Is neuroprotective efficacy of nNOS inhibitor 7-NI dependent on ischemic intracellular pH?
The purpose of this study was to test the hypothesis that the efficacy of 7-nitroindazole (7-NI), a selective neuronal nitric oxide (NO) synthase (NOS) inhibitor, is pH dependent in vivo during focal cerebral ischemia. Wistar rats underwent 2 h of focal cerebral ischemia under 1% halothane anesthesia. 7-NI, 10 and 100 mg/kg in 0.1 ml/kg DMSO, was administered 30 min before occlusion. Ischemic brain acidosis was manipulated by altering serum glucose concentrations. Confirmation of the effects of these serum glucose manipulations on brain intracellular pH (pH(i)) was confirmed in a group of acute experiments utilizing umbelliferone fluorescence. The animals were euthanized at 72 h for histology. 7-NI significantly (P < 0.05) reduced infarction volume in both the normoglycemic by 93.3% and hyperglycemic animals by 27.5%. In the moderate hypoglycemic animals, the reduction in infarction volume did not reach significance because moderate hypoglycemia in itself dramatically reduced infarction volume. We hypothesize that a mechanism to explain the published discrepancies on the effects of neuronal NOS inhibitors in vivo may be due to the effects by differences in ischemic brain acidosis on the production of NO.
Coert
Bernard A
BA
Thoralf M. Sundt Jr. Neurosurgery Research Laboratory, Mayo Clinic, Rochester, Minnesota 55905, USA.
Anderson
Robert E
RE
Meyer
Fredric B
FB
D000818:Animals; D001921:Brain / Q000378:metabolism; D002545:Brain Ischemia / Q000378:metabolism*; D002544:Cerebral Infarction / Q000473:pathology; D002560:Cerebrovascular Circulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005453:Fluorescence; D006859:Hydrogen / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007191:Indazoles / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D009243:NAD / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D007191:Indazoles; D018696:Neuroprotective Agents; D009243:NAD; D006859:Hydrogen; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496322:Nos1 protein, rat; C080122:7-nitroindazole