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Pharmacology. 1994 Apr;48(4):260-4.

Effect of l-glutamine on pulmonary hypertension in the perfused rabbit lung.

Xu H1, Pearl RG.

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Department of Anesthesia, Stanford University Medical Center, CA 94305-5123.


The effects of l-glutamine on pulmonary hypertension in the isolated perfused rabbit lung were investigated. Pulmonary hypertension was produced by the thromboxane-A2 mimetic U46619. l-Glutamine at a dose of 0.04 mM produced a sustained increase in pulmonary artery pressure (PAP) and subsequent administration of an equimolar dose of l-arginine did not affect PAP. l-Glutamine at a dose of 0.5 mM transiently increased PAP, which then decreased to baseline (pre-glutamine) values. When endogenous nitric oxide (NO) synthesis was inhibited with NG-nitro-l-arginine methylester, l-glutamine at a dose of 0.04 mM decreased PAP. These results demonstrate that the effect of l-glutamine on PAP during pulmonary hypertension depends upon dose, time and the presence of endogenous NO synthesis. We believe that the results can be explained by two different effects of l-glutamine, namely a direct inhibition of NO release by glutamine and the donation of nitrogen atoms by glutamine for additional NO or other vasodilator synthesis. Since plasma glutamine levels are 0.4-0.7 mM, endogenous l-glutamine may play a modulatory role during pulmonary hypertension.





[Indexed for MEDLINE]

The Emerging Role of l-Glutamine in Cardiovascular Health and Disease

William Durante

Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO 65212, USA;


Received: 16 August 2019; Accepted: 30 August 2019; Published: 4 September 2019

􏰀􏰁􏰂􏰀􏰃 􏰅􏰆􏰇___________________________________________________________________________________________________________________________________


Abstract: Emerging evidence indicates that l-glutamine (Gln) plays a fundamental role in cardiovascular physiology and pathology. By serving as a substrate for the synthesis of DNA, ATP, proteins, and lipids, Gln drives critical processes in vascular cells, including proliferation, migration, apoptosis, senescence, and extracellular matrix deposition. Furthermore, Gln exerts potent antioxidant and anti-inflammatory effects in the circulation by inducing the expression of heme oxygenase-1, heat shock proteins, and glutathione. Gln also promotes cardiovascular health by serving as an l-arginine precursor to optimize nitric oxide synthesis. Importantly, Gln mitigates numerous risk factors for cardiovascular disease, such as hypertension, hyperlipidemia, glucose intolerance, obesity, and diabetes. Many studies demonstrate that Gln supplementation protects against cardiometabolic disease, ischemia-reperfusion injury, sickle cell disease, cardiac injury by inimical stimuli, and may be beneficial in patients with heart failure. However, excessive shunting of Gln to the Krebs cycle can precipitate aberrant angiogenic responses and the development of pulmonary arterial hypertension. In these instances, therapeutic targeting of the enzymes involved in glutaminolysis such as glutaminase-1, Gln synthetase, glutamate dehydrogenase, and amino acid transaminase has shown promise in preclinical models. Future translation studies employing Gln delivery approaches and/or glutaminolysis inhibitors will determine the success of targeting Gln in cardiovascular disease.

Keywords: l-glutamine; l-glutamate; ammonia; metabolism; Krebs cycle; cardiovascular disease

1. Introduction

Cardiovascular disease is the primary cause of morbidity and mortality in the world, accounting for nearly one-third of all deaths [1]. Aside from its profound effect on the quality and duration of life, cardiovascular disease imposes a severe and costly demand on health services and is expected to surpass the medical cost for all chronic diseases [2]. Although the age-adjusted mortality rate for cardiovascular disease has diminished in industrialized countries owing to life-style changes, smoking cessation, advances in biomedical research, and improvements in medical care and technologies, the aging population and burgeoning epidemic of cardiometabolic disease characterized by obesity, insulin resistance, dyslipidemia, impaired glucose tolerance, and hypertension, threatens to reverse this progress, underscoring the requirement for additional therapeutic options that target this deadly disease.

Substantial evidence indicate that amino acids play a fundamental role in the cardiovascular system. While amino acids serve as basic building blocks for protein synthesis and constitute an important energy source, a select group has been widely studied in the context of cardiovascular disease. Decades of research have established the importance of l-arginine in promoting cardiovascular health through the generation of the gas nitric oxide (NO) by the enzyme NO synthase (NOS) [3–5]. The release of NO by endothelial cells (ECs) regulates blood flow and blood pressure by inhibiting arterial tone. Furthermore, NO maintains blood fluidity and prevents thrombosis by limiting platelet aggregation and adhesion.

Nutrients 2019, 11, 2092; doi:10.3390/nu11092092

Nutrients 2019, 11, 2092 2 of 16

NO also protects against intimal thickening by blocking smooth muscle cell (SMC) proliferation, migration, and collagen synthesis. Moreover, NO mitigates the development of atherosclerosis by blocking the inflammatory response within the vessel wall. Interestingly, l-homoarginine, a derivative of l-arginine, also elicits beneficial effects in the circulation. Clinical studies indicate that low circulating levels of l-homoarginine independently predicts mortality from cardiovascular disease while high levels are associated with reduced mortality. The mechanism mediating the protection by l-homoarginine is not known but likely involves its capacity to stimulate NO formation by serving as a substrate for NOS. Contrarily, extensive work has identified l-homocysteine, a sulfur containing amino acid formed from the metabolism of l-methionine, as an independent risk factor for atherosclerosis [6]. The atherogenic action of l-homocysteine has been attributed, in part, to its ability to impair the bioavailability of NO. Studies in the past decade have also revealed the complex and contradictory actions of l-tryptophan and its myriad of metabolites in regulating cardiovascular function [7]. Finally, although the role of l-glutamine (Gln) in nutrition and health have been extensively documented, its effects on the cardiovascular system have just recently come to light [8–11]. In this review, we describe the metabolism and function of Gln in cardiovascular physiology and pathology and highlight potential therapeutic approaches that target this amino acid in cardiovascular disease.

2. l-Glutamine Metabolism

Gln is the most abundant and versatile amino acid in the body and plays a critical role in nitrogen exchange between organs, intermediary metabolism, immunity, and pH homeostasis [9–11]. This nutrient is classified as a conditionally essential amino acid, as endogenous synthesis may be insufficient to meet optimal demands under conditions of catabolic stress, critical illness, and in preterm infants. Gln is an important substrate for the synthesis of peptides, proteins, lipids, purines, pyrimidines, amino sugars, nicotinamide adenine dinucleotide phosphate (NADPH), glucosamine, antioxidants, and for many other biosynthetic pathways involved in regulating cell function (Figure 1). Several enzymes are involved in Gln metabolism. Gln is predominantly synthesized from l-glutamate (Glu) and ammonia (NH3) by the action of the largely cytosolic enzyme Gln synthetase (GS), whereas the mitochondrial enzyme glutaminase (GLS) is responsible for the hydrolysis of Gln to Glu and NH3. GS is highly expressed in skeletal muscle, while GLS is found in most cells with the small intestine, kidney, leukocytes, and vascular endothelium possessing the highest activity. There are two distinct isoforms of GLS, GLS1 and GLS2, but GLS1 is the major isoform expressed in cardiovascular tissues [12–14]. Gln is also metabolized by glutamine:fructose-6-phosphate amidotransferase (GFAT), which condenses Gln’s amino group and fructose-6-phosphate into glucosamine-6-phosphate, a precursor for N- and O-linked glycosylation reactions [10].

The GLS product Glu is used for the synthesis of the antioxidant glutathione: a small three amino acid peptide (Glu-Cys-Gly) which is an efficient neutralizer of peroxide-based free radicals. Alternatively, Glu is further metabolized by Glu dehydrogenase and/or aminotransferases to α-ketoglutarate, which then enters the Krebs cycle generating ATP and serving as an anaplerotic source of carbon for the formation of non-essential amino acids and lipids. In addition, the production of NADPH by malate-pyruvate cycling promotes redox homeostasis by providing the reducing equivalents for glutathione reductase to regenerate glutathione. Finally, in the intestine, enterocytes convert Glu to delta1-pyrroline-5-carboxylate enabling the formation of l-proline, l-ornithine, and l-citrulline. By generating l-citrulline, which is subsequently metabolized to the NOS substrate l-arginine by the concerted action of argininosuccinate synthetase and argininosuccinate lyase in the kidney, Gln also functions as an l-arginine precursor to drive NO synthesis [15].


Nutrition. 2015 Jan;31(1):119-26. doi: 10.1016/j.nut.2014.05.014. Epub 2014 Jun 23.

Effect of glutamine supplementation on cardiovascular risk factors in patients with type 2 diabetes.

Mansour A1, Mohajeri-Tehrani MR2, Qorbani M3, Heshmat R4, Larijani B5, Hosseini S6.

Author information


School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences, Tehran, Iran; Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.


Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.


Department of Public Health, Alborz University of Medical Sciences, Karaj, Iran; Non-Communicable Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.


Chronic Diseases Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.


Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran; Diabetes Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran.


Endocrinology and Metabolism Research Center, Endocrinology and Metabolism Research Institute, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:



The aim of this study was to assess clinical relevance of long-term oral glutamine supplementation on lipid profile and inflammatory and metabolic factors in patients with diabetes.


Sixty-six patients with type 2 diabetes between the ages of 18 and 65 y were randomized to receive glutamine 30 g/d (10 g powder, three times a day) or placebo, in a double-blind, placebo-controlled trial during a 6-wk treatment period. Fifty-three patients completed the trial. Independent samples t test and analysis of covariance were used.


After a 6-wk treatment period, a significant difference was observed between the two groups in body fat mass (P = 0.01) and percentage of body fat (P = 0.008). Moreover, a significant reduction in waist circumference (P < 0.001) and a tendency for an increase in fat-free mass (P = 0.03), with no change in body weight and body mass index (BMI) was found. Enhancement in body fat-free mass was mainly attributed to trunk (P = 0.03). There was a downward trend in systolic blood pressure (P = 0.005) but not diastolic. Fasting blood glucose (mmol/L) concentration significantly decreased after the 6-wk intervention (P = 0.04). Mean hemoglobin A1c was significantly different between the groups at week 6 (P = 0.04). No significant difference was detected for fasting insulin, homeostasis model assessment for insulin resistance and quantitative insulin sensitivity index between groups (P > 0.05). No significant difference was observed between groups in total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglyceride. No treatment effect on C-reactive protein was found (P = 0.44).


We demonstrated that the 6-wk supplementation with 30 g/d glutamine markedly improved some cardiovascular risk factors, as well as body composition, in patients with type 2 diabetes. Future glutamine dose-response studies are warranted in these areas.

Copyright © 2015 Elsevier Inc. All rights reserved.


Body composition; GLP-1; Glutamine supplementation; Insulin; Type 2 diabetes





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