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Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
Umea Univ, Umea Univ Hosp, Dept Pharmacol & Clin Neurosci, Umea, Sweden..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cardiology.
Natl Vet Inst SVA, Dept Chem Environm & Feed Hyg, Uppsala, Sweden.;Uppsala Univ, Div Analyt Pharmaceut Chem, Dept Med Chem, SE-75185 Uppsala, Sweden..
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2015 (English)In: Vascular pharmacology, ISSN 1537-1891, E-ISSN 1879-3649, Vol. 73, p. 71-77Article in journal (Refereed) Published
Abstract [en]

Objective: We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine. Patients and methods: ADMA, SDMA, and arginine were measured (0-540 min) in 12 patients with pulmonary hypertension after a single oral dose of vardenafil. Invasive hemodynamic data were collected at baseline and after 60 min. Results: A reduction in ADMA was observed at 30 and 45 min with a median change of -11.1% (P = 0.021) and -12.5% (P = 0.002). SDMA decreased with a median -5.3% change (P = 0.032) at 45 min. An increase in arginine, median 40.3% (P = 0.002), 45.0% (P = 0.010), and 77.1% (P = 0.008) was observed at 120,300, and 540 min respectively. An increase in the arginine/ADMA ratio, median 11.7% (P = 0.012), 32.5% (P = 0.003), 26.5% (P = 0.021),33% (P = 0.007), 48.5% (P = 0.007), and 63.1% (P = 0.008) was observed at 15, 45, 60, 120, 300, and 540 min respectively. There was a positive correlation between vardenafil exposure and the percent change in the arginine/ADMA ratio from baseline to 540 min (r = 0.80; P = 0.01). A correlation between baseline mean right atrial pressure (mRAP) and baseline ADMA (r = 0.65; P = 0.023), and baseline SDMA (r = 0.61; P = 0.035) was observed. A correlation between the baseline arginine/ADMA ratio and baseline cardiac output (CO) (r = 0.59; P = 0.045) and baseline cardiac index (CI) (r = 0.61; P = 0.036) was observed. Baseline arginine/ADMA ratio correlated with baseline mRAP (r = -0.79; P = 0.002). A correlation between change (0-60 min) in CI and change in arginine (r = 0.77; P = 0.003) as well as change in the arginine/ADMA ratio (r = 0.61; P = 0.037) was observed. Conclusions: Vardenafil induced changes in ADMA, SDMA, arginine, and the arginine/ADMA ratio in patients with PH. An increase in arginine and the arginine/ADMA ratio was associated with improvement in Cl.

Place, publisher, year, edition, pages
2015. Vol. 73, p. 71-77
Keyword [en]
Pulmonary hypertension, Vardenafil, Hemodynamics, Dimethylarginines, Arginine
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-265699DOI: 10.1016/j.vph.2015.04.010ISI: 000362056600011PubMedID: 25934511OAI: oai:DiVA.org:uu-265699DiVA, id: diva2:866627
Available from: 2015-11-03 Created: 2015-11-02 Last updated: 2018-04-06Bibliographically approved
In thesis
1. Pulmonary Hypertension and the Nitric Oxide System
Open this publication in new window or tab >>Pulmonary Hypertension and the Nitric Oxide System
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Pulmonary hypertension (PH) is a pathophysiological state associated with several medical conditions, leading to progressive rise in pulmonary vascular resistance (PVR) and right ventricular failure. The clinical PH classification encompasses five main World Health Organization (WHO) groups; pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to lung diseases and/or hypoxia, chronic thromboembolic PH, and PH with unclear multifactorial mechanisms. Nitric oxide (NO) is a potent vasodilator. Impaired NO production via the classical L-arginine-NO synthase (NOS) pathway has been implicated in PH. Phosphodiesterase-5 (PDE5) inhibitors augment NO signalling, and are considered as one of the cornerstone treatments in PAH. The studies in this thesis aim at to explore and expand the understanding of the NO system in patients with PH.

In paper I, we found that PAH patients (WHO group 1) have lower bronchial NO flux compared to healthy controls and patients with PH (WHO group 2–4). This implies reduced bronchial NO formation in PAH. Compared to healthy controls, increased alveolar NO levels were found in patients with PH (WHO group 1-4) and patients with PAH. This may reflect NO diffusion disturbances in the alveoli. PAH patients had higher plasma and salivary levels of nitrite than healthy controls, which may reflect a compensatory upregulation of NOS-independent NO generating pathways.

In paper II, we observed that a single oral dose of vardenafil (a PDE5 inhibitor) causes rapid changes in cardiopulmonary haemodynamics in PH patients with PH (WHO group 1-4). We found a correlation between plasma vardenafil concentrations and the changes in mean pulmonary arterial pressure as well as PVR.

In paper III, we show that a single oral dose of vardenafil to patients with PH (WHO group 1-4) alter the plasma levels of arginine, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the arginine/ADMA ratio in a favourable manner. The increase in arginine and the arginine/ADMA ratio were associated with improved cardiac index, and the increase in the arginine/ADMA ratio at 540 min correlated with the exposure to vardenafil. Higher baseline plasma levels of ADMA and SDMA and a low arginine/ADMA ratio was associated with a more severe pulmonary haemodynamic disease state in patients with PH.

In paper IV, we found that ingestion of beetroot juice, containing inorganic nitrate, increased plasma and salivary levels of nitrate and nitrite, increased exhaled NO, decreased plasma ornithine levels and increased relative arginine availability in patients with PAH compared to placebo. Higher plasma levels of nitrite after the placebo period, reflecting basal conditions, were associated with a more severe PAH phenotype. Our findings indicate that the nitrate-nitrite-NO pathway is active and upregulated in PAH patients.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 83
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1461
Keyword
Pulmonary hypertension, nitric oxide, ADMA, arginine, nitrate, nitrite, vardenafil, beetroot juice
National Category
Cardiac and Cardiovascular Systems
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-347767 (URN)978-91-513-0325-3 (ISBN)
Public defence
2018-06-12, Enghoffsalen, Akademiska sjukhuset, Ingång 50 bv, Uppsala, 13:15 (Swedish)
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Available from: 2018-05-04 Created: 2018-04-06 Last updated: 2018-05-04

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Wernroth, LisaWikström, Gerhard

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