|Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1994: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1993: ¥1,200,000 (Direct Cost: ¥1,200,000)
The present study aimed at examining whether ischemic brain damage might develop mediated via a postischemic overproduction of nitric oxide in the brain tissue.
First, concentration of nitric oxide in the rat brain was directly measured, using newly devised microsensor. The exaggerated production (ca. 2-3 mumol) of nitric oxide was appeared in the affected hemisphere 15-20 minutes after MCAo and then reversed to the baseline. Three hours after MCAo, nitric oxide was yielded again over the baseline. The preischemic administration of LNA (Nomega-nitro-L-arginine, 1mg/kg, It is already reported that this dose is effective for prevention of ischemic brain edema following MCAo in rats) inhibited both of the above phenomena and ischemic brain edema was significantly blocked. Second, from the chronological study of Ca2^+-dependent and -independent NOS activity of cerebral MVs obtained from the affected hemisphere of the MCAo rats, Ca2^+-dependent NOS was first activated 10 times more than its
baseline value immediately after MCAo. At 4 hours after MCAo, Ca2^+-independent NOS (9 times of the baseline value, p<0.01 vs.control) was siginifcantly activated (p<0.01 vs.control). At 48,168 hr after MCAo, in place of Ca2^+-independent, Ca2^+-dependent NOS was activated again (3 times of the baseline value, p<0.01 vs.control).
Third, effects of LNA on brain water content subjected to MCAo was examined. it was elucidated that repeated intraperitoneal injection of 0.01 to 1mg/kg LNA found to be effective for prevention of increase in brain water content, 72 hours after MCAo.
The present study suggested that the ischemic brain is always subjected to high-concentrated nitric oxide, yielded from cerebral MVs and that adequate inhibition of both type of NOS in cerebral MVs by LNA might be beneficial for prevention of ischemic brain edema. The present study provided the first evidence that two distinct types of NOSs were activated and involved in the pathogenesis of ischemic brain damage and that a total inhibition of NOS is not required. Less