Antiremodeling effects of iloprost and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in chronic experimental pulmonary hypertension.
Severe pulmonary hypertension is a disabling disease with high mortality. We investigated acute and chronic effects of iloprost, a long-acting prostacyclin analogue, and the dual-selective phosphodiesterase 3/4 inhibitor tolafentrine in monocrotaline-induced pulmonary hypertension in rats. Twenty-eight and 42 days after administration of the alkaloid, right ventricular systolic pressure increased from 25.8+/-2.0 to 62.9+/-3.4 and 70.5+/-7.4 mm Hg, with concomitant decline in cardiac index, central venous oxygen saturation, and arterial oxygenation. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight, and massive thickening of the precapillary artery smooth muscle layer was shown histologically. Western blot analysis demonstrated increased levels of matrix metalloproteinases (MMPs) -2 and -9 and increased gelatinolytic activities in isolated pulmonary arteries. In these animals, both intravenous iloprost and tolafentrine displayed characteristic features of pulmonary vasodilators. When chronically infused from days 14 to 28, both agents significantly attenuated all monocrotaline-induced hemodynamic and gas exchange abnormalities as well as right heart hypertrophy. Full normalization of all variables including right ventricle size was achieved on combined administration of both agents during this period. This was also true for MMP-2 and MMP-9 expression and activity. Moreover, when iloprost plus tolafentrine was used for late therapeutic intervention, with infusion from days 28 to 42 after full establishment of severe pulmonary hypertension and cor pulmonale, hemodynamic, gas exchange, and cardiac and pulmonary vascular remodeling changes were significantly reversed. We conclude that the combined administration of iloprost and a dual-selective phosphodiesterase 3/4 inhibitor prevents and reverses the development of pulmonary hypertension and cor pulmonale in response to monocrotaline in rats. This regimen may therefore offer a possible antiremodeling therapy in severe pulmonary hypertension.
Schermuly
Ralph Theo
RT
Department of Internal Medicine, Justus-Liebig-University Giessen, Germany. ralph.schermuly@innere.med.uni-giessen.de
Kreisselmeier
Klaus Peter
KP
Ghofrani
Hossein Ardeschir
HA
Samidurai
Arun
A
Pullamsetti
Soni
S
Weissmann
Norbert
N
Schudt
Christian
C
Ermert
Leander
L
Seeger
Werner
W
Grimminger
Friedrich
F
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D018093:Gelatinases / Q000032:analysis; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D006984:Hypertrophy; D017380:Hypertrophy, Right Ventricular / Q000209:etiology / Q000517:prevention & control*; D016285:Iloprost / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D016686:Monocrotaline / Q000633:toxicity; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D010100:Oxygen / Q000097:blood; D010726:Phosphodiesterase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011651:Pulmonary Artery / Q000201:enzymology / Q000473:pathology; D011659:Pulmonary Gas Exchange / Q000187:drug effects; D011660:Pulmonary Heart Disease / Q000209:etiology / Q000517:prevention & control; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects*
D009287:Naphthyridines; D010726:Phosphodiesterase Inhibitors; D014665:Vasodilator Agents; C094030:tolafentrine; D016686:Monocrotaline; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D018093:Gelatinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D016285:Iloprost; D010100:Oxygen