A pharmacological analysis of the pathophysiological mechanisms of posttraumatic spinal cord ischemia

A pharmacological analysis was carried out to determine the possible role of aberrant calcium fluxes, vasoactive arachidonic acid metabolites, and microvascular lipid peroxidation in the development of posttraumatic spinal cord white matter ischemia. Pentobarbital-anesthetized cats were treated intravenously 30 minutes before a 500-gm-cm contusion injury to the lumbar spinal cord with one of the following test drugs: the Ca⁺⁺ channel antagonists verapamil, diltiazem, or nifedipine; the cyclo-oxygenase inhibitors ibuprofen or meclofenamate; the thromboxane A₂ (TXA₂) synthetase inhibitors furegrelate sodium; or the stable epoprostenol (prostacyclin, or PGI₂) analogue ciprostene calcium alone or in combination with furegrelate sodium. Another group of animals was pretreated for 5 days before spinal injury with a combination of the antioxidants vitamin E and selenium in high doses. The hydrogen clearance technique was used to make repeated measurements of spinal cord blood flow (SCBF) in the dorsolateral funiculus of the injured segment before and for 4 hours after injury. In 11 untreated uninjured cats, the mean preinjury SCBF was 12.7 ± 1.5 ml/100 gm/min. Following contusion, there was a progressive decline in SCBF to 6.8 ± 0.4 ml/100 gm/min, or 53.5% of the preinjury level at 4 hours. In comparison, the Ca⁺⁺ antagonists diltiazem and nifedipine (but nor verapamil) prevented a significant posttraumatic decrease in SCBF. Similarly, both cyclo-oxygenase inhibitors (ibuprofen and meclofenamate) maintained SCBF within normal limits (10 ml/100 gm/min or greater). However, neither TXA₂ synthetase inhibition nor the stable PGI₂ analogue alone had a significant effect in preventing ischemia, whereas a combination of the two agents did serve to support SCBF. The most impressive preservation of posttraumatic SCBF, however, was observed in the antioxidant-treated animals. Based upon these results, a hypothesis is presented concerning the pathogenesis of posttraumatic central nervous system ischemia which integrates an injury-induced rise in intracellular Ca⁺⁺, the increased synthesis of vasoactive prostanoids (such as prostaglandin F(2α) and TXA₂), and progressive microvascular lipid peroxidation.