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Differences in plasma L-arginine and dimethylarginines in diagnosis and treatment of pulmonary arterial hypertension: a prospective observational study
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Pharmacology.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Introduction Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance in vasoactive substances and remodelling of pulmonary vasculature. Asymmetric dimethylarginine (ADMA) inhibits the enzyme nitric oxide synthase, which generates nitric oxide (NO), a molecule causing smooth muscle cell relaxation. Our aim was to investigate the plasma concentrations of ADMA, symmetrical dimethylarginine (SDMA), L-arginine, L-ornithine and L- citrulline at diagnosis and during PAH-specific treatment in patients with PAH compared to patients with left heart failure (LVHF) and healthy subjects.

Methods This is an observational, prospective multicentre study of 21 PAH patients. For comparison 14 patients with LVHF and 27 healthy subjects were investigated. Blood samples were collected and ADMA, SDMA, L-arginine, L-ornithine and L-citrulline were analysed with liquid chromatography – tandem mass spectrometry (LC-MS/MS).

Results Baseline plasma concentrations of ADMA and SDMA were higher whereas the L-arginine concentrations and L-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p<0.001). Patients with PAH had lower L-arginine concentration than patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to L-arginine and L- arginine/ADMA in PAH at baseline (p<0.05). At follow-up, patients on mono- or combination therapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on phosphodiesterase type-5 inhibitors (PDE5-inhibitors) had higher ADMA levels compared to patients without PDE5-inhibitor treatment (p<0.05).

Conclusion Concentrations of L-arginine were decreased and dimethylarginines were increased in PAH compared to healthy subjects. L-arginine was decreased in PAH compared to LVHF. L- arginine/ADMA ratio correlated to WHO functional class and L-arginine and L-arginine/ADMA ratio correlated to 6MWD. PAH-specific treatment influences the levels of L-arginine and dimethylarginines. 

Keyword [en]
pulmonary arterial hypertension, dimethylarginines, L-arginine, haemodynamics, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists
National Category
Cardiac and Cardiovascular Systems Pharmacology and Toxicology
Research subject
Clinical Pharmacology
Identifiers
URN: urn:nbn:se:umu:diva-113901OAI: oai:DiVA.org:umu-113901DiVA: diva2:891007
Available from: 2016-01-05 Created: 2016-01-05 Last updated: 2016-01-05
In thesis
1. Vardenafil and methylarginines in pulmonary hypertension
Open this publication in new window or tab >>Vardenafil and methylarginines in pulmonary hypertension
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Background: Pulmonary hypertension (PH) is a rare condition characterized by endothelial dysfunction and vascular remodelling, leading to increased pulmonary vascular resistance (PVR) and right ventricular heart failure. Endothelial dysfunction is associated with an imbalance between vasoconstrictor compounds, such as endothelin and thromboxane A2, and vasodilator compounds, such as prostacyclin and nitric oxide (NO). Asymmetric dimethylarginine (ADMA), a methyl derivate of L-arginine, inhibits synthesis of NO. Vardenafil, a phosphodiesterase type 5 inhibitor (PDE5-inhibitors), causes vasodilation through the NO/cGMP pathway.

Aim: This thesis investigates the pharmacological effects and diagnostic utility of vardenafil in PH patients. In addition, to evaluate the change of L-arginine and dimethylarginines before and during PAHspecific therapy in PAH patients compared to patients with left ventricular heart failure (LVHF) and healthy subjects.

Methods: The pharmacokinetics and hemodynamic effects of vardenafil were examined during right heart catheterization (RHC) in 16 PH patients and plasma concentrations were measured for up to nine hours after oral administration. In 20 PH patients, acute vasoreactivity test with vardenafil was performed during RHC. Hemodynamic responses were recorded, responders were defined and followed for up to seven years. Additionally, plasma ADMA, symmetric dimethylarginine (SDMA), L-arginine, L-citrulline and L-ornithine levels before and after PAH drug treatment were monitored in 21 PAH patients and compared to values measured in 14 LVHF patients and 27 healthy subjects.

Results: Vardenafil concentrations increased rapidly to maximum plasma concentration (tmax 1h) and elimination half-life was 3.4 h. Patients co-medicated with bosentan had reduced vardenafil concentration. Significant acute hemodynamic responses were observed for mean pulmonary artery pressure (mPAP) (p<0.001), pulmonary vascular resistance (PVR) (p<0.001), cardiac output (CO) (p=0.015), cardiac index (CI) (p=0.010), systemic vascular resistance (SVR) (p<0.001) and PVR/SVR (p=0.002) and were related to plasma vardenafil concentrations. PAH patients had significantly higher ADMA and SDMA levels and significantly lower L-arginine levels and L-arginine/ADMA ratio compared with healthy subjects (p<0.001). L-arginine was also lower in PAH patients compared to patients with LVHF (p<0.05). WHO functional class and six minutes walking distance (6MWD) correlated to Larginine and L-arginine/ADMA ratio in PAH at baseline (p<0.05). At follow-up, patients on mono- or combinationtherapy with endothelin receptor antagonists (ERA) had lower ADMA levels than patients without ERA (p<0.05). In contrast, patients on PDE5-inhibitors had higher ADMA levels compared to patients without PDE5-inhibitors (p<0.05).

Conclusion: Vardenafil is safe in acute vasoreactivity test in PH patients. Cardiopulmonary hemodynamic response was related to plasma drug concentrations. There was a high inter-individual variability of vardenafil pharmacokinetics and co-medication with bosentan caused a pharmacokinetic drug interaction. Baseline L-arginine and dimethylarginines levels were different in PAH patients compared to LVHF patients and healthy controls. PAH-specific treatment influenced L-arginine and dimethylarginines. Our data suggest that L-arginine might be useful for differentiating PAH from LVHF, and L-arginine/ADMA ratios were related to the severity of PAH and might be useful for follow-up evaluations of PAH patients.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. 73 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1747
Keyword
vardenafil, pulmonary hypertension, pharmacokinetics, haemodynamics, right heart catheterization, adenosine, dimethylarginines, phosphodiesterase type 5 inhibitors, endothelin receptor antagonists
National Category
Pharmacology and Toxicology Cardiac and Cardiovascular Systems
Research subject
Clinical Pharmacology
Identifiers
urn:nbn:se:umu:diva-113903 (URN)978-91-7601-376-2 (ISBN)
Public defence
2016-01-22, Hörsal B, tandläkarhögskolan våning 9, Norrlands universitetssjukhus, Umeå, 13:00 (English)
Opponent
Supervisors
Available from: 2016-01-08 Created: 2016-01-05 Last updated: 2016-02-09Bibliographically approved

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