Modification of focal cerebral ischemia by prostacyclin and indomethacin

Abstract

✓ The object of this investigation was to study the effects of prostacyclin (PGI2), with and without indomethacin, upon the evolution of cerebral infarction in the cat. Thirty-five fasted adult cats, lightly anesthetized with nitrous oxide, underwent right middle cerebral artery (MCA) occlusion. Eleven cats received an intracarotid infusion of 10 mg/ml PGI2 in buffered saline, pH 10.5, at a rate of 0.01 ml/kg/min (100 ng/kg/min), 10 cats received the same infusion plus a single dose of intravenous indomethacin (4 mg/kg) in buffered saline, and 11 cats received intracarotid buffered saline, pH 10.5, at a rate of 0.01 ml/kg/min, without therapeutic agents. Treatment with PGI2 was started upon MCA occlusion and continued for 6 hours, whereas indomethacin was given immediately prior to occlusion. Thirty minutes before perfusion, the animals were given fluorescein and Evans blue by intravenous injection. The cats were perfusion-fixed in vivo with carbon and buffered formalin 6 hours after MCA occlusion. Another five cats received tritium-labeled PGI2, and peripheral venous samples were collected and assayed for PGI2 and its alpha-keto metabolite. Mean arterial pressure was stable in treated animals during 6 hours of MCA occlusion, while untreated cats had significant (α = 0.05) progressive hypertension during that period. The regional cerebral blood flow (rCBF), measured by the intracarotid xenon-133 clearance method, decreased markedly in all animals immediately upon MCA occlusion. Untreated animals had a significant progressive improvement in rCBF during the occlusion period (α = 0.005), while treated animals had no such improvement. Quantitative electroencephalographic changes, gross edema, areas of fluorescein extravasation, and microscopic morphology (edema and infarct size) were not significantly different in the three groups. Prostacyclin appeared to reduce the extravasation of Evans blue dye. Systemic PGI2 levels were significant despite intracarotid administration. The authors conclude that 1) intracarotid PGI2 has a protective effect against the breakdown of the blood-brain barrier to protein-bound dyes seen in ischemic edema; 2) the systemic hemodynamic influence of PGI2, in the presence of impaired autoregulation, may compromise rCBF in the ischemic zone and offset any direct beneficial effects; and 3) indomethacin fails to modify the effects of PGI2.