Experimental study of cerebral ischemia in dogs - Effect of inhibition of cyclooxygenase and thromboxaneA(2) synthetase on cerebral blood flow -

The left middle cerebral artery and the common trunk of the anterior cerebral artery were simultaneously occluded via a transorbital approach in 35 dogs. Local cerebral blood flow (1-CBF) and platelet aggregability were measured during 2 hours of arterial occlusion followed by 2 hours of recirculation. The animals were divided into four groups according to drug administration. Eight dogs were control animals. Nine dogs received OKY-1581, a selective thromboxane A(2) synthetase inhibitor 75mg/kg intravenously 1 hour before cerebral ischemia. In another 9 dogs, OKY-1581 was infused intravenously at a rate of 100μg/kg/min during the ischemia and recirculation periods. The remaining 9 dogs received indomethacin, a selective cyclooxygenase inhibitor 4mg/kg intravenously 1 hour before occlusion of the vessels. Both OKY-1581 75mg/kg and indomethacin 4mg/kg resulted in a slight reduction in mean 1-CBF before ischemia. In control animals, mean 1-CBF decreased by 70% following clipping of the arteries. By releasing the clips, mean 1-CBF was restored to near the pre-occlusion level, followed by another decrease (postischemic hypoperfusion). In animals which received OKY-1581 100μg/kg/min, hyperemia was apparent in the immediate post-recirculation period, followed by aggravation of hypoperfusion. In animals which received indomethacin 4mg/kg, neither hyperemia nor hypoperfusion was demonstrated through recirculation period. Changes in platelet aggregability induced by ADP was not observed by cerebral ischemia and restoration of circulation. The platelet aggregability was reduced only by surgical procedures and by administration of indomethacin. These results suggest that the postischemic recirculation is strongly influenced by arachidonic acid degradation products, such as thromboxane A(2) and other cyclooxygenase products. It seems that the inhibition of cyclooxygenase is more beneficial than that of thromboxane A(2) synthetase, in the protection of hypoperfusion after recirculation of cerebral blood flow