Therefore, studies using Griess reaction to detect stable metabolites NO 2 - and NO 3 - to measure NO synthesis may have significant methodological limitations, as compared to fluorometric techniques associated with HPLC.
It is important to note that this study associated other amino acids besides L-arginine, including L-citrulline quantities not expressed in the study , which have been shown to increase NO production, as measured by plasma concentrations of NO 2 - [ 29 ] and urinary excretion of NO 3 - and cGMP [ 28 ]. Interestingly, the authors did not measure plasma NO 2 - at baseline; they had just done so 1 hour after supplementation, which is a major methodological limitation, since it is not known whether there were any differences in the samples prior to supplementation.
Furthermore, taking into consideration that diet can influence nitrite plasma concentrations, no dietary control to limit the consumption of foods rich in NO 2 - and NO 3 - was conducted. Others studies also have showed improvements in NO production by using L-arginine supplementation [ 30 — 33 ]. However, all of these studies had administered L-arginine in subjects with some cardiovascular risk factors or cardiopathy.
It appears that L-arginine is a limiting factor for NO synthesis in patients at risk for atherosclerosis, but not for healthy individuals [ 34 ]. Therefore, L-arginine supplementation may be necessary only for individuals with atherosclerosis risk factors. Among the possible explanations for this phenomenon is the presence of high levels of asymmetric dimethylarginine ADMA , an endogenous NOS inhibitor. Higher concentrations of ADMA were encountered in individuals with atherosclerosis, as well as in individuals with atherosclerosis risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus, kidney failure, hyperhomocysteinaemia, smoking and aging [ 10 ].
In these conditions, L-arginine supplementation does not affect enzyme activity. In contrast, in the presence of elevated plasma concentrations of ADMA the endothelial NOS activity diminishes, resulting in lower physiological levels of NO production.
Therefore, L-arginine supplementation may exert a beneficial effect on vascular function. This finding may explain the absence of significant changes in NO production after L-arginine supplementation. The baseline plasma concentrations of ADMA observed in the present study are similar to previous studies in healthy subjects which reported ADMA concentrations ranging between 0.
Therefore, it may be speculated that there should be no further increase in NO production after L-arginine supplementation in subjects with normal levels of ADMA. Therefore, it is not advisable to recommend dietary supplements containing L-arginine for the purposes of increasingacutely NO production in healthy subjects. This result does not discard the possible effect of L-arginine on NO production in individuals with pathophysiologicalconditions e. J Int Soc Sports Nutr.
Article Google Scholar. Sports Med. Appleton J: Arginine: Clinical potential of a semi-essential amino. Altern Med Rev. Google Scholar. J Clin Invest. Eur J Pharmacol. J Nutr. J Appl Physiol. Med Sci Sports Exerc. Vasc Med. Appl Physiol Nutr Metab. Nutr J. Br J Clin Pharmacol. Li H, Meininger CJ, Wu G: Rapid determination of nitrite by reversed-phase high-performance liquid chromatography with fluorescence detection.
Tsikas D: Methods of quantitative analysis of the nitric oxide metabolites nitrite and nitrate in human biological fluids. Free Radic Res. Methods Enzymol.
J NutrBiochem. CAS Google Scholar. Am J Physiol. J Am CollCardiol. J Nutr Biochem. Sureda A, Cordova A, Ferrer MD: Effects of L-citrulline oral supplementation on polymorphonuclear neutrophils oxidative burst and nitric oxide production after exercise. J Am Coll Cardiol.
Am J Physiol Endocrinol Metab. FEBS Lett. Scand J Clin Lab Invest. Teerlink T: Measurement of asymmetric dimethylarginine in plasma: methodological considerations and clinical relevance. Clin Chem Lab Med. Horowitz JD, Heresztyn T: An overview of plasma concentrations of asymmetric dimethylarginine ADMA in health and disease and in clinical studies: methodological considerations. Download references. The authors would like to thank Ricky Toledano for the preparation of the English version of the manuscript.
You can also search for this author in PubMed Google Scholar. Correspondence to Thiago Silveira Alvares. Each author certifies that he or she has no commercial associations e. All funding sources supporting the Work and all institutional or corporate affiliations of the authors are acknowledged in a footnote in the Work. TSA contributed substantially to data acquisition and chromatographic analysis, statistical analysis and data interpretation, and was the manuscript writer.
CACJ contributed substantially to chromatographic analysis, interpretation of results, and reviewing the manuscript. JTS contributed to data interpretation and manuscript revision. VMFP contributed to data interpretation and manuscript revision.
The factor mediating the vasomotor effect of acetylcholine ACh turned out to be a gas molecule, nitric oxide NO , which—among many other biological effects—in a very potent manner relaxes vascular smooth muscle Loscalzo, L-Arg, however, can be used by arginase and also L-Arg methylated, thus both pathways can decrease its availability for NOS.
Interestingly, the chemical nature of NO was assumed primarily on the basis of the vasomotor responses could be inhibited by methylated L-arginines Fukuto et al.
The biological importance of NO was further substantiated by isolated organ Koller et al. After the discovery of the steps of the early signaling of the NO pathway, they were investigated on the cardiovascular system in order to be used in clinical practice. Thus, in this review, we aimed to summarize some of the main findings, conflicting results, controversies, significant development, and the potential clinical use of the early part of NO signaling, focusing on their vasomotor effects, primarily in the coronary circulation Figure 1.
Figure 1 This figure shows a simplified overview of nitric oxide NO pathway with most of the molecular steps. The substrate for nitric oxide synthases, the amino-acid L-arginine can enter into three main metabolic pathways. It is either used by arginase, producing urea, and L-ornithine or used by nitric oxide synthase NOS to produce NO or methylated, producing methylated L-arginines, which being a false substrate inhibit NOS. Other metabolic pathways are connected that are modifying the level of NO or affected by NO.
L-Arg is metabolized to urea and l-ornithine by the arginase enzyme via hydrolysis in the urea cycle. The two arginase isoforms arginase I and arginase II are established to have different tissue as well as cellular distribution and immunoreactivity. These isoforms are both present in the endothelium of the vascular bed and they have been identified to have an important role in NO synthesis, thus in maintaining proper endothelial function.
L-Arg is the common substrate for both NOS and arginase. The upregulation of arginase decreases L-Arg bioavailability and consequently decreases NO synthesis Jenkinson et al. Furthermore, arginase activity can result in NOS uncoupling and the production of superoxide and peroxynitrite. These compounds can also weaken NOS function Durante et al. Moreover, reactive oxygen species and pro-inflammatory cytokines can increase the activity of arginine methyltransferases, inhibit dimethylarginine dimethylaminohydrolase DDAH , and up-regulate arginase.
These effects result in the increased synthesis of methylarginines and ornithine Hein et al. It is worth mentioning that peroxynitrite enhances arginase activity which then increases peroxynitrite production leading to the worsening of vascular dysfunction Sankaralingam et al. Arginase can also lead to impaired vascular function via a NO-independent way.
Specifically, l-ornithine can be further metabolized either to polyamine or to proline which may induce vascular SMC growth and proliferation, and collagen deposition, respectively. These mechanisms may proceed to neointima formation and remodeling of the vascular wall Li et al. It has been established that both the expression and the activity of arginase are increased in coronary arteries from ischemic myocardium and arginase inhibition mediates cardioprotection in ischemia-reperfusion injury Shemyakin et al.
Kuo et al. L-Arg has many biological functions—among others—being the substrate for NO-synthases producing NO, which plays important roles in maintaining endothelial health by promoting vasodilatation, inhibiting endothelial cell apoptosis, leucocyte adhesion, and thrombocyte aggregation Cocks et al.
Beside these actions, it also exerts its beneficial effect on microcirculation by smooth muscle relaxation, inhibition of leucocyte adhesion, thrombocyte aggregation, and the expression of adhesion molecules as well as chemotactic peptides through a NO-dependent pathway.
Experiments were carried out on isolated arterioles of rat gracilis muscle. Measurement of endothelial calcium concentration was assessed with a fluorescence method.
The main finding of the study was that NO-mediated vasodilatation in response to shear stress results in only a mild increase in the endothelial calcium concentration. The authors concluded that in healthy, intact endothelium of skeletal muscle arterioles, shear stress does not stimulate calcium from intracellular stores and induces only a minor influx of extracellular calcium Ungvari et al.
Thus, shear stress induced arteriolar dilatation seems to be a calcium-independent signaling pathway in arteriolar endothelial cells. It is of note, however, that L-Arg has many biological actions that are not related to NO Tousoulis et al. L-Arg is important in the regulation of both intra- and extracellular pH and has an important role in reducing lipid peroxidation and the elimination of superoxide anion Figure 2.
High concentration of L-Arg can decrease blood viscosity by inhibiting the binding of macromolecules to the surface of red blood cells via insulin release Walter et al. The authors assumed that this decreased blood viscosity may explain the improved blood flow after L-Arg administration seen in previous studies Bode-Boger et al. L-Arg regulates blood pressure by directly inhibiting angiotensin-converting enzyme ACE Higashi et al. It affects fibrinolysis via this inhibition and the decrease of thromboxane B2 synthesis, an increase of plasmin generation and fibrinogenolysis Udvardy et al.
It can also induce the release of insulin that can result in further vasodilatory effect and reduced platelet aggregation. Figure 2 Illustrating the multiple biological roles of L-arginine modified after Tousoulis et al. Summarizing the multiple biological actions of L-arginine, which are either nitric oxide NO dependent panel A or independent panel B.
These are important facts to keep in mind, in order to understand and interpret the complex effects of L-Arg administration supplementation to biological systems and in humans.
The complexity is highlighted in Figure 2 , summarizing the NO-dependent and independent action of L-Arg Tousoulis et al. L-Arg has a beneficial effect on endothelial function in patients with ischemic heart disease and dilates the atherosclerotic, stenotic coronary arteries Tousoulis et al. In humans normal daily diet contains 5.
It is worth mentioning, however, that the methylated derivatives of arginine act as inhibitors of NOS via competing with arginine for the active site of NOS. It is still not clear whether sustained administration of L-Arg has any effect on clinical endpoints in patients with atherosclerotic coronary artery disease CAD.
Inhibition of arginase seemed to increase intracellular L-Arg bioavailability better than done by exogenous L-Arg supplementation Berkowitz et al. We have made a search in literature regarding the vasomotor and hemodynamic effects of L-Arg Khalaf et al. There have been many interesting studies and findings and we include here those showing various results under various conditions to highlight the complexity of issues.
In , Palmer and his working group demonstrated that NO can be synthesized by porcine aortic endothelial cells when cultured with L-Arg as measured through the release of NO with bioassay, chemiluminescence, and mass spectrometry Palmer et al.
They found that the increase in the amount of NO is reversible after the administration of L-Arg, but not D-arginine, and that NO was synthesized from the terminal guanidino nitrogen atoms of L-Arg.
In , Gold et al. They observed a significant decline of cGMP level in case the concentration of L-Arg decreased in endothelium-intact pulmonary artery rings. It could then reasonably be assumed that exogenous L-Arg will elicit dilation of the vessels. Removal of the endothelium also resulted in diminished Ach and the L-Arg induced vasodilatation. Based on these results, the authors concluded that in skeletal muscle arterioles the dilations to ACh and L-Arg are endothelium dependent.
Kaley et al. They measured the change in arteriolar diameter with in vivo television microscopy. We have to note, that it is very difficult to measure NO, and most of the time effects of methylated L-arginines MLA were taken as equal to NO mediation. Thus it is likely that the mediator role of NO was overestimated in many previous studies using high concentrations of MLAs. The working group of Agullo Agullo et al.
The authors concluded that the beneficial effect of L-Arg supplementation is predominantly mediated by the increased cGMP availability during reperfusion. Fujita and coworkers examined the effect of 3-week orally administered L-Arg in spontaneously hypertensive rats SHR Fujita et al.
Systolic blood pressure was measured once a week. They found that blood pressure did not change. After the treatment the heart was excised and perfused with Krebs-Henselite solution in a Langendorff preparation.
Perfusion flow was measured with a drop counter. After stabilization of the solution, adenosine was used to achieve maximal vasodilatation of the coronary arteries. The myocardium was weighed after the removal of the atria and aorta and there was no change in cardiac hypertrophy. L-arginine supplementation has been identified to improve endothelial function both in animal and human subjects El-Kirsh et al. Experimental studies have shown that L-Arg supplementation might be beneficial after coronary angioplasty Tousoulis et al.
It has also been demonstrated that L-Arg may play a role in both the prevention and progression of CAD Tousoulis et al. There are several human and experimental studies investigating the effect of L-Arg treatment on vascular health, taking into account that this amino acid is the substrate for NO-synthase, thus NO production, which is essential in maintaining proper endothelial function.
In , Hishikawa et al. Cooke et al. Dubois-Rande et al. Intracoronary infusion of ACh infusion induced a dose-dependent decrease of the diameter of the distal LAD, which response was enhanced by the intracoronary administration of L-Arg. Egashira et al. The study protocol was the following: 30 min after completion of the diagnostic angiography ACh was administered intracoronary through the guiding catheter.
Ten minutes later, intracoronary infusion of L-Arg was performed and simultaneously the ACh study was repeated. Another 10 min after the completion of the L-Arg infusion, isosorbide dinitrate was infused via the intracoronary catheter and in the last step, papaverine was infused in the same way.
The ACh infusion increased blood flow more in control subjects than in patients with microvascular angina pectoris, which was significantly attenuated with L-arginine infusion in patients but not in control subjects. The latter effect of L-Arg was also confirmed by Quyyumi and coworkers in a study involving 32 patients with coronary atherosclerosis or its risk factors Quyyumi et al.
In an important clinical study, Tousoulis et al. They found that L-Arg administration resulted in a marked vasodilatation of both normal and diseased coronary arteries. The mean percentage change of luminal diameter from baseline was 8. In the control group these changes were Obviously, intravenous or intra-arterial administration of L-Arg are inconvenient ways for patients, thus studies were necessary to examine the effect of oral supplementation of L-Arg in humans.
Based on the beneficial results of L-Arg supplementation observed in hypercholesterolemic rabbits, Clarkson et al. They measured the diameter of the brachial artery at rest, in response to reactive hyperemia, at rest afterwards and finally after the administration of sublingual nitroglycerin. They observed a significant improvement of the post-occlusion endothelium-dependent vasodilatation of the brachial artery from 1.
Lerman at al. These findings show an important link between NO and endothelin pathways. Luscher et al. Importantly, not every human study showed beneficial effects of L-Arg supplementation. For example, Blum et al. Similarly, Walker et al. First, they found a significant improvement in ACh-induced vasodilatation after the intra-arterial administration of L-Arg that remained practically unchanged after the 2 weeks of oral supplementation of the amino acid In an interesting study of Neri et al.
In this placebo-controlled trial, oral L-Arg 2 g twice a day was administered. After 10—12 weeks, the BP change as the primary outcome of the study was examined by a h ambulatory BP monitoring. There was no significant difference in BP changes between the placebo and the treatment group.
However, L-Arg supplementation was associated with less need of antihypertensive drugs and fewer maternal and neonatal complications. Exercise has been shown to increase eNOS activity, and superoxide dismutase SOD expression, both of them resulting in increased release and bioavailability of endothelium-derived NO with the consequent increase in vascular diameter and reduction of peripheral resistance Koller et al.
Based on similar logic, Ceremuzynski et al. In their study, treadmill exercise test according to the modified Bruce protocol was performed before and after L-Arg treatment. Because the methods used for L-Arg supplementations varied, in a meta-analysis of 11 randomized, double-blinded, placebo-controlled trials examined the effect of a median daily dose of 9 g arginine ranging from 4 to 24 g daily administered orally for a median of 4 weeks Dong et al.
L-Arg supplementation caused a 5. Although the findings of this meta-analysis support the beneficial effects of L-Arg administration on hemodynamic parameters, it should be emphasized that comorbidities of the patients, baseline blood pressure, dosage of L-Arg supplementation, and the duration of therapy differed considerably between the trials.
There are conflicting results regarding the outcome of oral L-Arg supplementation in clinical studies, which can be due to the heterogeneous patient population and the treatment protocol used in investigating the effect of this amino acid.
Although the maximal effective dose of L-Arg supplementation with only minor gastrointestinal side effects seems to be 21 g, daily divided into three doses Clarkson et al.
Explaining the somewhat conflicting results, Boger vs. However, it is worth mentioning—as discussed above—that L-Arg is the substrate for both NO and for methylated arginine products, which may outweigh the beneficial effects of L-Arg on NO synthesis. Schneider et al. This dose is twice the average daily intake of this amino acid in a normal Western diet.
They concluded that the main effect of oral L-Arg supplementation is enhancing the bioactivity and not the synthesis of NO induced by eNOS potentially by preventing the renal loss of nitrite.
According to their study, the dietary intake of L-Arg should not be less than 10 g a day in order to see the beneficial effects of the amino acid. Lundberg and coworkers Lundberg et al.
The activity of eNOS is reduced in case of hypoxia, when the nitrite-induced increase in NO bioactivity becomes more important.
Thus it seems that in general, L-Arg does not improve CBF, but in certain selected conditions L-Arg can be used in patients to reduce systemic blood pressure and improve coronary circulation without major side effects. These conditions need to be clarified and investigated in future studies in order to include them in the guidelines.
The regulation of coronary circulation and blood flow distribution in the coronary arteries are accomplished through the regulation of the tone and the resistance of coronary microcirculation. Coronary vascular resistance is the most important factor in determining CBF Reitsma et al. Endothelium-derived vasoactive derivatives, metabolic factors, and neuro-hormones deliver the vasodilator and vasoconstrictor signals that should be balanced to maintain proper coronary vascular tone Vanhoutte et al.
Since the identification of the endothelium-derived relaxing factor by Furchgott and Zawadzki hundreds of studies were conducted to elucidate the relationship between NO and CBF in healthy and diseased conditions. These studies revealed that myocardial perfusion is regulated by eNOS-synthetized NO in the coronary arteries.
It is of note that these results are based on the effects of methylated L-arginines, because it is complicated to detect the level of NO in vivo. Many experiments were conducted on isolated large vessels, showing that L-Arg, ACh, and other agonists bradykinin, substance P, etc. Less, if any, were known, whether or not the endothelium of small resistance vessels is also able to produce NO, thereby contributing to the regulation of vasomotor tone and peripheral vascular resistance.
Ungvari et al. The first step of mechanotransduction is the activation of endothelial glycocalyx GC Hein et al. It comprises a network of glycoproteins, proteoglycans, and glycosaminoglycans GAGs. Heparan sulfate, chondroitin sulfate, and hyaluronan are the major GAG constituents. Their volume and composition are actively regulated by the endothelial cells; and they proved to be tissue- and vessel-specific.
The volume of GC in healthy individuals is estimated to be 1. It functions to protect vascular integrity by regulating vascular wall permeability and hemostasis and by possessing anti-atherogenic and anti-inflammatory properties. It is also essential for the flow-dependent NO production.
In response to shear stress adaptive increase occurs in the amount of GC Reitsma et al. When the amount of GC is markedly reduced, these protective functions are compromised and the sodium load reaches the cell surface, induces the expression and activity of endothelial sodium channels that allow sodium influx into the cells. Sodium loaded endothelial cells stiffen, their NO production impairs resulting in increased vascular tone Kusche-Vihrog et al.
Degradation of GC and shedding of its components is commonly observed in certain clinical conditions including inflammation, atherosclerosis, ischemia, diabetes mellitus, chronic renal failure, and major vascular surgery Mulivor and Lipowsky, ; Rehm et al. With these observations in line, Dekker et al. Moreover, they provided evidence for the prolonged postoperative impairment and for the delayed recovery of the functional integrity of the vascular walls after on-pump surgery Dekker et al.
Therapeutic attempts to preserve and restore GC with highly purified mixture of its constituents sulodexide are promising, however, further studies are warranted to draw definitive conclusions Broekhuizen et al.
Various data from experimental and human studies completed during the last three decades demonstrated that the deterioration of NO-synthesis and bioavailability has a pivotal role in the development of several cardiovascular diseases.
This is due to the fact that NO also inhibits thrombocyte aggregation and adhesion, resulting in the prevention of coronary circulatory dysfunction, thrombosis, and atherosclerosis Toda and Toda, Reduced expression of NO synthase Dornyei et al. Decreased expression and function of NOS, reduced NO bioavailability, and enhanced generation of oxygen radicals may also play a pivotal role in the deterioration of endothelial function.
Risk factors of cardiovascular diseases including smoking, obesity, aging, hyperglycemia, hypercholesterolemia and hypertension and excessive salt intake can also lead to impaired endothelial function Hadi et al.
Lefroy et al. L-NMMA did not alter heart rate and systemic blood pressure throughout the infusions, ruling out confounding hemodynamic factors. These observations clearly demonstrated that there is a small basal release of NO in the distal epicardial coronary arteries and resistance vessels Lefroy et al.
The role of NO in the control of vasomotor tone in human coronary arteries under resting conditions has been confirmed by several groups Quyyumi et al. Previously, substance P was shown to elicit endothelium-dependent relaxation via release of endogenous NO in isolated human epicardial coronary arteries Chester et al.
Local administration of substance P resulted in both epicardial and microvascular coronary vasodilatation in patients, and these effects were suppressed by L-NMMA Quyyumi et al. Notably, substance P-induced coronary dilation was attenuated in patients with hypertension and hypercholesterolemia, although there was no sign of coronary atherosclerosis during angiography.
This may suggest the development of endothelial dysfunction under these conditions Quyyumi et al. Clinical and experimental studies have indicated that insulin plays an essential role in the regulation of endothelial function DeFronzo and Ferrannini, ; Muniyappa et al. It operates in two opposite ways. On the other hand, it activates the mitogen activated protein kinase MAPK —dependent signaling pathway that regulates the excretion of vasoconstrictor ET Under physiological conditions these opposing endothelial effects of insulin are in balance.
This imbalance may lead to endothelial dysfunction characteristic of insulin resistant states and may progress to the remodeling of vascular wall and atherosclerotic lesions Muniyappa and Sowers, ; Janus et al.
It is particularly relevant to patients with coronary artery diseases who encounter tissue hypoxia- related high-levels of reactive oxygen species and pro-inflammatory molecules which are further augmented by their surge in response to ischemia-reperfusion at revascularization intervention Gao et al.
Although the lack of NO can lead to decreased CBF and imperfect myocardial perfusion, the increased production of NO—because of the enhanced activation of inducible nitric oxide synthase iNOS —can result in excessive production of free-radicals thus myocardial damage.
Long-standing regional ischemia caused by LAD occlusion in a swine model increased the expression of iNOS in the myocardium.
Enhanced iNOS activity may have a role in contractile dysfunction through the increased nitrite contents. Prolonged ischemia reperfusion elicits serious injury to the microvascular segment of coronary circulation. Among others, perfusion pressure decreases, glycocalyx degrades, endothelium became impaired, and increased leucocyte adhesion as well as platelet aggregation occurs. Moreover, during ischemia some of the endothelial cells become necrotic and together with other cells produce debris.
In addition, reperfusion initiates a series of events, including increased level of endothelin-1 and asymmetric dimethylarginine ADMA , the latter activates the vascular renin angiotensin system followed by activation of nicotinamide adenine dinucleotide phosphate NADPH -oxidase and increased superoxide as well as peroxynitrite production, and increases constrictor prostanoid level, all of which constrict microvessels.
In subsequent pro-inflammatory conditions cytokines are produced, initiating a full inflammatory response, apoptosis, and necrosis. Myocardial oxygen demand increases during physical exercise or cardiac pacing. Normally, CBF increases because of the vasodilatation of human coronary arteries Laughlin et al.
Growing evidence suggests that NO contributes to microvascular dilation and epicardial vasodilation in response to metabolic stimulation with atrial pacing in patients with normal or almost normal coronary arteries Quyyumi et al. However, others reported that L-NMMA inhibited the pacing-induced dilatation of the large coronary arteries, but pacing-induced increases in CBF did not change Egashira et al.
Importantly, coronary dilation in the face of increased metabolic demand is significantly attenuated in the presence of risk factors for coronary atherosclerosis or definitive CAD Quyyumi et al. The complexity of the effect of NO is highlighted by Berstein et al.
Also, in the presence of L-NNA myocardial oxygen consumption increased significantly, reduced FFA consumption, indicating that NO influences myocardial substrate metabolisms Bernstein et al. Recently, it has been established that nNOS plays a role in mental stress-induced vasodilatation in human coronary circulation Khan et al. However, further studies are warranted to explore how the relative contribution of eNOS and nNOS may be modified in certain diseases.
Despite great success in basic science regarding the mechanism and function of NO in the control of coronary circulation and maintaining the healthy condition of large vessels, there is little if any advancement in clinical areas. The clinical use of organic nitrite and nitrate esters is limited due to the fact that increased angiotensin II-dependent generation of superoxide anions can be observed from NAD P H oxidase and eNOS Ignarro et al.
They have also been shown to have mutagenic effects. Organic nitrates are a heterogeneous group of vasodilators Gori and Daiber, There are some progresses in the development of organic nitrates to find new therapeutic applications. All nitrates examined induced tolerance, but only TEAN and GTN significantly enhanced mitochondrial oxidative stress in vitro and in vivo. This study demonstrated that high potency nitrates do not automatically induce oxidative stress or tolerance.
It has been also documented that not all the high potency nitrates are activated by ALDH-2 Daiber et al. In pulmonary hypertension, NO as a gas is used to reduce mean pulmonary arterial pressure, and pulmonary vascular resistance index, indicating reduced vascular resistance Atz et al.
At present, inhaling or administration of NO in other ways is not used routinely to improve coronary circulation in humans. Thus, future innovation may help to find a way to use this multipurpose molecule to improve the function of coronary circulation and the heart.
ADMA is mainly metabolized in the kidney and the liver Nijveldt et al. We have found that ADMA elicited a dose dependent decrease in basal diameter myogenic tone , and inhibited wall shear stress-induced NO release and dilation Toth et al.
The relationship between increased ADMA level and mortality or major adverse cardiovascular events has been documented by several prospective clinical studies Moncada and Higgs, ADMA plays an important role in the control of coronary vascular function.
Cable et al. Large clinical trials have emphasized the prognostic significance of ADMA, because there is a considerable relationship between elevated ADMA concentration and adverse cardiovascular events. A meta-analysis of Willeit et al. They reported a significant association between elevated baseline serum ADMA concentration and all the outcomes mentioned before. The combined risk ratios were 1. Moreover, ADMA also seems to be an important predictor of cardiovascular death in patients with high-, intermediate-, and low cardiovascular risk Boger et al.
The relationship between increased ADMA serum concentration and congestive heart failure has been proposed by experimental and human studies raising the suspicion that ADMA might have an etiological role in the pathogenesis of heart failure Feng et al. Seljeflot et al. Intravenous administration of low dose ADMA has been reported to decrease heart rate and cardiac output and increase blood pressure Achan et al.
A meta-analysis including 16 case—control studies of 4, participants investigated the relationship between the serum ADMA concentration and the risk of CAD Xuan et al. Willeit and coworkers observed that in the meta-analysis of 22 prospective studies, there were 2, cases of CVD, coronary heart disease, and stroke during the mean follow-up of 7.
This association was similar in participants with and without preexisting CVD or kidney disease at baseline and across studies that used diverse methods to measure dimethylarginine levels. On the basis of somewhat limited data available on symmetric dimethylarginine SDMA , no significant association between SDMA concentration and the risk of cardiovascular outcomes could be observed.
Mangiacapra and coworkers demonstrated that serum ADMA concentration significantly correlated with the presence and extent of coronary atherosclerosis in subjects undergoing elective coronary angiography Mangiacapra et al. Blood samples were harvested for the detection of ADMA serum concentration before coronary angiography. They found that ADMA levels across tertiles were significantly correlated with both the stenosis score 2. Plasma NOx concentrations measured by chemiluminescence did not show any circadian variation on either diet.
Plasma L-arginine concentrations change during the day and are influenced by dietary intake. Importantly, plasma NOx do not seem to vary with this pattern in healthy individuals.
Abstract The amino acid L-arginine is the precursor of nitric oxide NO , a powerful vasodilator with antiplatelet properties.
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