The role of the central arachidonic acid-thromboxane A(2) cascade in cardiovascular regulation during hemorrhagic shock in rats

Abstract

The aim of the current study was to elucidate the underlying central mechanism(s) of the cardiovascular effects evoked by centrally injected melittin and arachidonic acid (AA) in hemorrhaged hypotensive condition, specifically, from central AA release from the cell membrane under the influence of phospholipase A(2) (PLA(2)) to central thromboxane A(2) (TXA(2)) signaling via the cyclooxygenase (COX) pathway. As the main control of the study, melittin (3 mu g) or AA (150 mu g) was injected intracerebroventricularly (i.c.v.) after the hemorrhage procedure, which was performed by withdrawing a total volume of 2.2 ml of blood/100 g body weight over a period of 10 min. Both treatments generated a pressor response and abolished the hypotension-induced hemorrhage. Pretreatment with the PLA(2) inhibitor mepacrine (500 mu g; i.c.v.) completely blocked the pressor response to melittin in the hemorrhagic hypotensive state. Pretreatments with the nonselective COX inhibitor indomethacin (200 mu g; i.c.v.) or the TXA(2) synthesis inhibitor furegrelate (250 or 500 mu g; i.c.v.) were made to test the role of central COX activity and, subsequently, the TXA(2) signaling pathway in the melittin- or AA-mediated reversal of hemorrhagic hypotension. Indomethacin completely prevented the pressor response to melittin and AA in the hemorrhaged, hypotensive state, but furegrelate did so only partially.

In conclusion, these findings suggest that central COX activity and, subsequently, the central TXA(2) signaling pathway, are, at least in part, involved in the melittin- or AA-induced reversal effect during hemorrhagic shock.