Cycloheximide rapidly inhibits cortical COX activity and COX-dependent pial arteriolar dilation in piglets.
We have previously shown that cycloheximide (CHX) preserved neuronal function after global cerebral ischemia in piglets, in a manner similar to indomethacin. To elucidate the mechanism of this protection, we tested the hypothesis that CHX would inhibit cyclooxygenase (COX) activity in the piglet cerebral cortex and vasculature. Pial arteriolar responses to hypercapnia, arterial hypotension, and sodium nitroprusside (SNP) were determined before and 20 min after treatment with CHX (0.3-1 mg/kg iv) using a closed cranial window and intravital microscopy. We also determined baseline and arachidonic acid (AA)-stimulated cortical PGF(2alpha) and 6-keto-PGF(1alpha) production before and 20-60 min after CHX (1 mg/kg iv) treatment, using ELISA kits. CHX did not affect baseline diameters (approximately 100 microm) but significantly decreased arteriolar dilation to COX-dependent stimuli, such as hypercapnia and hypotension, but not to COX-independent SNP. In the 1 mg/kg CHX-treated 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, respectively, n = 8), from 12 +/- 3 to 3 +/- 1%, and from 26 +/- 5 to 6 +/- 2% ( approximately 25 and 40% decreases in blood pressure, respectively, n = 6). CHX also inhibited conversion of exogenous AA to both PGF(2alpha) and 6-keto-PGF(1alpha); for example, 20 min after CHX treatment 10 microg/ml AA-stimulated PGF(2alpha) concentrations in the artificial cerebrospinal fluid decreased from 14.28 +/- 3.04 to 5.90 +/- 1.26 ng/ml (n = 9). Thus CHX rapidly decreases COX activity in the piglet cerebral cortex. This result may explain in part the preservation of neuronal function of CHX in cerebral ischemia.
Domoki
F
F
Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1010, USA. fdomoki@wfubmc.edu
Perciaccante
J V
JV
Veltkamp
R
R
Robins
G
G
Bari
F
F
Louis
T M
TM
Busija
D W
DW
D000818:Animals; D000831:Animals, Newborn; D016718:Arachidonic Acid / Q000494:pharmacology; D002540:Cerebral Cortex / Q000502:physiology*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology*; D003513:Cycloheximide / Q000494:pharmacology*; D015237:Dinoprost / Q000502:physiology; D011464:Epoprostenol / Q000502:physiology; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D011500:Protein Synthesis Inhibitors; D016718:Arachidonic Acid; D003513:Cycloheximide; D015237:Dinoprost; D011464:Epoprostenol; D011451:Prostaglandin-Endoperoxide Synthases