Medical, Sydney, Australia) will be used.

The system derives (non invasively) the ascending aortic pressure waveform from the brachial waveform using a validated generalised transfer function.

The SphygmoCor X-CEL system measures the carotid-femoral pulse wave velocity (PWV), the speed of the arterial pressure waveform as it travels through the descending aorta to the femoral artery, which is detected from simultaneously measured carotid and femoral arterial pulses.

Design

The study is a matched double blind study with an experimental group and a placebo group. As the number of the groups is small (20 in each group) the patients will be matched according to age, sex and BMI during the recruitment phase, in order to get to comparable groups. The principal investigator is responsible of the matching.

The experimental group will receive arginoline 30 ml twice a day and the placebo group will receive placebo at the same schedule

Visits:

Week -2:

Sign of informed consent

Office BP. Physical examination. BMI.

Blood exams: Hemoglobin (g%), urea (mg%), creatinine (mg%), Natrium (mEq/l), Potassium (mEq/l), alanine transaminase (ALT),Aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT), glucose, cholesterol and triglycerides. and lipid profile.

Urine analysis: microalbuminuria (morning spot)

All patients will receive a booklet with detailed information about healthy life style recommendation to lower blood pressure.

Hypertensive patients on monotherapy will stop treatment.

Week 0

ABPM

Measurement of Central aortic blood pressure and arterial stiffness

Blind group allocation (experimental or placebo group).

Week 2

Office BP measurement.

Week 4

Office BP measurement

Week 6

Office BP measurement

Week 8: ABPM, office BP,

Repeat blood and urine exams as detailed at week -2.

Measurement of Central aortic blood pressure and Arterial stiffness

Statistical evaluation

Will be done using the IBM SPSS statistical software. Pi<0.05 is considered significative

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

    • Hasharon Area
      • Herzliya, Hasharon Area, Israel
        • ADAM Institute of High Blood Pressure, Clalit Health Services
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

30 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion criteria:

  • Stage 1 hypertensive patients, with an office Systolic BP between 140-159 mmHg and/or a diastolic BP between 9-99 mmHg , untreated or treated with monotherapy.
  • None to two risk factors [smoking, hyperlipidemia, obesity , family history of cardiovascular disease].
  • BMI between 25 to 32.
  • Twenty for hours ambulatory blood pressure monitor (ABPM) with a mean Systolic BP of 130-149 mmHg and/or a mean Diastolic BP of 80-89 mmHg.

Exclusion criteria:

  • Use of any drug that may affect nitric oxide synthesis and/or blood pressure values (nitrates, antihypertensive drugs, non steroidal anti-inflammatory drugs , steroids, pseudoephedrine).
  • Diabetes mellitus.
  • Renal failure defined as estimated glomerular filtration rate (eGFR) less than 60 ml/min, using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula.
  • A previous diagnosis of ischemic heart disease, Transient ischemic attack (TIA), Stroke or peripheral arterial disease.
  • Patients with recurrent herpes and women who are planning pregnancy during the next year.
  • Cancer treated with radiotherapy or chemotherapy during the last year.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: l-arginine
Patients will receive L-arginine 30 ml twice a day for 8 weeks.
30 ml arginoline contains 5 gr l-arginine
Other Names:
  • Arginoline
Placebo Comparator: syrup
Patients will receive placebo, 30 ml twice a day for 8 weeks.
The same bottle of the experimental group, but without l-arginine
Other Names:
  • placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Blood Pressure, mmHg
Time Frame: baseline [visit 0] to eight weeks
change in systolic and/or diastolic blood pressure
baseline [visit 0] to eight weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Central aortic BP, mmHg
Time Frame: baseline (visit 0) to eight weeks
changes in Central aortic BP values
baseline (visit 0) to eight weeks
Pulse pressure (mmHg)
Time Frame: baseline (visit 0] to eight weeks
changes in central pulse pressure
baseline (visit 0] to eight weeks
Augmentation Index (%)
Time Frame: baseline (visit 0] to eight weeks
changes in augmentation index
baseline (visit 0] to eight weeks
carotid femoral pulse wave velocity (m/s)
Time Frame: baseline (visit 0] to eight weeks
changes in carotid femoral pulse wave velocity
baseline (visit 0] to eight weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2016

Primary Completion (Anticipated)

February 1, 2017

Study Completion (Anticipated)

May 1, 2017

Study Registration Dates

First Submitted

August 15, 2016

First Submitted That Met QC Criteria

September 4, 2016

First Posted (Estimate)

September 9, 2016

Study Record Updates

Last Update Posted (Estimate)

September 9, 2016

Last Update Submitted That Met QC Criteria

September 4, 2016

Last Verified

June 1, 2016

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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