Cycloheximide rapidly inhibits cortical COX activity and COX-dependent pial arteriolar dilation in piglets

We have previously shown that cycloheximide (CIM) preserved neuronal functi on after global cerebral ischemia in piglets, in a manner similar to indome thacin. To elucidate the mechanism of this protection, we tested the hypoth esis that CHX would inhibit cyclooxygenase (COX) activity in the piglet cer ebral cortex and vasculature. Pial arteriolar responses to hypercapnia, art erial hypotension, and sodium nitroprusside (SNP) were determined before an d 20 min after treatment with CHX (0.3-1 mg/kg iv) using a closed cranial w indow and intravital microscopy. We also determined baseline and arachidoni c acid (AA)-stimulated cortical PGF(2 alpha) and 6-keto-PGF(1 alpha) produc tion before and 20-60 min after CHX (1 mg/kg iv) treatment, using ELISA kit s. CHX did not affect baseline diameters (similar to 100 um) but significan tly decreased arteriolar dilation to COX-dependent stimuli, such as hyperca pnia and hypotension, but not to COX-independent SNP. In the 1 mg/kg CHX-tr eated group, increases in vascular diameters were reduced from 22 +/- 2 to 10 +/- 2%, from 49 +/- 5 to 31 +/- 3% (means +/- SE, 5 and 10% CO2, respect ively, n 1 8), from 12 +/- 3 to 3 +/- 1%, and from 26 +/- 5 to 6 +/-. 2% (s imilar to 25 and 40% decreases in blood pressure, respectively, n = 6). CHX also inhibited conversion of exogenous AA to both PGF(2 alpha), and 6-keto -PGF(1 alpha),; for example, 20 min after CHX treatment 10 mu g/ml AA-stimu lated PGF(2 alpha), concentrations in the artificial cerebrospinal fluid de creased from 14.28 +/- 3.04 to 5.90 +/- 1.26 ng/ml (n = 9). Thus CHX rapidl y decreases COX activity in the piglet cerebral cortex. This result may exp lain in part the preservation of neuronal function of CHX in cerebral ische mia.