L-arginine Treatment in Mild Hypertension
L-arginine Treatment in Mild 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.
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
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.