Pentaerythritol Tetranitrate In Vivo Treatment Improves Oxidative Stress and Vascular Dysfunction by Suppression of Endothelin-1 Signaling in Monocrotaline-Induced Pulmonary Hypertension.
Objective. Oxidative stress and endothelial dysfunction contribute to pulmonary arterial hypertension (PAH). The role of the nitrovasodilator pentaerythritol tetranitrate (PETN) on endothelial function and oxidative stress in PAH has not yet been defined.Methods and Results. PAH was induced by monocrotaline (MCT, i.v.) in Wistar rats. Low (30 mg/kg; MCT30), middle (40 mg/kg; MCT40), or high (60 mg/kg; MCT60) dose of MCT for 14, 28, and 42 d was used. MCT induced endothelial dysfunction, pulmonary vascular wall thickening, and fibrosis, as well as protein tyrosine nitration. Pulmonary arterial pressure and heart/body and lung/body weight ratio were increased in MCT40 rats (28 d) and reduced by oral PETN (10 mg/kg, 24 d) therapy. Oxidative stress in the vascular wall, in the heart, and in whole blood as well as vascular endothelin-1 signaling was increased in MCT40-treated rats and normalized by PETN therapy, likely by upregulation of heme oxygenase-1 (HO-1). PETN therapy improved endothelium-dependent relaxation in pulmonary arteries and inhibited endothelin-1-induced oxidative burst in whole blood and the expression of adhesion molecule (ICAM-1) in endothelial cells.Conclusion. MCT-induced PAH impairs endothelial function (aorta and pulmonary arteries) and increases oxidative stress whereas PETN markedly attenuates these adverse effects. Thus, PETN therapy improves pulmonary hypertension beyond its known cardiac preload reducing ability.
Center for Cardiology, Department of Cardiology, Mainz, Germany; Center of Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
Sebastian
S
Steven
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Matthias
M
Oelze
Center for Cardiology, Department of Cardiology, Mainz, Germany; Center of Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
Moritz
M
Brandt
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Elisabeth
E
Ullmann
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Swenja
S
Kröller-Schön
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Tjebo
T
Heeren
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Lan P
LP
Tran
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Steffen
S
Daub
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Mobin
M
Dib
Freelancer Consultant, 76199 Karlsruhe, Germany.
Dirk
D
Stalleicken
Center for Cardiology, Department of Cardiology, Mainz, Germany; Center of Thrombosis and Hemostasis, University Medical Center Mainz, Mainz, Germany.
Philip
P
Wenzel
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Thomas
T
Münzel
Center for Cardiology, Department of Cardiology, Mainz, Germany.
Andreas
0000-0002-2769-0094
A
Daiber
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002460:Cell Line; D004452:Echocardiography; D019332:Endothelin-1 / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006321:Heart / Q000000981:diagnostic imaging; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects*; D010417:Pentaerythritol Tetranitrate / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D019332:Endothelin-1; D014665:Vasodilator Agents; D010417:Pentaerythritol Tetranitrate; D018799:Intercellular Adhesion Molecule-1; D016686:Monocrotaline; D051547:Heme Oxygenase-1; D000109:Acetylcholine