Relative contributions from neuronal and endothelial nitric oxide synthases to regional cerebral blood flow changes during forebrain ischemia in rats

The principal aim of this study was to examine the relative contributions f rom the neuronal and endothelial isoforms of nitric oxide synthase (nNOS an d eNOS, respectively) in their capacity to modulate intra-ischemic cerebral blood flow (CBF) changes, in the ischemically vulnerable hippocampus and s triatum. CBF changes were monitored, using laser-Doppler flowmetry, in rats subjected to 30 min of forebrain ischemia (right common carotid occlusion + hemorrhagic hypotension). Rats were pretreated with a selective nNOS inhi bitor (ARR 17477), a NOS inhibitor that blocks both eNOS and nNOS (N-G-nitr o-L-arginine; F-NNA), or saline (control). In initial experiments, where is chemic MABP was targeted to exactly 30 mmHg, NOS inhibition reduced intra-i schemic cortical CBF from the control level of similar to 20% of baseline t o 3% (L-NNA) or 6% (ARR 17477) of baseline. The statistically similar effec ts of the two NOS inhibitors confirmed that nNOS is the predominant NO sour ce supporting intra-ischemic vasodilation in the cortex. In subsequent expe riments, CBF was measured in the right hippocampus, and striatum, as well a s the cortex, and, to reduce data variability, blood withdrawal was adjuste d to achieve an intra-ischemic cortical CBF of 20% (controls) or 5% (NOS in hibited rats) of baseline. In those groups, mean ischemic MABP levels range d from 28 to 32 mmHg. In controls, intra-ischemic CBF fell to 20%, 45%, and 47% of baseline in the cortex, hippocampus, and striatum, respectively. Wi th nNOS inhibition, intra-ischemic CBF was further reduced to 5%, 15%, and 18% of baseline, respectively. However, with combined eNOS/nNOS inhibition, the CBF values were 5%, 37%, and 21%, respectively. These results suggest that the nNOS contribution to intra-ischemic vasodilation in vulnerable reg ions is substantially greater than eNOS. The significantly higher intra-isc hemic CBF level in the hippocampus in combined eNOS/nNOS vs nNOS-inhibited rats may relate, in contrast to other regions, to a low eNOS influence on v ascular function in that structure and CBF redistribution to the hippocampu s when eNOS activity is blocked globally. NeuroReport 11:1549-1553 (C) 2000 Lippincott Williams & Wilkins.