Plasma Arginine Research Articles

Fermented soybean enhances post-meal response in appetite-regulating hormones among Indonesian girls with obesity

ObjectiveTo assess the post-meal response in appetite-regulating hormones acyl-ghrelin and insulin after fermented soybean (tempeh) consumption in girls with obesity. MethodsA randomized counter-balanced crossover study was conducted using a breakfast (307 kcal, protein: 28%, fat: 23%, and carbohydrate: 55%) containing fermented soybean or isocaloric non-fermented soybean among 13 females (aged 18–20 y; BMI 25–30) after an overnight fast. The outcome variables were plasma acyl-ghrelin, insulin, arginine and score of the visual analog scale (VAS) appetite questionnaire. ResultsWhile no change was observed after the non-fermented soybean meal, plasma acyl-ghrelin decreased by 35% at 30 min and remained below baseline until 120 min after the fermented soybean meal (P < 0.05). Plasma insulin increased after consumption of both meals and fermented soybean meal-induced 30% greater response in insulin at 120 min than non-fermented soybean meal (P < 0.05). Circulating arginine levels were slightly greater (24%) at 120 min after the fermented soybean meal than the non-fermented soybean meal (P < 0.05). No difference in subjective appetite was observed between the fermented soybean meal and the non-fermented soybean meal. ConclusionsFermented soybean meal induced greater response in appetite-regulating hormones compared with non-fermented soybean meal. No difference in post-meal satiety feeling between fermented and non-fermented soybean meal suggests poor sensitivity of the brain to the appetite-regulating hormones among girls with obesity.

Arginine Vasopressin as an Important Mediator of Fluctuations in the Serum Creatinine Concentration Under Decongestion Treatment in Heart Failure Patients.

Background: The mechanism underlying serum creatinine (SCr) fluctuations in heart failure (HF) patients remains unclear. This study examined mediators of SCr fluctuations under diuretic treatment in HF patients.Methods and Results: Data from 26 HF patients were analyzed. Clinical tests included measurement of peripheral blood, blood urea nitrogen, SCr, serum and urinary electrolytes, B-type natriuretic peptide (BNP), and plasma neurohormones. Among the 26 patients recovering from worsening HF, changes in SCr were negatively correlated with changes in serum Cl, and positively correlated with changes in plasma arginine vasopressin (AVP). According to the median change in SCr, patients were divided into high (range 0.16–0.79 mg/dL; n=13) and low (range −0.35 to 0.14 mg/dL; n=13) change groups. Plasma AVP concentrations after treatment decreased in the low SCr change group and increased in the high SCr change group (−1.28±2.8 vs. 2.14±4.4 pg/mL, respectively; P=0.027). In both groups, there was no change in plasma volume, plasma BNP and norepinephrine concentrations decreased, and plasma renin activity increased after treatment. Multivariate logistic regression analysis showed a tendency towards an independent association between an increase in SCr and an increase or no change in the plasma AVP after decongestion (odds ratio 4.44; 95% confidence interval 0.81–24.3; P=0.086).Conclusions: Plasma AVP appears to be a physiologically important mediator of SCr fluctuations under decongestion treatment in HF patients.

A Review of the Single-Dose Pharmacokinetics of Different Delivery Forms of Inositol-Stabilized Arginine Silicate (Nitrosigine®) in Healthy Males

Abstract Objectives The purpose of this review is to evaluate the pharmacokinetics of arginine absorption in healthy adult males taking inositol-stabilized arginine silicate (ASI; Nitrosigine®) in different delivery forms. Previous studies have evaluated ASI, showing it to be a readily absorbed form of arginine, bioavailable for an extended period of time, and efficacious at increasing blood flow. This study looks to compare the pharmacokinetics of ASI when consumed orally as a capsule, tablet, or beverage. Methods The results of three (3) pharmacokinetic studies were evaluated: one using ASI capsules, one using ASI tablets, and one using an ASI beverage. In all studies, healthy males aged 18–40 were enrolled with a BMI of 18–30 kg/m2. In the ASI capsule study, ten participants were given three 500 mg ASI capsules (total of 1,500 mg/day). In the ASI tablet study, ten participants were given three 500 mg ASI tablets (total of 1,500 mg/day). In the ASI beverage study, 16 participants were given 1,500 mg of ASI in a beverage. For all studies, fasting blood samples were collected pre-dose and 0.5, 1, 1.5, 2, 3, 4, 5, and 6 hours post-dose, and analyzed for arginine content. Results The pharmacokinetics of arginine absorption were similar for all three dose formulations. There were significant increases in plasma arginine levels at 0.5 hours, which was the first post dose blood draw. All three ASI formulations had a similar arginine time of maximum concentration (tMax), with the beverage being the fastest at 0.6 ± 0.2 hours, followed by ASI tablets at 1.05 ± 0.50 hours, and ASI capsules at 1.13 ± 0.52 hours. All three ASI formulations demonstrated extended duration of increased arginine plasma levels with significant levels above baseline detected 5 to 6 hours after dosing. Conclusions These data show that inositol-stabilized arginine silicate (Nitrosigine®), when used in these delivery forms, increases plasma arginine levels in as early as 0.5 hours (first timepoint tested), lasting up to 6 hours. Funding Sources This work was supported by Nutrition 21, LLC.

Editors' Note: Clinical Characterization of Delayed Alcohol-Induced Headache: A Study of 1,108 Participants

In “Clinical Characterization of Delayed Alcohol-Induced Headache: A Study of 1,108 Participants,” Garcia-Azorin et al. reported that after surveying 1,108 university students who had headaches and consumed alcohol, they found that 95% of respondents met the criteria for delayed alcohol-induced headache (DAIH), which has features of both migraine and low-CSF-pressure headache. The latter headache phenotype was suggested because 66% of participants reported worsening headache in the upright or standing position. Gupta commented that the delay between consumption of alcohol and headache onset, which can also be seen with exposure to other headache triggers, may be related to the antinociceptive properties of vasopressin, serotonin, noradrenaline, and alcohol itself. Garcia-Azorin et al. responded that future studies on DAIH would benefit from serial measurement of blood and urine osmolarity, sodium, and copeptin, the precursor of plasma arginine vasopressin. Goadsby noted that although the results of this study are interesting, it is important to recognize that there are limitations to surveys and respondent perspectives on the definitions of key terms to describe their headaches may be inconsistent. Garcia-Azorin and Guerrero concurred that future studies should avoid variability in terminology by exploring the cadence of headache stabs, but reinforced the similarity between features of migraine and DAIH. Smith questioned the authors' conclusion about the frequency of low-CSF-pressure headaches among respondents given that they did not have documentation of CSF pressure or neuroimaging results. Garcia-Azorin and Guerrero agreed that this was an important point. They also noted that although research on the effects of alcohol is challenging, given that ethical considerations preclude forced intoxication, further creative approaches to research on DAIH are needed. In “Clinical Characterization of Delayed Alcohol-Induced Headache: A Study of 1,108 Participants,” Garcia-Azorin et al. reported that after surveying 1,108 university students who had headaches and consumed alcohol, they found that 95% of respondents met the criteria for delayed alcohol-induced headache (DAIH), which has features of both migraine and low-CSF-pressure headache. The latter headache phenotype was suggested because 66% of participants reported worsening headache in the upright or standing position. Gupta commented that the delay between consumption of alcohol and headache onset, which can also be seen with exposure to other headache triggers, may be related to the antinociceptive properties of vasopressin, serotonin, noradrenaline, and alcohol itself. Garcia-Azorin et al. responded that future studies on DAIH would benefit from serial measurement of blood and urine osmolarity, sodium, and copeptin, the precursor of plasma arginine vasopressin. Goadsby noted that although the results of this study are interesting, it is important to recognize that there are limitations to surveys and respondent perspectives on the definitions of key terms to describe their headaches may be inconsistent. Garcia-Azorin and Guerrero concurred that future studies should avoid variability in terminology by exploring the cadence of headache stabs, but reinforced the similarity between features of migraine and DAIH. Smith questioned the authors' conclusion about the frequency of low-CSF-pressure headaches among respondents given that they did not have documentation of CSF pressure or neuroimaging results. Garcia-Azorin and Guerrero agreed that this was an important point. They also noted that although research on the effects of alcohol is challenging, given that ethical considerations preclude forced intoxication, further creative approaches to research on DAIH are needed.

Author Response: Clinical Characterization of Delayed Alcohol-Induced Headache: A Study of 1,108 Participants

We appreciate Dr. Gupta's comment on our article.1 The study of the effects of alcohol is challenging. Ethical concerns would not allow a “randomized controlled hangover,” in which participants would consume a controlled amount of alcohol. The goal of gaining new knowledge should never surpass the need to protect the rights and health of our patients.2 Some of the mentioned confounders3 were controlled in our study.1 We excluded participants who did consume other drugs. In addition, no patients declared prior history of hepatic, endocrinologic, or renal disorders. However, we agree that the observational nature of the study implies that all the hypotheses are merely speculative. To properly associate the clinical presentation of alcohol-induced headache (AIH) with the effect and degree of dehydration, blood and urine osmolarity and sodium levels should be measured regularly during the study.4 Measurement of plasma arginine vasopressin (AVP) concentration is technically difficult.

CENTRAL SYSTOLIC BLOOD PRESSURE RELATES INVERSELY TO NITRIC OXIDE SYNTHESIS IN YOUNG BLACK ADULTS: THE AFRICAN-PREDICT STUDY

Objective: Lower nitric oxide bioavailabilty associates with hypertension in diseased and elderly populations. With hypertension known to develop earlier in black populations, we compared both plasma and urinary nitric oxide-related markers and their associations with central systolic blood pressure and arterial stiffness in healthy young black and white adults. Design and method: We included healthy black and white men and women (n = 1110; 20–30 years) and measured central systolic blood pressure and pulse wave velocity, along with both plasma and urinary arginine, homoarginine, asymmetric dimethylarginine, symmetric dimethylarginine, as well as urinary ornithine/citrulline, nitrite and nitrate. Additionally, the urinary nitrate-to-nitrite ratio was calculated. Results: The black men and women had higher central systolic blood pressure and higher plasma arginine and asymmetric dimethylarginine, but lower urinary nitrate and urinary nitrate-to-nitrite ratio (all p&lt; = 0.003) than their white counterparts. In single and forward stepwise multiple regression analyses, we found an inverse association of central systolic blood pressure (adj. R2 = 0.124; β= –0.134; p = 0.006) and plasma homoarginine in black men. Central systolic blood pressure associated inversely with urinary nitrate-to-nitrite ratio in black women only (adj. R2 = 0.171; β= –0.130; p = 0.029). In the white women, central systolic blood pressure associated positively with urinary asymmetric dimethylarginine (adj. R2 = 0.372; β= 0.162; p = 0.015). Pulse wave velocity associated inversely with plasma asymmetric dimethylarginine (adj. R2 = 0.253; β= –0.163; p = 0.024) in the white women only. Conclusions: The lower nitric oxide synthesis and the higher central systolic blood pressure in our black cohort support the notion of a potential increased risk for future large artery stiffness and hypertension development in later life.

An infant with congenital nephrogenic diabetes insipidus presenting with hypercalcemia and hyperphosphatemia.

SummaryWe report a male infant with congenital nephrogenic diabetes insipidus (NDI) who presented with hypercalcemia and hyperphosphatemia since birth. Serum sodium started to increase at 39 days. Although there was no polyuria, urine osmolality was 71 mOsm/kg, when serum osmolality was 296 mOsm/kg with plasma arginine vasopressin 22.5 pg/mL. He was thus diagnosed as NDI. An undetectable level of urine calcium and unsuppressed intact parathyroid hormone suggested hyperparathyroidism including calcium-sensing receptor mutations that could cause hypercalcemia-induced NDI. Polyuria became apparent after the initiation of i.v. infusion for the treatment of hypernatremia. Low calcium and low sodium formula with hypotonic fluid infusion did not correct hypernatremia, hypercalcemia, or hyperphosphatemia. Hydrochlorothiazide and subsequently added celecoxib effectively decreased urine output and corrected electrolytes abnormalities. Normal serum electrolytes were maintained after the discontinuation of low calcium formula. The genetic analysis revealed a large deletion of the arginine vasopressin receptor-2 (AVPR2) gene but no pathogenic variant in the calcium-sensing receptor (CASR) gene. Whether hypercalcemia and hyperphosphatemia were caused by dehydration alone or in combination with other mechanisms remains to be clarified. Learning pointsCongenital NDI can present with neonatal hypercalcemia and hyperphosphatemia. Hypercalcemia and hyperphosphatemia can be treated with low calcium and low sodium formula, hydration, hydrochlorothiazide, and celecoxib. Genetic testing is sometimes necessary in the differentiating diagnosis of hypercalcemia associated with NDI.

Ornithine Transcarbamylase Deficiency Presenting with Symptoms of Mania in a Young Adult Male

The purpose of this case study is to review the clinical presentation and medical workup of a young adult male presenting with acute behavior changes in the setting of undiagnosed ornithine transcarbamylase deficiency (OTCD). This case study involves a 19-year-old male with a psychiatric history of depression and one previous suicide attempt, who presented to a large midwestern university hospital emergency department after being found by police naked in a neighbor's yard. He displayed manic signs and symptoms, including euphoria, lack of sleep for five days, and attempting to purchase a new car and three large screen TVs. Family reported the patient uncharacteristically announced three weeks earlier that he was vegetarian and stopped eating his frequent customary cheeseburgers. Due to increased anxiety and inability to sleep, the patient received lorazepam 2 mg in the emergency department. Upon transfer to the psychiatric unit, therapy was initiated with aripiprazole 5 mg daily and valproate 1000 mg nightly on Day 1 of treatment. The patient refused medications on hospital Day 2, then received this combination again on Day 3. The next morning, the patient complained of lethargy, headache, nausea, and vomiting. The patient's ammonia level was found to be 204 micromol/L with ALT and AST of 714 and 647 IU/L respectively. Tests for infectious hepatitis were negative. Medical consultation recommended discontinuation of current medications, vigorous hydration, and further work up. On further investigation, the patient was found to have low plasma citrulline level of 8 micromol/L, undetectable plasma arginine, and high urinary orotic acid. The laboratory data showed a biochemical phenotype consistent with a diagnosis of partial OTCD, an X-linked urea cycle disorder resulting in toxic hyperammonemia. The patient was treated with a low protein diet modification as well as a combination of sodium benzoate and sodium phenylbutyrate to reduce serum ammonia concentration. With treatment the patient's laboratory values normalized, and mental status improved. In conclusion, partial ornithine transcarbamylase deficiency may manifest with psychiatric symptoms in early adulthood. In young patients with elevated ammonia and mental status change, OTCD is an important diagnosis to consider, as it is the most common inherited cause of hyperammonemia.

Arginine to ornithine ratio as a diagnostic marker in patients with positive newborn screening for hyperargininemia

Arginase deficiency is a rare inborn error of metabolism that interrupts the final step of the urea cycle. Untreated individuals often present with episodic hyperammonemia, developmental delay, cognitive impairment, and spasticity in early childhood. The newborn screening (NBS) algorithms for arginase deficiency vary between individual states in the US but often include hyperargininemia and elevated arginine to ornithine (Arg/Orn) ratio. Here, we report 14 arginase deficiency cases, including two patients with positive NBS for hyperargininemia in whom the diagnosis of arginase deficiency was delayed owing to normal or near normal plasma arginine levels on follow-up testing. To improve the detection capability for arginase deficiency, we evaluated plasma Arg/Orn ratio as a secondary diagnostic marker in positive NBS cases for hyperargininemia. We found that plasma Arg/Orn ratio combined with plasma arginine was a better marker than plasma arginine alone to differentiate patients with arginase deficiency from unaffected newborns. In fact, elevated plasma arginine in combination with an Arg/Orn ratio of ≥1.4 identified all 14 arginase deficiency cases. In addition, we examined the impact of age on plasma arginine and ornithine levels. Plasma arginine increased 0.94 μmol/L/day while ornithine was essentially unchanged in the first 31 days of life, which resulted in a similar increasing trend for the Arg/Orn ratio (0.01/day). This study demonstrated that plasma Arg/Orn ratio as a secondary diagnostic marker improved the detection capability for arginase deficiency in newborns with hyperargininemia, which will allow timely detection of arginase deficiency and hence initiation of treatment before developing symptoms.

Pegylated arginine deiminase depletes plasma arginine but maintains tissue arginine availability in young pigs.

Pegylated arginine deiminase (ADI-PEG20) results in the depletion of arginine with the production of isomolar amounts of citrulline. This citrulline has the potential to be utilized by the citrulline recycling pathway regenerating arginine and sustaining tissue arginine availability. The goal of this research was to test the hypothesis that ADI-PEG20 depletes circulating arginine in pigs but maintains tissue arginine concentration and function, and to characterize the kinetics of citrulline and arginine. Two multitracer approaches (bolus dose and primed-continuous infusion) were used to investigate the metabolism of arginine and citrulline in Control (n = 7) and ADI-PEG20 treated (n = 8) pigs during the postprandial period. In addition, blood pressure was monitored by telemetry, and multiple tissues were collected to determine arginine concentration. Plasma arginine was depleted immediately after ADI-PEG20 administration, with an increase in plasma citrulline concentration (P < 0.01). The depletion of arginine did not affect (P > 0.10) blood pressure, whole body protein synthesis, or urea production. Despite the lack of circulating arginine in ADI-PEG20-treated pigs, most tissues were able to maintain concentrations similar (P > 0.10) to those in Control animals. The kinetics of citrulline and arginine indicated the high citrulline turnover and regeneration of arginine through the citrulline recycling pathway. ADI-PEG20 administration resulted in an absolute and almost instantaneous depletion of circulating arginine, thus reducing global availability without affecting cardiovascular parameters and protein metabolism. The citrulline produced from the deimination of arginine was in turn utilized by the citrulline recycling pathway restoring local tissue arginine availability.NEW & NOTEWORTHY Pegylated arginine deiminase depletes circulating arginine, but the citrulline generated is utilized by multiple tissues to regenerate arginine and sustain local arginine availability. Preempting the arginine depletion that occurs as result of sepsis and trauma with arginine deiminase offers the possibility of maintaining tissue arginine availability despite negligible plasma arginine concentrations.

The shifted balance of arginine metabolites in acute myocardial infarction patients and its clinical relevance

The arginine metabolism as a target for cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI) remains insufficiently understood. Arginine, ornithine, citrulline, asymmetric dimethylarginine (ADMA) and proline plasma levels were measured using liquid chromatography and tandem mass spectrometry in 70 consecutive STEMI patients upon admission and at 6-month follow-up and were compared with left ventricular function, volumes, and infarct characteristics determined by cardiac magnetic resonance imaging, and with 5-year clinical outcomes. Baseline median concentration of arginine was higher by 49% (P = 0.002) when compared to 6-month measurements and was correlated with an ischemia risk area (R = 0.34, P = 0.004) and infarct size (R = 0.33, P = 0.006). Following ischemia median citrulline/arginine index decreased when compared with 6-month result (P = 0.002), while citrulline/ornithine and arginine/ADMA ratios maintained unchanged indicating a shift of arginine metabolism from nitric oxide synthase (NOS) towards arginase. The 6-month arginine concentration reached the area under the ROC curve of 0.67 (95% confidence interval 0.54–0.81) for prediction of death, myocardial infarction or heart failure hospitalization and its value of < 29 µM was associated with lower event free survival (P = 0.02). In STEMI patients, during ischemia conversion of elevated plasma arginine was shifted from NOS towards arginase. Decreased 6-month arginine concentrations were associated with worse long-term outcomes.

Serum amino acid profiles in patients with mild cognitive impairment and in patients with mild dementia or moderate dementia.

Neurodegenerative disorders are one of the greatest global challenges for social and health care in the twenty-first century. Nowadays, determination of cerebrospinal fluid biomarkers for early diagnosis is served by a complex sample preparation procedure with limited diagnostic accuracy. Furthermore, neuroimaging methods are expensive, time-consuming and are not readily available for use as a complimentary and common screening method. Recently, researchers have shown an increased interest in the identification and characterization of new blood biomarkers of dementia to minimize the limitations associated with the current methods of biomarker determination. Amino acids play many important roles in the central nervous system, acting as neuromodulators, neurotransmitters and regulators of energy metabolism. The aim of this study was to evaluate if serum amino acid levels change along the continuum from no cognitive impairment to moderate dementia, and to identify putative biomarkers for early diagnosis of neurodegenerative diseases. Serum levels of 16 amino acids were determined in 3 groups of patients-22 with mild cognitive impairment, 45 with mild dementia and 28 with moderate dementia-by high-performance liquid chromatography (HPLC) with fluorescence detection using AccQ Tag column (Waters). The most exciting result is the significantly elevated concentration of arginine in patients with both stages of dementia as compared to mild cognitive impairment individuals. Recent accumulating evidence suggests the implication of changed arginine metabolism in the pathogenesis of neurodegenerative diseases. We conclude that amino acids profiling might be helpful in searching for biomarkers of neurogenerative diseases. In the present study, we discovered that arginine in plasma may have a putative diagnostic value for dementia.

Vasopressin antagonism in heart failure: a review of the hemodynamic studies and major clinical trials.

For decades, plasma arginine vasopressin (AVP) levels have been known to be elevated in patients with congestive heart failure (HF). Excessive AVP signaling at either or both the V1a and V2 receptors could contribute to the pathophysiology of HF by several mechanisms. V1a activation could cause vasoconstriction and/or direct myocardial hypertrophy as intracellular signaling pathways are closely related to those for angiotensin II. V2 activation could cause fluid retention and hyponatremia. A hemodynamic study with the pure V2 antagonist tolvaptan (TV) showed minimal hemodynamic effects. Compared with furosemide in another study, the renal and neurohormonal effects of TV were favorable. Several clinical trials with TV as adjunctive therapy in acute HF have shown beneficial effects on fluid balance and dyspnea, with no worsening of renal function or neurohormonal stimulation. Two smaller studies, one in acute and one in chronic HF, have shown comparable clinical and more favorable renal and neurohormonal effects of TV compared with loop diuretics. However, long-term treatment with TV did not alter outcomes in acute HF. No data are available other than single-dose studies of an intravenous pure V1a antagonist, which showed a vasodilating effect if plasma AVP levels were elevated. One hemodynamic study and one short-duration clinical trial with the balanced intravenous V1a/V2 antagonist conivaptan (CV) showed hemodynamic and clinical effects largely similar to those with TV in similar studies. A new orally effective balanced V1/V2 antagonist (pecavaptan) is currently undergoing phase II study as both adjunctive and alternative therapy during and after hospitalization for acute HF. The purpose of this review is to summarize what we have learned from the clinical experience with TV and CV, and to suggest implications of these findings for future work with newer agents.

Metabolic changes induced by oral glucose tests in horses and their diagnostic use.

BackgroundLittle is known about the implications of hyperinsulinemia on energy metabolism, and such knowledge might help understand the pathophysiology of insulin dysregulation.ObjectivesDescribe differences in the metabolic response to an oral glucose test, depending on the magnitude of the insulin response.AnimalsTwelve Icelandic horses in various metabolic states.MethodsHorses were subjected to 3 oral glucose tests (OGT; 0.5 g/kg body weight glucose). Basal, 120 and 180 minutes samples were analyzed using a combined liquid chromatography tandem mass spectrometry and flow injection analysis tandem mass spectrometry metabolomic assay. Insulin concentrations were measured using an ELISA. Analysis was performed using linear models and partial least‐squares regression.ResultsThe kynurenine : tryptophan ratio increased over time during the OGT (adjusted P‐value = .001). A high insulin response was associated with lower arginine (adjusted P‐value = .02) and carnitine (adjusted P‐value = .03) concentrations. A predictive model using only baseline samples performed well with as few as 7 distinct metabolites (sensitivity, 86%; 95% confidence interval [CI], 81%‐90%; specificity, 88%; 95% CI, 84%‐92%).Conclusions and Clinical ImportanceOur results suggest induction of low‐grade inflammation during the OGT. Plasma arginine and carnitine concentrations were lower in horses with high insulin response and could constitute potential therapeutic targets. Development of screening tools to identify insulin‐dysregulated horses using only baseline blood sample appears promising.

Central systolic blood pressure relates inversely to nitric oxide synthesis in young black adults: the African-PREDICT study.

Lower nitric oxide (NO) bioavailabilty associates with hypertension in patients and elderly populations. With hypertension known to develop earlier in black populations, we compared both plasma and urinary NO-related markers and their associations with central systolic blood pressure (cSBP) and arterial stiffness in healthy young black and white adults. We included healthy black and white men and women (n = 1110; 20-30 years) and measured cSBP and pulse wave velocity (PWV), along with both plasma and urinary arginine, homoarginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), as well as urinary ornithine/citrulline, nitrite and nitrate. In addition, the urinary nitrate-to-nitrite ratio (UNOxR) was calculated. The black men and women had higher cSBP and higher plasma arginine and ADMA, but lower urinary nitrate and UNOxR (all p ≤ 0.003) than their white counterparts. In single and forward stepwise multiple regression analyses, we found an inverse association of cSBP (adj. R2 = 0.124; β = -0.134; p = 0.006) and plasma homoarginine in black men. Central SBP associated inversely with UNOxR in black women only (adj. R2 = 0.171; β = -0.130; p = 0.029). In the white women, cSBP associated positively with urinary ADMA (adj. R2 = 0.372; β = 0.162; p = 0.015). PWV associated inversely with plasma ADMA (adj. R2 = 0.253; β = -0.163; p = 0.024) in the white women only. The lower NO synthesis and the higher cSBP in our black cohort support the notion of a potential increased risk for future large artery stiffness and hypertension development in later life.

Metabolic markers for diagnosis and risk-prediction of multiple myeloma

AimsTo discriminate metabolic biomarkers for diagnosis and risk prediction of multiple myeloma (MM) on a basis of metabolic characteristics in systemic circulation and local pathogenic niche. Main methodsA gas chromatography mass spectrometry-based untargeted metabolomics analysis was performed within the bone marrow (BM) supernatants and peripheral plasma from healthy donors and patients with MM. Key findingsDistinct metabolic features between MM patients and healthy volunteers were profiled in both BM and plasma. Metabolic profiles of subgroups in which MM patients undergo high/medium/low risk displayed risk-dependent metabolic shift especially in BM. In MM patients, up-regulated glutamate level and down-regulated glutamine level in BM indicated enhanced glutamate metabolism which provided NH4+ for ammonia utilization. This resulted in increased level of urea and creatinine produced from urea cycle, arginine and proline metabolism in both BM and plasma collected from MM patients. The disorders of tricarboxylic acid cycle and carnitine synthesis were unique in BM of MM patients. Receiver operating characteristic curve analysis indicated that aspartate was a candidate plasma biomarker for diagnosis with the highest sensitivity and specificity in both BM and plasma. Threonine was identified as a preferential plasma biomarker for risk prediction due to significant relation with various risk indexes of MM in both BM and plasma. SignificanceThe perturbed glutamate metabolism and carnitine synthesis in BM of MM patients provided a new sight on pathogenesis of MM. The plasma level of aspartate and threonine may become a preferential metabolic marker for diagnosis and risk prediction of MM, respectively.

Efficacy of citrulline supplementation to decrease the risk of pulmonary hypertension after congenital heart disease surgery. A local experience.

Pulmonary hypertension (PH) is a major cause of morbi-mortality among patients with congenital heart disease (CHD) and also a potentially severe complication after surgical repair. Oral citrulline, a precursor to NO synthesis, is safe and efficacious for decreasing the risk of postoperative PH. Objective: The aim of the present study was to investigate in pediatric patients the changes of plasma citrulline, arginine, homocysteine and nitric oxide (NO) metabolites and pulmonary artery pressures (PAP) pre-post cardiac surgery in order to describe our population status with regard to the risk of pulmonary hypertension and look for potential biomarkers for early detection and treatment. 16 Argentine pediatric patients with CHD undergoing cardiopulmonary bypass were randomized in two groups: (A) with and (B) without perioperative citrulline supplementation. We found that plasma citrulline median levels before surgery were lower in both groups respect to referential values, probably due to the poor nutritional status of our patients; only group A surpassed post-surgery the minimum recommended level to avoid PH. Furthermore, none of the patients in group A showed mean PAP higher than 20 mmHg, whereas in group B, 67% of the measurements were ≥ than the reference level. We reaffirm that citrulline supplementation it is effective in reducing postoperative pulmonary hypertension and biomarkers could evidence patient status as a translational medicine application.

Arginase II Plays a Central Role in the Sexual Dimorphism of Arginine Metabolism in C57BL/6 Mice

Sex differences in plasma concentration of arginine and arginase activity of different tissues have been reported in mice. In addition, male but not female C57BL/6 mice have a dietary arginine requirement for growth. The goal of this research was to test the hypothesis that arginase II is a key factor in the sexual dimorphism of arginine metabolism. Young adult male and female wild type (WT), and heterozygous and arginase II knockout mice on a C57BL/6 background mice were infused with labeled citrulline, arginine, ornithine, phenylalanine, and tyrosine to determine the rates of appearance and interconversion of these amino acids. Tissue arginase activity was measured in the liver, heart, jejunum, kidney, pancreas, and spleen with an arginine radioisotope. The effect of genotype, sex, and their interaction was tested. Female mice produced ∼36% more citrulline than their male littermates, which translated into a greater arginine endogenous synthesis, flux, and plasma concentration (42, 6, and 27%, respectively; P< 0.001). Female mice also had a greater phenylalanine flux (10%) indicating a greater rate of whole protein breakdown; however, they had a lower protein synthesis rate than males (18%; P< 0.001). The ablation of arginase II reduced the production of citrulline and the de novo synthesis of arginine in females and increased the rate of appearance of arginine and plasma arginine concentration in male mice (16 and 22%, respectively; P< 0.001). No effect of arginase II deletion, however, was observed for whole-body protein kinetics. Arginase II activity was present in the pancreas, kidney, jejunum, and spleen; WT females had a ∼2-fold greater renal arginase activity than their WT counterparts. A clear sexual dimorphism exists in the endogenous synthesis of arginine and its disposal. Female mice have a greater arginine availability than their male littermates. The ablation of arginase II increases arginine availability in male mice.

Arginine and Arginine/ADMA Ratio Predict 90-Day Mortality in Patients with Out-of-Hospital Cardiac Arrest-Results from the Prospective, Observational COMMUNICATE Trial.

(1) Background: In patients with shock, the L-arginine nitric oxide pathway is activated, causing an elevation of nitric oxide, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) levels. Whether these metabolites provide prognostic information in patients after out-of-hospital cardiac arrest (OHCA) remains unclear. (2) Methods: We prospectively included OHCA patients, recorded clinical parameters and measured plasma ADMA, SDMA and Arginine levels by liquid chromatography tandem mass spectrometry (LC-MS). The primary endpoint was 90-day mortality. (3) Results: Of 263 patients, 130 (49.4%) died within 90 days after OHCA. Compared to survivors, non-survivors had significantly higher levels of ADMA and lower Arginine and Arginine/ADMA ratios in univariable regression analyses. Arginine levels and Arginine/ADMA ratio were significantly associated with 90-day mortality (OR 0.51 (95%CI 0.34 to 0.76), p < 0.01 and OR 0.40 (95%CI 0.26 to 0.61), p < 0.001, respectively). These associations remained significant in several multivariable models. Arginine/ADMA ratio had the highest predictive value with an area under the curve (AUC) of 0.67 for 90-day mortality. Results for secondary outcomes were similar with significant associations with in-hospital mortality and neurological outcome. (4) Conclusion: Arginine and Arginine/ADMA ratio were independently associated with 90-day mortality and other adverse outcomes in patients after OHCA. Whether therapeutic modification of the L-arginine-nitric oxide pathway has the potential to improve outcome should be evaluated.

Cross-sectional analysis of plasma and CSF metabolomic markers in Huntington’s disease for participants of varying functional disability: a pilot study

Huntington’s Disease (HD) is a progressive, fatal neurodegenerative condition. While generally considered for its devastating neurological phenotype, disturbances in other organ systems and metabolic pathways outside the brain have attracted attention for possible relevance to HD pathology, potential as therapeutic targets, or use as biomarkers of progression. In addition, it is not established how metabolic changes in the HD brain correlate to progression across the full spectrum of early to late-stage disease. In this pilot study, we sought to explore the metabolic profile across manifest HD from early to advanced clinical staging through metabolomic analysis by mass spectrometry in plasma and cerebrospinal fluid (CSF). With disease progression, we observed nominally significant increases in plasma arginine, citrulline, and glycine, with decreases in total and d-serine, cholesterol esters, diacylglycerides, triacylglycerides, phosphatidylcholines, phosphatidylethanolamines, and sphingomyelins. In CSF, worsening disease was associated with nominally significant increases in NAD+, arginine, saturated long chain free fatty acids, diacylglycerides, triacylglycerides, and sphingomyelins. Notably, diacylglycerides and triacylglyceride species associated with clinical progression were different between plasma and CSF, suggesting different metabolic preferences for these compartments. Increasing NAD+ levels strongly correlating with disease progression was an unexpected finding. Our data suggest that defects in the urea cycle, glycine, and serine metabolism may be underrecognized in the progression HD pathology, and merit further study for possible therapeutic relevance.