Stevens, Mark K.

The time-dependent release of prostaglandin E 2 (PGE 2 ), prostaglandin F 2α (PGF 2α ), thromboxane (Tx) B 2 , and 6-keto-PGF 1α (6-keto) from brain was measured before, during, and after a 15-min interval of total ischemia (four-vessel occlusion) in halothane-anesthetized cats using the technique of cerebroventricular perfusion. Resting levels of PGE 2 , PGF 2α , 6-keto, and Tx were: 253 ± 75, 953 ± 300, 650 ± 200, and 550 ± 170 pg/ml, respectively. During the 15-min ischemia, all prostanoids rose significantly, yet the highest levels were not observed until the first 15–60 min of the reflow at which time levels of PGE 2 , PGF 2α , 6-keto, and Tx, as compared with the preischemic baseline, rose ∼8, 3.4, 3, and 55-fold, respectively. Significantly, although all prostanoids showed increases relative to baseline, the ratios of PGF 2α /6-keto and PGE 2 /6-keto remained stable throughout the experiment in both groups of animals. In contrast, the Tx/6-keto ratio rose from ∼1 to ∼ 30 during the 60 min after reflow in untreated cats. Treatment with zomepirac sodium (5 mg/kg, i.v.), a cyclooxygenase inhibitor, resulted in highly significant reductions in the levels of all prostanoids during the preischemic period. In zomepirac sodium-treated animals, there were also highly significant reductions in the prostanoid response to ischemia. Of particular interest was that the degree of inhibition of Tx as compared with 6-keto, during the post-ischemic period of peak secretion was such that the Tx/6-keto ratio fell from 30 in the control ischemic animal to 0.3 in the zomepirac sodium-treated animal, suggesting a selective blockade of the formation of Tx as compared with prostacyclin.

Zomepirac sodium (ZS) (5 mg/kg i.v.) was used to evaluate the effects of preischemia cyclooxygenase inhibition on CBF (as assessed by 133 Xe clearance), CBF–P a CO 2 responsiveness, and electrophysiologic (EEG) parameters before and after a 15-min period of complete global ischemia produced by four-vessel occlusion and mild hypotension. During the 15-min period of ischemia, CBF was essentially zero. Following reflow all groups displayed an initial hyperemia as compared with control (92 ± 11 vs. 141–146 ml/100 g/min). Saline-treated animals during reflow displayed a delayed hypoperfusion (26 ± 3 ml/100 g/min), which showed no improvement during the 2-h reflow period prior to death. In contrast, ZS-treated animals during reflow displayed significantly higher flows during the hypoperfusion phase (72 ± 9 ml/100 g/min). The CBF–P a CO 2 response displayed an approximately sevenfold reduction in slope at 2 h after reflow in saline-treated animals. This decrease in P a CO 2 reactivity was not observed in the ZS-pretreated animals. With regard to EEG, all animals showed a total flattening during the 15 min of ischemia. In saline-treated animals only one of seven showed any sign of even marginal recovery. In ZS-treated animals EEG activity showed prominent recovery in seven of seven. Brainstem auditory evoked potentials were monitored and showed prominent recovery of amplitude and latency in ZS but not saline-treated animals during reflow.

The dose-dependent effects of MK-801, a glutamate receptor antagonist, on changes in CBF, CBF-P a co 2 responsiveness ( 133 Xe clearance), EEG, and blood-brain barrier (methylene blue) were examined after a 15-min period of reversible complete global ischemia induced in halothane-anesthetized cats by occlusion of the vertebral and carotid arteries. Pretreatment with doses of MK-801 of ≥0.5 mg/kg had no effect on resting CBF measures and produced a dose-dependent slowing of the dominant EEG frequency. In animals receiving this agent, there was an almost immediate return of baseline EEG patterns upon reinstitution of flow, no hypoperfusion after 2 h of reflow, preservation of CBF and CBF-P a co 2 responsiveness, and maintenance of blood-brain barrier integrity. In contrast, parallel control animals and animals treated with MK-801 at a dose of 0.1 mg/kg exhibited poor recovery based on the above parameters. MK-801 also diminished in a dose-dependent manner the CSF levels of 6-keto-prostaglandin (PG) F 1α (stable metabolite of PGI 2 ) and thromboxane (Tx) B 2 (stable metabolite of TxA 2 ), which were otherwise elevated in vehicle-treated animals 2 h after reflow. Of particular interest, the CSF TxB 2 /6-keto-PGF 1α ratio in vehicle-treated animals was near 2. In animals pretreated with MK-801, at doses of ≥0.5 mg/kg, this ratio was nearly 1. These observations are consistent with a possible triggering role of glutamate release in initiating at least part of the acute sequelae of ischemia. Such release in an electrically silent cell would increase C a 2+ influx and activate free fatty acid metabolism, leading to probable changes in vascular function and changes in blood-brain barrier permeability.