Thromboxane A2-induced vascular endothelial cell damage and respiratory smooth muscle cell contraction: inhibition by flunarizine, a Ca2+-overload blocker.
The fast intravenous injection of arachidonic acid (AA) in mice produces, in a dose-related way, mortality due to respiratory distress. Upon electron microscopical examination an extensive oedematous damage of the capillary endothelium was found; thrombotic platelet obstructions were present in a minority of pulmonary capillaries only. Protection against this toxic AA-effect is obtained with inhibitors of fatty acid cyclo-oxygenase and of thromboxane (TXA2) synthetase, suggesting involvement of TXA2 as a causative mediator. The Ca2+-entry blockers flunarizine, niludipine and nimodipine, not affecting TXA2 synthesis by murine platelets, also provide protection, but not the antiplatelet drugs ticlopidine, dipyridamole or suloctidil; thrombocytopenia induced by busulphan does not affect the AA-induced mortality nor the protection obtained with flunarizine. Platelet-independent bronchoconstriction induced by AA in guinea-pigs is also inhibited by flunarizine. This study suggests that the AA-induced mortality test reflects pulmonary conversion of AA to TXA2 producing endothelial cell damage and respiratory smooth muscle cell contraction rather than a thrombotic phenomenon. The protective effect of flunarizine against TXA2 induced changes in vivo may contribute to its effectiveness in particular hypoxic conditions associated with liberation of AA.
De Clerck
F
F
Loots
W
W
Somers
Y
Y
Van Gorp
L
L
Verheyen
A
A
Wouters
L
L
D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000633:toxicity; D001792:Blood Platelets / Q000378:metabolism; D001980:Bronchi / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002936:Cinnarizine / Q000031:analogs & derivatives / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors; D004727:Endothelium / Q000187:drug effects; D005444:Flunarizine; D006168:Guinea Pigs; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000097:blood; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000648:ultrastructure; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000648:ultrastructure; D010879:Piperazines / Q000494:pharmacology*; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin / Q000378:metabolism; D012306:Risk; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D013931:Thromboxanes / Q000494:pharmacology*; D013997:Time Factors
D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D016861:Cyclooxygenase Inhibitors; D010879:Piperazines; D018077:Receptors, Leukotriene; D011982:Receptors, Prostaglandin; D013931:Thromboxanes; D016718:Arachidonic Acid; D002936:Cinnarizine; D008315:Malondialdehyde; D013928:Thromboxane A2; D013930:Thromboxane-A Synthase; D005444:Flunarizine