NITRIC-OXIDE SYNTHASE IN CEREBRAL-ISCHEMIA - POSSIBLE CONTRIBUTION OFNITRIC-OXIDE SYNTHASE ACTIVATION IN BRAIN MICROVESSELS TO CEREBRAL ISCHEMIC-INJURY

The results of our continuing studies on the role of nitric oxide (NO) in cellular mechanisms of ischemic brain damage as well as related re ports from other laboratories are summarized in this paper. Repetitive ip administration of N-G-nitro-L-arginine (L-NNA), a NO synthase (NOS ) inhibitor, protected against neuronal necrosis in the gerbil hippoca mpal CA1 field after transient forebrain ischemia with a bell-shaped r esponse curve, the optimal dose being 3 mg/kg. Repeated ip administrat ion of L-NNA also mitigated rat brain edema or infarction following pe rmanent and transient middle cerebral artery (MCA) occlusion with a U- shaped response. The significantly ameliorative dose-range and optimal dose were 0.01-1 mg/kg and 0.03 mg/kg, respectively. Studies using a NO-sensitive microelectrode revealed that NO concentration in the affe cted hemisphere was remarkably increased by 15-45 min and subsequently by 1.5-4 h after MCA occlusion. Restoration of blood flow after 2 h-M CA occlusion resulted in enhanced NO production by 1-2 h after reperfu sion. Administration of L-NNA (1 mg/kg, ip) diminished the increments in NO production during ischemia and reperfusion, leading to a remarka ble reduction in infarct volume. In brain microvessels obtained from t he affected hemisphere, Ca2+-dependent constitutive NOS (cNOS) was act ivated significantly at 15 min, and Ca2+-independent inducible NOS (iN OS) was activated invariably at 4 h and 24 h after MCA occlusion. Two hour reperfusion following 2 h-MCA occlusion caused more than fivefold increases in cNOS activity with no apparent alterations in iNOS activ ity. Thus, we report here based on available evidence that there is go od reason to think that NOS activation in brain microvessels may play a role in the cellular mechanisms underlying ischemic brain injury.