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Journal of Applied Physiology... Feb 2018Nitric oxide (NO)-mediated vasodilation contributes to the rapid rise in muscle blood flow at exercise onset. This occurs via increased cyclic guanosine monophosphate...
Nitric oxide (NO)-mediated vasodilation contributes to the rapid rise in muscle blood flow at exercise onset. This occurs via increased cyclic guanosine monophosphate (cGMP), which is catabolized by phosphodiesterase-5 (PDE-5). Whether PDE-5 limits exercise vasodilation onset kinetics is unknown. We hypothesized the time course of exercise vasodilation would be 1) accelerated during PDE-5 inhibition (sildenafil citrate, SDF) and 2) decelerated during NO synthase inhibition ( N-monomethyl-l-arginine, l-NMMA), and 3) the effect of SDF on vasodilation onset kinetics would be attenuated with concurrent l-NMMA. Data from 29 healthy adults were analyzed. Individuals completed 5 min of moderate-intensity forearm exercise under control conditions and during 1) oral SDF ( n = 8), 2) intra-arterial l-NMMA ( n = 15), or 3) combined SDF + l-NMMA ( n = 6). Forearm blood flow (FBF; Doppler ultrasound of the brachial artery) and mean brachial artery blood pressure (MAP) were measured continuously. Forearm vascular conductance (FVC, FBF ÷ MAP) was curve-fit with a monoexponential model, and vasodilation onset kinetics were assessed by mean response time (MRT, time to achieve 63% of steady state). SDF had no effect on MRT ( P = 0.90). NOS inhibition increased MRT ( P = 0.01). MRT during SDF+l-NMMA was not different from control exercise ( P = 0.76). PDE-5 inhibition alone has no effect on rapid-onset vasodilation. Whereas NOS inhibition decelerates vasodilator kinetics, when combined with SDF, vasodilator kinetics do not differ from control. These data suggest NO-independent activation of cGMP occurs at exercise onset; thus PDE-5 inhibition may improve vasodilation in pathologies where NO bioavailability is impaired. NEW & NOTEWORTHY We show that when NO bioavailability is reduced, PDE-5 inhibition can restore vasodilation onset kinetics of exercise-mediated vasodilation via NO-independent cGMP pathways. These data suggest PDE-5 inhibition may improve exercise vasodilation onset kinetics in pathologies where NO bioavailability is impaired.
Topics: Adult; Cyclic GMP; Exercise; Female; Humans; Male; Nitric Oxide Synthase; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Vasodilation; Young Adult; omega-N-Methylarginine
PubMed: 28982942
DOI: 10.1152/japplphysiol.00483.2017 -
Journal of Applied Physiology... Dec 2017Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment...
Broxterman RM, Trinity JD, Gifford JR, Kwon OS, Kithas AC, Hydren JR, Nelson AD, Morgan DE, Jessop JE, Bledsoe AD, Richardson RS. Single passive leg movement assessment of vascular function: contribution of nitric oxide. J Appl Physiol 123: 1468-1476, 2017. First published August 31, 2017; doi:10.1152/japplphysiol.00533.2017.-The assessment of passive leg movement (PLM)-induced leg blood flow (LBF) and vascular conductance (LVC) is a novel approach to assess vascular function that has recently been simplified to only a single PLM (sPLM), thereby increasing the clinical utility of this technique. As the physiological mechanisms mediating the robust increase in LBF and LVC with sPLM are unknown, we tested the hypothesis that nitric oxide (NO) is a major contributor to the sPLM-induced LBF and LVC response. In nine healthy men, sPLM was performed with and without NO synthase inhibition by intra-arterial infusion of N-monomethyl-l-arginine (l-NMMA). Doppler ultrasound and femoral arterial pressure were used to determine LBF and LVC, which were characterized by the peak change (ΔLBF and ΔLVC) and area under the curve (LBF and LVC). l-NMMA significantly attenuated ΔLBF [492 ± 153 (l-NMMA) vs. 719 ± 238 (control) ml/min], LBF [57 ± 34 (l NMMA) vs. 147 ± 63 (control) ml], ΔLVC [4.7 ± 1.1 (l-NMMA) vs. 8.0 ± 3.0 (control) ml·min·mmHg], and LVC [0.5 ± 0.3 (l-NMMA) vs. 1.6 ± 0.9 (control) ml/mmHg]. The magnitude of the NO contribution to LBF and LVC was significantly correlated with the magnitude of the control responses ( r = 0.94 for ΔLBF, r = 0.85 for LBF, r = 0.94 for ΔLVC, and r = 0.95 for LVC). These data establish that the sPLM-induced hyperemic and vasodilatory response is predominantly (~65%) NO-mediated. As such, sPLM appears to be a promising, simple, in vivo assessment of NO-mediated vascular function and NO bioavailability. NEW & NOTEWORTHY Passive leg movement (PLM), a novel assessment of vascular function, has been simplified to a single PLM (sPLM), thereby increasing the clinical utility of this technique. However, the role of nitric oxide (NO) in mediating the robust sPLM hemodynamic responses is unknown. This study revealed that sPLM induces a hyperemic and vasodilatory response that is predominantly NO-mediated and, as such, appears to be a promising simple, in vivo, clinical assessment of NO-mediated vascular function and, therefore, NO bioavailability.
Topics: Adult; Arterial Pressure; Enzyme Inhibitors; Hemodynamics; Humans; Hyperemia; Leg; Male; Movement; Nitric Oxide; Regional Blood Flow; Vasodilation; Young Adult; omega-N-Methylarginine
PubMed: 28860173
DOI: 10.1152/japplphysiol.00533.2017 -
Journal of Cerebral Blood Flow and... Feb 2019Our goal was to examine whether in utero exposure to alcohol impaired reactivity of cerebral arterioles during development. We fed Sprague-Dawley dams a liquid diet with...
Our goal was to examine whether in utero exposure to alcohol impaired reactivity of cerebral arterioles during development. We fed Sprague-Dawley dams a liquid diet with or without alcohol (3% ethanol) for the duration of pregnancy (21-23 days). Around 4-6 weeks after birth, we examined reactivity of cerebral arterioles to eNOS- (ADP) and nNOS-dependent (NMDA) agonists in the offspring. We found that in utero exposure to alcohol attenuated responses of cerebral arterioles to ADP and NMDA, but not to nitroglycerin in rats exposed to alcohol in utero. L-NMMA reduced responses to agonists in control rats, but not in rats exposed to alcohol in utero. Treatment of dams with apocynin for the duration of pregnancy rescued the impairment in reactivity to ADP and NMDA in the offspring. Protein expression of NOX-2 and NOX-4 was increased in alcohol rats compared to control rats. We also found an increase in superoxide levels in the cortex of rats exposed to alcohol in utero. Our findings suggest that in utero exposure to alcohol impairs eNOS and nNOS reactivity of cerebral arterioles via a chronic increase in oxidative stress.
Topics: Acetophenones; Adenosine Diphosphate; Animals; Arterioles; Cerebral Cortex; Chronic Disease; Ethanol; Female; Male; Maternal Exposure; NADPH Oxidase 2; NADPH Oxidase 4; Nitric Oxide Synthase Type I; Nitric Oxide Synthase Type III; Oxidative Stress; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Sprague-Dawley; Superoxides; omega-N-Methylarginine
PubMed: 28840777
DOI: 10.1177/0271678X17728163 -
PloS One 2017Nitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with...
RATIONALE
Nitric oxide synthase (NOS) is a biomarker/target in sepsis. NOS activity is driven by amino acids, which cycle to regulate the substrate L-arginine in parallel with cycles which regulate the endogenous inhibitors ADMA and L-NMMA. The relationship between amines and the consequence of plasma changes on iNOS activity in early sepsis is not known.
OBJECTIVE
Our objective was to apply a metabolomics approach to determine the influence of sepsis on a full array of amines and what consequence these changes may have on predicted iNOS activity.
METHODS AND MEASUREMENTS
34 amino acids were measured using ultra purification mass spectrometry in the plasma of septic patients (n = 38) taken at the time of diagnosis and 24-72 hours post diagnosis and of healthy volunteers (n = 21). L-arginine and methylarginines were measured using liquid-chromatography mass spectrometry and ELISA. A top down approach was also taken to examine the most changed metabolic pathways by Ingenuity Pathway Analysis. The iNOS supporting capacity of plasma was determined using a mouse macrophage cell-based bioassay.
MAIN RESULTS
Of all the amines measured 22, including L-arginine and ADMA, displayed significant differences in samples from patients with sepsis. The functional consequence of increased ADMA and decreased L-arginine in context of all cumulative metabolic changes in plasma resulted in reduced iNOS supporting activity associated with sepsis.
CONCLUSIONS
In early sepsis profound changes in amine levels were defined by dominant changes in the iNOS canonical pathway resulting in functionally meaningful changes in the ability of plasma to regulate iNOS activity ex vivo.
Topics: Adult; Aged; Amines; Animals; Arginine; Cell Line; Chromatography, Liquid; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Mass Spectrometry; Metabolomics; Mice; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Sepsis; omega-N-Methylarginine
PubMed: 28813479
DOI: 10.1371/journal.pone.0183025 -
Nitric oxide synthase inhibition restores orthostatic tolerance in young vasovagal syncope patients.Heart (British Cardiac Society) Nov 2017Syncope is sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). We previously...
OBJECTIVE
Syncope is sudden transient loss of consciousness and postural tone with spontaneous recovery; the most common form is vasovagal syncope (VVS). We previously demonstrated impaired post-synaptic adrenergic responsiveness in young VVS patients was reversed by blocking nitric oxide synthase (NOS). We hypothesised that nitric oxide may account for reduced orthostatic tolerance in young recurrent VVS patients.
METHODS
We recorded haemodynamics in supine VVS and healthy volunteers (aged 15-27 years), challenged with graded lower body negative pressure (LBNP) (-15, -30, -45 mm Hg each for 5 min, then -60 mm Hg for a maximum of 50 min) with and without NOS inhibitor N-monomethyl-L-arginine acetate (L-NMMA). Saline plus phenylephrine (Saline+PE) was used as volume and pressor control for L-NMMA.
RESULTS
Controls endured 25.9±4.0 min of LBNP during Saline+PE compared with 11.6±1.4 min for fainters (p<0.001). After L-NMMA, control subjects endured 24.8±3.2 min compared with 22.6±1.6 min for fainters. Mean arterial pressure decreased more in VVS patients during LBNP with Saline+PE (p<0.001) which was reversed by L-NMMA; cardiac output decreased similarly in controls and VVS patients and was unaffected by L-NMMA. Total peripheral resistance increased for controls but decreased for VVS during Saline+PE (p<0.001) but was similar following L-NMMA. Splanchnic vascular resistance increased during LBNP in controls, but decreased in VVS patients following Saline+PE which L-NMMA restored.
CONCLUSIONS
We conclude that arterial vasoconstriction is impaired in young VVS patients, which is corrected by NOS inhibition. The data suggest that both pre- and post-synaptic arterial vasoconstriction may be affected by nitric oxide.
Topics: Administration, Intravenous; Adolescent; Adult; Age Factors; Arterial Pressure; Arteries; Cardiac Output; Enzyme Inhibitors; Female; Hemodynamics; Humans; Lower Body Negative Pressure; Male; Nitric Oxide Synthase; Syncope, Vasovagal; Time Factors; Treatment Outcome; Vascular Resistance; Vasoconstriction; Young Adult; omega-N-Methylarginine
PubMed: 28501796
DOI: 10.1136/heartjnl-2017-311161 -
High Altitude Medicine & Biology Sep 2017Lüneburg, Nicole, Patricia Siques, Julio Brito, Juan José De La Cruz, Fabiola León-Velarde, Juliane Hannemann, Cristian Ibanez, and Rainer Böger. Long-term...
Lüneburg, Nicole, Patricia Siques, Julio Brito, Juan José De La Cruz, Fabiola León-Velarde, Juliane Hannemann, Cristian Ibanez, and Rainer Böger. Long-term intermittent exposure to high altitude elevates asymmetric dimethylarginine in first exposed young adults. High Alt Med Biol. 18:226-233, 2017.-Hypoxia-induced dysregulation of pulmonary and cerebral circulation may be related to an impaired nitric oxide (NO) pathway. We investigated the effect of chronic intermittent hypobaric hypoxia (CIH) on metabolites of the NO pathway. We measured asymmetric and symmetric dimethylarginine (ADMA and SDMA) and monomethyl-L-arginine (L-NMMA) and assessed their associations with acclimatization in male draftees (n = 72) undergoing CIH shifts at altitude (3550 m) during 3 months. Sixteen Andean natives living at altitude (3675 m) (chronic hypobaric hypoxia [CH]) were included for comparison. In CIH, ADMA and L-NMMA plasma concentrations increased from 1.14 ± 0.04 to 1.95 ± 0.09 μmol/L (mean ± SE) and from 0.22 ± 0.07 to 0.39 ± 0.03 μmol/L, respectively, (p < 0.001 for both) after 3 months, whereas SDMA did not change. The concentrations of ADMA and L-NMMA were higher in CH (3.48 ± 0.07, 0.53 ± 0.08 μmol/L; p < 0.001) as compared with CIH. In both CIH and CH, ADMA correlated with hematocrit (r = 0.07, p < 0.05; r = 0.26; p < 0.01). In CIH, an association of ADMA levels with poor acclimatization status was observed. We conclude that the endogenous NO synthase inhibitors, ADMA and L-NMMA, are elevated in hypoxia. This may contribute to impaired NO production at altitude and may also be predictive of altitude-associated health impairment.
Topics: Acclimatization; Adolescent; Altitude; Altitude Sickness; Arginine; Chile; Humans; Hypoxia; Male; Military Personnel; Occupational Diseases; Young Adult; omega-N-Methylarginine
PubMed: 28453332
DOI: 10.1089/ham.2016.0123 -
European Journal of Applied Physiology Jun 2017Animal studies suggest that the inhibition of nitric oxide synthase (NOS) affects blood flow differently in different skeletal muscles according to their muscle fibre...
PURPOSE
Animal studies suggest that the inhibition of nitric oxide synthase (NOS) affects blood flow differently in different skeletal muscles according to their muscle fibre type composition (oxidative vs glycolytic). Quadriceps femoris (QF) muscle consists of four different muscle parts: vastus intermedius (VI), rectus femoris (RF), vastus medialis (VM), and vastus lateralis (VL) of which VI is located deep within the muscle group and is generally regarded to consist mostly of oxidative muscle fibres.
METHODS
We studied the effect of NOS inhibition on blood flow in these four different muscles by positron emission tomography in eight young healthy men at rest and during one-leg dynamic exercise, with and without combined blockade with prostaglandins.
RESULTS
At rest blood flow in the VI (2.6 ± 1.1 ml/100 g/min) was significantly higher than in VL (1.9 ± 0.6 ml/100 g/min, p = 0.015) and RF (1.7 ± 0.6 ml/100 g/min, p = 0.0015), but comparable to VM (2.4 ± 1.1 ml/100 g/min). NOS inhibition alone or with prostaglandins reduced blood flow by almost 50% (p < 0.001), but decrements were similar in all four muscles (drug × muscle interaction, p = 0.43). During exercise blood flow was also the highest in VI (45.4 ± 5.5 ml/100 g/min) and higher compared to VL (35.0 ± 5.5 ml/100 g/min), RF (38.4 ± 7.4 ml/100 g/min), and VM (36.2 ± 6.8 ml/100 g/min). NOS inhibition alone did not reduce exercise hyperemia (p = 0.51), but combined NOS and prostaglandin inhibition reduced blood flow during exercise (p = 0.002), similarly in all muscles (drug × muscle interaction, p = 0.99).
CONCLUSION
NOS inhibition, with or without prostaglandins inhibition, affects blood flow similarly in different human QF muscles both at rest and during low-to-moderate intensity exercise.
Topics: Adult; Enzyme Inhibitors; Exercise; Humans; Male; Muscle, Skeletal; Nitric Oxide Synthase; Prostaglandin Antagonists; Regional Blood Flow; omega-N-Methylarginine
PubMed: 28432421
DOI: 10.1007/s00421-017-3604-2 -
Antiviral Chemistry & Chemotherapy Apr 2017L-N-monomethyl-arginine (L-NMMA) is an experimental compound that suppresses nitric oxide production in animals. The compound was combined with oseltamivir to treat...
L-N-monomethyl-arginine (L-NMMA) is an experimental compound that suppresses nitric oxide production in animals. The compound was combined with oseltamivir to treat lethal influenza A/California/04/2009 (H1N1) pandemic virus infections in mice. Treatments were given twice a day for five days starting 4 h (oseltamivir, by oral gavage) or three days (L-NMMA, by intraperitoneal route; corresponding to the time previously reported for nitric oxide induction in the animals) after infection. Low doses of oseltamivir were used in order to demonstrate synergy or antagonism. Oseltamivir monotherapy protected 70% of mice from death at 1 mg/kg/day. L-NMMA (40 and 80 mg/kg/day) was ineffective alone in preventing mortality. Compared to oseltamivir treatment alone, L-NMMA combined with oseltamivir was synergistically effective (as evaluated by three-dimensional MacSynergy analysis), resulting in survival increases from 20 to 70% when 40 or 80 mg/kg/day of L-NMMA was combined with 0.3 mg/kg/day of oseltamivir, and from 70 to 100% survival increases when these doses were combined with 1 mg/kg/day of oseltamivir. These data demonstrate that a nitric oxide inhibitor such as L-NMMA has the potential to be beneficial when combined with oseltamivir in treating influenza virus infections.
Topics: Animals; Antiviral Agents; Disease Models, Animal; Drug Synergism; Enzyme Inhibitors; Female; Influenza A Virus, H1N1 Subtype; Mice; Mice, Inbred BALB C; Orthomyxoviridae Infections; Oseltamivir; omega-N-Methylarginine
PubMed: 28417640
DOI: 10.1177/2040206617691885 -
The Journal of Clinical Endocrinology... Jun 2017Arginine, its methylated metabolites, and other metabolites related to the urea cycle have been independently associated with cardiovascular risk, but the potential...
CONTEXT
Arginine, its methylated metabolites, and other metabolites related to the urea cycle have been independently associated with cardiovascular risk, but the potential causal meaning of these associations (positive for some metabolites and negative for others) remains elusive due to a lack of studies measuring metabolite changes over time.
OBJECTIVE
To examine the association between baseline and 1-year concentrations of urea cycle metabolites and cardiovascular disease (CVD) in a case-cohort setting.
DESIGN
A case-cohort study was nested within the Prevención con Dieta Mediterránea trial. We used liquid chromatography-tandem mass spectrometry to assess metabolite levels at baseline and after 1-year follow-up. The primary CVD outcome was a composite of myocardial infarction, stroke and cardiovascular death. We used weighted Cox regression models (Barlow weights) to estimate multivariable-adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs).
SETTING
Multicenter randomized trial in Spain.
PARTICIPANTS
Participants were 984 participants accruing 231 events over 4.7 years' median follow-up.
MAIN OUTCOME MEASURE
Incident CVD.
RESULTS
Baseline arginine/asymmetric dimethylarginine ratio [HR per standard deviation (SD) = 0.80; 95% CI, 0.67 to 0.96] and global arginine availability [arginine / (ornithine + citrulline)] (HR per SD = 0.83; 95% CI, 0.69 to 1.00) were significantly associated with lower risk of CVD. We observed no significant association for 1-year changes in these ratios or any effect modification by the Mediterranean diet (MD) intervention.
CONCLUSIONS
A higher baseline arginine/asymmetric dimethylarginine ratio was associated with lower CVD incidence in a high cardiovascular risk population. The intervention with the MD did not change 1-year levels of these metabolites.
Topics: Aged; Arginine; Cardiovascular Diseases; Case-Control Studies; Chromatography, Liquid; Citrulline; Cohort Studies; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Ornithine; Proportional Hazards Models; Prospective Studies; Risk Factors; Stroke; Tandem Mass Spectrometry; omega-N-Methylarginine
PubMed: 28323949
DOI: 10.1210/jc.2016-3569 -
Kidney International Jun 2017We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the...
We assessed the association between urinary metabolites, genetic variants, and incident chronic kidney disease (CKD) in the Framingham Offspring cohort. Among the participants, 193 individuals developed CKD (estimated glomerular filtration rate under 60 ml/min/1.73m) between cohort examinations 6 (1995-1998) and 8 (2005-2008, mean follow-up 9.7 years). They were age- and sex-matched to 193 control individuals free of CKD. A total of 154 urinary metabolites were measured using mass spectrometry, and the association between metabolites and CKD was examined using logistic regression. Next, we tested the genetic associations of each metabolite with an Illumina exome chip. Urinary glycine and histidine were associated with a lower risk of incident CKD with an odds ratio of 0.59 (95% confidence interval [CI] 0.43-0.80) and 0.65 (0.50-0.85) respectively, per one standard deviation increase in metabolite concentration. Follow-up in the Atherosclerosis Risk in Communities cohort confirmed the association of urinary glycine with CKD. In exome chip analyses, 36 single nucleotide polymorphisms at 30 loci were significantly associated with 31 metabolites. We surveyed exome chip findings for associations with known renal function loci such as rs8101881 in SLC7A9 coding for an amino acid transporter, which has been associated with a lower risk of CKD. We found this polymorphism was significantly associated with higher levels of lysine and NG-monomethyl-L-arginine (NMMA). Increased urinary lysine and NMMA were associated with a lower risk of CKD (0.73 [0.50-0.90] and 0.66 [0.53-0.83], respectively) in the univariate model. Thus, low urinary glycine and histidine are associated with incident CKD. Furthermore, genomic association of urinary metabolomics identified lysine and NMMA as being linked with CKD and provided additional evidence for the association of SLC7A9 with kidney disease.
Topics: Aged; Amino Acid Transport Systems, Basic; Amino Acids; Biomarkers; Case-Control Studies; Chi-Square Distribution; Female; Genetic Predisposition to Disease; Glycine; Histidine; Humans; Incidence; Logistic Models; Lysine; Male; Mass Spectrometry; Massachusetts; Metabolomics; Middle Aged; Odds Ratio; Oligonucleotide Array Sequence Analysis; Phenotype; Polymorphism, Single Nucleotide; Proportional Hazards Models; Prospective Studies; Protective Factors; Renal Insufficiency, Chronic; Risk Assessment; Risk Factors; Urinalysis; omega-N-Methylarginine
PubMed: 28302371
DOI: 10.1016/j.kint.2017.01.007