L-arginine Treatment in Mild Hypertension

Hypertension Clinical Trial

— LAHN  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT02894723
• Other study ID #: 0216-15-COM2
• Status: Not yet recruiting
• Phase: Phase 4
• First received: August 15, 2016
• Last updated: September 4, 2016
• Start date: September 2016
• Est. completion date: May 2017

Study information

• Verified date: June 2016
• Source: Meir Medical Center
• Contact: Eduardo Podjarny, MD
• Phone: 0528339193
• Email: epodjarny[@]gmail.com
• Is FDA regulated: No
• Health authority: Israel: The Israel National Institute for Health Policy Research and Health Services Research
• Study type: Interventional

Clinical Trial Summary

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.

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

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: May 2017
• Est. primary completion date: February 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years to 70 Years

Eligibility

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 Design

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension

Intervention

Dietary Supplement:
• L-arginine
30 ml arginoline contains 5 gr l-arginine
• syrup
The same bottle of the experimental group, but without l-arginine

Locations

Country	Name	City	State
Israel	ADAM Institute of High Blood Pressure, Clalit Health Services	Herzliya	Hasharon Area

Sponsors (1)

Lead Sponsor	Collaborator
Meir Medical Center

Country where clinical trial is conducted

Israel, 

References & Publications (20)

Archer SL, Huang JM, Hampl V, Nelson DP, Shultz PJ, Weir EK. Nitric oxide and cGMP cause vasorelaxation by activation of a charybdotoxin-sensitive K channel by cGMP-dependent protein kinase. Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7583-7. — View Citation

Ast J, Cieslewicz AR, Korzeniowska K, Bogdanski P, Kazmierczak E, Olszewski J, Skoluda A, Jablecka A. Supplementation with L-arginine does not influence arterial blood pressure in healthy people: a randomized, double blind, trial. Eur Rev Med Pharmacol Sci. 2011 Dec;15(12):1375-84. — View Citation

Ast J, Jablecka A, Bogdanski P, Smolarek I, Krauss H, Chmara E. Evaluation of the antihypertensive effect of L-arginine supplementation in patients with mild hypertension assessed with ambulatory blood pressure monitoring. Med Sci Monit. 2010 May;16(5):CR266-71. — View Citation

Böger RH. Asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, explains the "L-arginine paradox" and acts as a novel cardiovascular risk factor. J Nutr. 2004 Oct;134(10 Suppl):2842S-2847S; discussion 2853S. Review. — View Citation

Butlin M, Qasem A, Avolio AP. Estimation of central aortic pressure waveform features derived from the brachial cuff volume displacement waveform. Conf Proc IEEE Eng Med Biol Soc. 2012;2012:2591-4. doi: 10.1109/EMBC.2012.6346494. — View Citation

Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004 Jun 15;109(23 Suppl 1):III27-32. Review. — View Citation

Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012 Apr;33(7):829-37, 837a-837d. doi: 10.1093/eurheartj/ehr304. Epub 2011 Sep 1. Review. — View Citation

Gallagher D, Adji A, O'Rourke MF. Validation of the transfer function technique for generating central from peripheral upper limb pressure waveform. Am J Hypertens. 2004 Nov;17(11 Pt 1):1059-67. Review. — View Citation

Gui S, Jia J, Niu X, Bai Y, Zou H, Deng J, Zhou R. Arginine supplementation for improving maternal and neonatal outcomes in hypertensive disorder of pregnancy: a systematic review. J Renin Angiotensin Aldosterone Syst. 2014 Mar;15(1):88-96. doi: 10.1177/1470320313475910. Epub 2013 Feb 22. Review. — View Citation

Higashi Y, Oshima T, Ozono R, Watanabe M, Matsuura H, Kajiyama G. Effects of L-arginine infusion on renal hemodynamics in patients with mild essential hypertension. Hypertension. 1995 Apr;25(4 Pt 2):898-902. — View Citation

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Joannides R, Haefeli WE, Linder L, Richard V, Bakkali EH, Thuillez C, Lüscher TF. Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo. Circulation. 1995 Mar 1;91(5):1314-9. — View Citation

Li Q, Youn JY, Cai H. Mechanisms and consequences of endothelial nitric oxide synthase dysfunction in hypertension. J Hypertens. 2015 Jun;33(6):1128-36. doi: 10.1097/HJH.0000000000000587. Review. — View Citation

Naseem KM. The role of nitric oxide in cardiovascular diseases. Mol Aspects Med. 2005 Feb-Apr;26(1-2):33-65. Epub 2005 Jan 24. Review. — View Citation

Panza JA, García CE, Kilcoyne CM, Quyyumi AA, Cannon RO 3rd. Impaired endothelium-dependent vasodilation in patients with essential hypertension. Evidence that nitric oxide abnormality is not localized to a single signal transduction pathway. Circulation. 1995 Mar 15;91(6):1732-8. — View Citation

Podjarny E, Ben-Chetrit S, Rathaus M, Korzets Z, Green J, Katz B, Bernheim J. Pregnancy-induced hypertension in rats with adriamycin nephropathy is associated with an inadequate production of nitric oxide. Hypertension. 1997 Apr;29(4):986-91. — View Citation

Schlaich MP, Parnell MM, Ahlers BA, Finch S, Marshall T, Zhang WZ, Kaye DM. Impaired L-arginine transport and endothelial function in hypertensive and genetically predisposed normotensive subjects. Circulation. 2004 Dec 14;110(24):3680-6. Epub 2004 Nov 29. — View Citation

Taddei S, Virdis A, Mattei P, Ghiadoni L, Sudano I, Salvetti A. Defective L-arginine-nitric oxide pathway in offspring of essential hypertensive patients. Circulation. 1996 Sep 15;94(6):1298-303. — View Citation

Tanaka Y, Tang G, Takizawa K, Otsuka K, Eghbali M, Song M, Nishimaru K, Shigenobu K, Koike K, Stefani E, Toro L. Kv channels contribute to nitric oxide- and atrial natriuretic peptide-induced relaxation of a rat conduit artery. J Pharmacol Exp Ther. 2006 Apr;317(1):341-54. Epub 2006 Jan 4. — View Citation

Treasure CB, Klein JL, Vita JA, Manoukian SV, Renwick GH, Selwyn AP, Ganz P, Alexander RW. Hypertension and left ventricular hypertrophy are associated with impaired endothelium-mediated relaxation in human coronary resistance vessels. Circulation. 1993 Jan;87(1):86-93. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Blood Pressure, mmHg	change in systolic and/or diastolic blood pressure	baseline [visit 0] to eight weeks	No
Secondary	Central aortic BP, mmHg	changes in Central aortic BP values	baseline (visit 0) to eight weeks	No
Secondary	Pulse pressure (mmHg)	changes in central pulse pressure	baseline (visit 0] to eight weeks	No
Secondary	Augmentation Index (%)	changes in augmentation index	baseline (visit 0] to eight weeks	No
Secondary	carotid femoral pulse wave velocity (m/s)	changes in carotid femoral pulse wave velocity	baseline (visit 0] to eight weeks	No