Thromboxane A2 accounts for bronchoconstriction but not for platelet sequestration and microvascular albumin exchanges induced by fMLP in the guinea pig lung.
When injected i.v. to guinea pigs, the granulocyte secretagog N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP) induces bronchoconstriction (BC), lung platelet sequestration and increased transendothelial albumin exchanges in lungs. We evaluated BC and the variations of the lung contents in radiolabeled platelets, erythrocytes and extravascular albumin, as measurements of platelet lung entrapment, reduction of lung blood volume and increase of transendothelial albumin exchanges, respectively. Trimetoquinol, a thromboxane A2 (TXA2)-endoperoxide receptor antagonist, inhibited BC and platelet entrapment by lungs induced by fMLP, but protection was nonspecific because it also suppressed BC by histamine. The specific TXA2 synthetase inhibitor/endoperoxide receptor antagonist ridogrel suppressed BC and reduced lung platelet entrapment, but failed to prevent the increase of extravascular albumin and the decrease of erythrocyte lung contents due to fMLP. Consequently, the fMLP-induced increase of vascular albumin exchanges and reduction of lung blood volume are TXA2-independent. Aspirin prevented BC, but failed to suppress lung platelet entrapment by fMLP, indicating that in vivo platelet activation is not TXA2-dependent, even though the levels of circulating TXB2, the stable metabolite of TXA2, were increased after fMLP concomitantly with that of 6-keto-prostaglandin (PG)F1 alpha, the stable metabolite of PGI2. The ridogrel-treated animals showed reduced blood level of TXB2 and increased levels of 6-keto-PGF1 alpha after fMLP challenge. Blocking the cyclooxygenase pathway with aspirin prevented ridogrel-induced protection against lung platelet sequestration after fMLP, supporting the concept that rechanneling of arachidonate metabolism toward protective prostaglandins accounts for protection by ridogrel.
Bureau
M F
MF
Unité de Pharmacologie Cellulaire, Institut Pasteur-Institut National de la Santé et de la Recherche Medicale, Paris, France.
De Clerck
F
F
Lefort
J
J
Arreto
C D
CD
Vargaftig
B B
BB
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects*; D006168:Guinea Pigs; D007093:Imidazoles / Q000494:pharmacology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology*; D010421:Pentanoic Acids / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011863:Radioimmunoassay; D012709:Serum Albumin / Q000378:metabolism*; D013496:Suprofen / Q000494:pharmacology; D013921:Thrombocytopenia / Q000139:chemically induced; D013928:Thromboxane A2 / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014213:Tretoquinol / Q000494:pharmacology
D007093:Imidazoles; D010421:Pentanoic Acids; D011450:Prostaglandin Endoperoxides, Synthetic; D011725:Pyridines; D012709:Serum Albumin; C029166:dazoxiben; D016718:Arachidonic Acid; D013929:Thromboxane B2; D013928:Thromboxane A2; D015121:6-Ketoprostaglandin F1 alpha; D009240:N-Formylmethionine Leucyl-Phenylalanine; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013496:Suprofen; D013930:Thromboxane-A Synthase; D014213:Tretoquinol; C060219:ridogrel