Submitted on October 18, 2007
Accepted on May 22, 2008
Interaction of nitric oxide, 20-HETE, and EETs during functional hyperemia in whisker barrel cortex
Xiaoguang Liu1, Chunyuan Li1, John R. Falck2, Richard J. Roman3, David R. Harder4, and Raymond C. Koehler1*
1 Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland, United States
2 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, United States
3 Department of Physiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
4 Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
* To whom correspondence should be addressed. E-mail: rkoehler{at}jhmi.edu.
Nitric oxide (NO) modulates vasodilation in cerebral cortex during sensory activation. NO is known to inhibit the synthesis of 20-HETE, which has been implicated in arteriolar constriction during astrocyte activation in brain slices. We tested the hypothesis that the attenuated cerebral blood flow (CBF) response to whisker stimulation seen after NO synthase (NOS) inhibition requires 20-HETE synthesis and that the ability of an EETs antagonist to reduce the CBF response is blunted after NOS inhibition but restored with simultaneous blockade of 20-HETE synthesis. In anesthetized rats, the increase in CBF during whisker stimulation was attenuated after blockade of neuronal NOS with 7-nitroindazole. Subsequent administration of the 20-HETE synthesis inhibitor N-hydroxy-N'-(4-n-butyl-2-methylphenyl)formamidine (HET0016) restored the CBF response to control levels. After administration of 7-nitroindazole, the inhibitory effect of an EETs antagonist 14,15-EEZE on the CBF response was lost, whereas simultaneous administration of 7-nitroindazole and HET0016 restored the inhibitory effect of 14,15-EEZE. Administration of HET0016 alone had only a small effect on the evoked CBF response in rats. Furthermore, in neuronal NOS+/+ and NOS-/- mice, HET0016 administration did not increase the CBF response to whisker stimulation. In neuronal NOS+/+ mice, HET0016 also blocked the reduction in the response seen with acute NOS inhibition. These results indicate that 20-HETE synthesis normally does not substantially restrict functional hyperemia. Increased NO production during functional activation may act dynamically to suppress 20-HETE synthesis or downstream signaling and permit EETs-dependent vasodilation. With chronic loss of neuronal NOS in mice, other mechanisms apparently suppress 20-HETE synthesis or signaling.
