Interaction of nitric oxide and 20‐HETE during cortical functional hyperemia

Abstract

Nitric oxide (NO) is postulated to modulate rather than mediate increased cerebral blood flow (CBF) during sensory activation. We tested whether this modulation can be explained by NO inhibition of synthesis of the vasoconstrictor, 20-HETE, which may counteract opening of KCa channels by EETs. In anesthetized rats, the increase in CBF during whisker stimulation was reduced from 27±10% (±SD; n=8) to 18±6% by the neuronal NO synthase inhibitor 7-nitroindazole (7-NI 40 mg/kg). Subsequent subdural superfusion of the 20-HETE synthesis inhibitor HET0016 (1 μM) restored the CBF response to 25±12%. HET0016 alone had only a small effect on the evoked CBF response (21±5 to 24±5%; n=8). Simultaneous administration of 7-NI and HET0016 resulted in no change in the CBF response (25±5 to 24±6%; n=8). Subsequent superfusion of the EET antagonist 14,15-EEZE (30 μM) reduced the response to 19±5%. However, when 7-NI decreased the CBF response from 26±7 to 17±3%, subsequent superfusion of 14,15-EEZE had no further effect (17±5%). Thus, the inhibitory effect of 7-NI on the cortical CBF response to sensory activation requires 20-HETE synthesis. The ability of an EET antagonist to reduce the response is lost in the presence of 7-NI, but is restored when 20-HETE synthesis is simultaneously inhibited. These results suggest that increased NO synthesis during functional activation acts to suppress 20-HETE synthesis and permit vasodilation by EETs. (Supported by NIH HL59996 and GM31278)