Ridogrel prevents the thromboxane-mediated pressor response and oedema induced by hydrogen peroxide in isolated rabbit lungs.
Perfusion of isolated rabbit lungs with hydrogen peroxide (H2O2, 3 x 10(-5) M) raised the overflow of thromboxane B2 (TXB2) and the perfusion pressure. H2O2 induced oedema formation and endothelial distress, as evidenced by an increased production of 6-oxo-prostaglandin F1 alpha (6-oxo-PGF1 alpha). Endothelial cell death did not occur since there was no release of lactate dehydrogenase. The thromboxane A2 (TXA2)-synthase inhibitor/receptor antagonist ridogrel (R68070) further enhanced 6-oxo-PGF1 alpha output, while inhibiting TXB2 release. Ridogrel prevented the rise in pulmonary artery pressure and oedema formation. These data indicate that TXA2 is probably involved in the acute pulmonary pressor response and concomitant oedema formation induced by H2O2. In order to assess the functional activity of the pulmonary endothelium, the uptake of 5-hydroxytryptamine (5-HT) was measured before and 15 min after exposure to H2O2. As the H2O2-induced effects were not associated with any change in the uptake of 5-hydroxytryptamine (5-HT), we conclude that the endothelial injury was reversible or that the 5-HT uptake was not sensitive enough to evaluate the integrity of the pulmonary endothelium during oxidant-induced injury.
Corten
I
I
Division of Pharmacology, Faculty of Medicine, University of Antwerp UIA, Belgium.
Peeters
F A
FA
Rampart
M
M
Bult
H
H
Buyssens
N
N
Herman
A G
AG
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D016923:Cell Death; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D010421:Pentanoic Acids / Q000494:pharmacology*; D011654:Pulmonary Edema / Q000139:chemically induced / Q000517:prevention & control*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D012701:Serotonin / Q000378:metabolism; D013928:Thromboxane A2 / Q000032:analysis / Q000378:metabolism; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D010421:Pentanoic Acids; D011725:Pyridines; D012701:Serotonin; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D013930:Thromboxane-A Synthase; C060219:ridogrel