Inhibitors of protein synthesis preserve the N-methyl-D-aspartate-induced cerebral arteriolar dilation after ischemia in piglets.
BACKGROUND AND PURPOSE--Cerebral arteriolar dilation to N-methyl-D-aspartate (NMDA) is a neuronally mediated process that is sensitive to cerebral ischemia. We tested the hypothesis that pretreatment with transcription or translation inhibitors preserves the vascular response to NMDA after global cerebral ischemia. METHODS--Pial arteriolar diameters were measured in anesthetized piglets by use of a closed cranial window and intravital microscopy. Arteriolar responses to NMDA (10(-5) and 10(-4) mol/L) were measured before and 1, 2, and 4 hours after 10 minutes of ischemia. Ischemia was induced by increasing intracranial pressure. Subgroups were pretreated with vehicle, topical actinomycin D (Act-D) 10(-5) or 10(-6) mol/L, or intravenous cycloheximide (CHX) 1.0 or 0.3 mg/kg 15 minutes before ischemia. The effects of Act-D and CHX on vascular responses to NMDA without preceding ischemia were also examined. RESULTS--In the vehicle group, arteriolar responses to NMDA were clearly attenuated 1 hour after ischemia but returned to baseline at 2 to 4 hours. Preischemic compared with 1 hour postischemic arteriolar dilation to NMDA was 10+/-2% versus 1+/-0% at 10(-5) mol/L and 40+/-4% versus 20+/-4% at 10(-4) mol/L NMDA (mean+/-SEM; both P<0.05, n=7). In contrast, pretreatment with Act-D resulted in preservation of the arteriolar responses to NMDA 1 hour after ischemia. For 10(-6) mol/L (n=5) of Act-D, dilations were 6+/-2% versus 6+/-2% at 10(-5) mol/L and 51+/-9% versus 39+/-10% at 10(-4) mol/L of NMDA. For 10(-5) mol/L (n=5) of Act-D, arterioles dilated by 7+/-2% versus 7+/-2% at 10(-5) mol/L and 38+/-4% versus 35+/-4% at 10(-4) mol/L NMDA. Similarly, CHX preserved NMDA-induced vasodilation. For 0.3 mg/kg of CHX (n=5), dilations were 8+/-2% versus 8+/-1% at 10(-5) mol/L and 39+/-4% versus 28+/-6% at 10(-4) mol/L NMDA. For 1.0 mg/kg of CHX (n=5), arterioles dilated by 10+/-2% versus 6+/-2% at 10(-5) mol/L and 37+/-7% versus 35+/-6% at 10(-4) mol/L NMDA. In experiments without ischemia, NMDA-induced vasodilation before and 85 minutes after administration of Act-D or CHX was not significantly different. CONCLUSIONS--Vascular responses of cerebral arterioles to NMDA after ischemia are preserved by pretreatment with either Act-D or CHX. Without preceding ischemia, Act-D and CHX do not potentiate neuronal-vascular responses to NMDA. Our results suggest that continued or augmented protein synthesis is involved in the transient attenuation of NMDA-induced dilation during the early reperfusion phase and that inhibitors of protein synthesis may protect neurons against ischemic stress.
Veltkamp
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Stroke Research Center and Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston Salem, NC 27157- 1083, USA. veltkamp@bgsm.edu
Domoki
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Bari
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Louis
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Busija
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D000818:Animals; D000831:Animals, Newborn; D001784:Blood Gas Analysis; D001794:Blood Pressure; D002536:Cerebral Arteries / Q000187:drug effects; D002560:Cerebrovascular Circulation / Q000187:drug effects; D003513:Cycloheximide / Q000494:pharmacology; D003609:Dactinomycin / Q000494:pharmacology*; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D006863:Hydrogen-Ion Concentration; D002546:Ischemic Attack, Transient / Q000188:drug therapy*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000188:drug therapy; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D018690:Excitatory Amino Acid Agonists; D011500:Protein Synthesis Inhibitors; D003609:Dactinomycin; D016202:N-Methylaspartate; D003513:Cycloheximide