Changes in plasma levels of asymmetric dimethylarginine, symmetric dimethylarginine, and arginine after a single dose of vardenafil in patients with pulmonary hypertension.
OBJECTIVE
We investigated whether vardenafil, a phosphodiesterase-5 inhibitor, alters plasma levels of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and arginine.


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 CI.
Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden. Electronic address: dan_henrohn@hotmail.com.
Dan
D
Henrohn
Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå University Hospital, Umeå, Sweden.
Anna
A
Sandqvist
Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
Hanna
H
Egeröd
Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute, (SVA), Uppsala, Sweden; Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
Mikael
M
Hedeland
Uppsala Clinical Research Center, Uppsala, Sweden.
Lisa
L
Wernroth
Department of Chemistry, Environment and Feed Hygiene, National Veterinary Institute, (SVA), Uppsala, Sweden; Division of Analytical Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Uppsala, Sweden.
Ulf
U
Bondesson
Department of Medical Sciences, Uppsala University, Uppsala University Hospital, Uppsala, Sweden.
Gerhard
G
Wikström
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D016280:Atrial Function, Right / Q000187:drug effects; D062185:Atrial Pressure / Q000187:drug effects; D015415:Biomarkers / Q000097:blood; D002302:Cardiac Output / Q000187:drug effects; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000008:administration & dosage*; D013997:Time Factors; D016896:Treatment Outcome; D000069058:Vardenafil Dihydrochloride / Q000008:administration & dosage*; D014665:Vasodilator Agents / Q000008:administration & dosage*
D000959:Antihypertensive Agents; D015415:Biomarkers; D058986:Phosphodiesterase 5 Inhibitors; D014665:Vasodilator Agents; C024917:symmetric dimethylarginine; D000069058:Vardenafil Dihydrochloride; C018524:N,N-dimethylarginine; D001120:Arginine
Arginine; Arginine (PubChem CID: 6322); Asymmetric dimethylarginine (PubChem CID: 123831); Dimethylarginines; Hemodynamics; Pulmonary hypertension; Symmetric dimethylarginine (PubChem CID: 169148); Vardenafil; Vardenafil (INN) (PubChem CID: 110634)