Mechanism of complement-mediated thromboxane production by the perfused rabbit liver: lack of effect of dantrolene sodium.
Activated components of the complement system have been shown to stimulate the arachidonic acid cascade. We have reported that hepatic thromboxane production in response to plasma activated with zymosan is self-limiting, not affected by nifedipine, but inhibited by mepacrine, a phospholipase inhibitor. To further study this relationship, we have tested the effects of dantrolene sodium, an agent reported to immobilize intracellular calcium. Control group livers were perfused with Krebs-Henseleit bicarbonate buffer at a rate of 120 ml/min in a nonrecirculating perfusion system and administered 1 ml/min of normal rabbit plasma for 10 minutes. This group of livers demonstrated stable wet weight, perfusion pressure, and rates of release of lactic dehydrogenase, thromboxane B2, and prostacyclin over a 150 minute experimental period. In contrast, the administration of 1 ml/min of zymosan-activated plasma resulted in significant increases in the rate of thromboxane B2 release at 1, 3, and 5 minutes after the start of the infusion. The rate of thromboxane production then returned to baseline values. Neither prostacyclin nor lactic dehydrogenase release changed significantly after ZAP. A similar change in thromboxane production following ZAP administration was seen in livers being continually perfused with 10 microM dantrolene sodium. Perfusion pressure was significantly elevated in this group during the ZAP infusion period. These results confirm complement-mediated thromboxane production in the isolated rabbit liver model but do not describe a definitive role of dantrolene-sensitive intracellular calcium release in the mechanism of ZAP-mediated thromboxane production.
D015121:6-Ketoprostaglandin F1 alpha / Q000096:biosynthesis*; D000818:Animals; D002118:Calcium / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology*; D003620:Dantrolene / Q000494:pharmacology*; D066298:In Vitro Techniques; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D010477:Perfusion; D011817:Rabbits; D013929:Thromboxane B2 / Q000096:biosynthesis*; D015054:Zymosan / Q000494:pharmacology
D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D003165:Complement System Proteins; D015054:Zymosan; D007770:L-Lactate Dehydrogenase; D003620:Dantrolene; D002118:Calcium