Inhibition of Na+/H+ exchanger reduces infarct volume of focal cerebral ischemia in rats.
Activation of Na+/H+ exchanger (NHE) may have an important role in ischemic cell death by means of intracellular overload of Na(+) and Ca(2+). Recent evidence has suggested that inhibitors of NHE have protective effects on myocardial ischemia both in vivo and in vitro. In this study, we tested the hypothesis that FR183998, an inhibitor of NHE, reduces infarct volume produced by focal cerebral ischemia in rats. We used 20 male spontaneously hypertensive rats. Either FR183998 (1 mg/kg; n=10), or vehicle (n=10) was given intravenously to the rats and the distal middle cerebral artery of each animal was occluded using a photothrombotic technique. We measured regional cerebral blood flow using laser-Doppler flowmetry throughout the experiments. After 3 days, infarct volume was measured in each animal group. To estimate the brain edema, we also calculated the cortical volume in both hemispheres. The infarct volume in the FR183998-treated group (82+/-8 mm(3), mean+/-S.E.M.) was significantly smaller than that in the control group (115+/-12 mm(3)) (P=0.034). The cortical volume of the occluded side in the FR183998-treated group (359+/-7 mm(3)) tended to be smaller than that in the control group (378+/-9 mm(3)) (P=0.116). The regional cerebral blood flow and physiological variables during ischemia were not significantly different between the two groups throughout the experiments. These results suggest that inhibition of NHE by FR183998 may have beneficial effects in reducing infarct volume and brain edema during cerebral ischemia. Thus, NHE may play an important role in the development of neuronal damage during acute cerebral ischemia.
Kitayama
J
J
Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Fukuoka 812-8582, Japan.
Kitazono
T
T
Yao
H
H
Ooboshi
H
H
Takaba
H
H
Ago
T
T
Fujishima
M
M
Ibayashi
S
S
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000201:enzymology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000201:enzymology; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D012964:Sodium / Q000378:metabolism*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D016896:Treatment Outcome
D004791:Enzyme Inhibitors; C449400:FR 183998; D006146:Guanidines; D018696:Neuroprotective Agents; D017923:Sodium-Hydrogen Exchangers; D013876:Thiophenes; D012964:Sodium; D002118:Calcium