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1 Physiology, University of Tennessee Health Science Center, Memphis, TN, USA
* To whom correspondence should be addressed. E-mail: cleffler{at}physio1.utmem.edu.
Carbon monoxide (CO) and nitric oxide (NO) can be involved in regulation of cerebral circulation. Inhibition of production of either one of these gaseous intercellular messengers inhibits newborn pig cerebral arteriolar dilation to the excitatory amino acid glutamate. Glutamate can increase NO production. Therefore, the present study tests the hypothesis that NO, which is increased by glutamate, stimulates the production of CO by cerebral microvessels. Experiments used freshly isolated cerebral microvessels from piglets that express only heme oxygenase-2 (HO-2). CO production was measured by gas chromatography-mass spectrometry. Although inhibition of nitric oxide synthase with L-nitro arginine (LNA) did not alter basal HO-2 catalytic activity or CO production, LNA blocked glutamate stimulation of HO-2 activity and CO production. Further, the NO donor sodium nitroprusside mimicked the actions of glutamate on HO-2 and CO production. The action of NO appears to be via cGMP because 8-br-cGMP mimics and ODQ blocks, glutamate stimulation of CO production and HO-2 catalytic activity. Inhibitors of neither casein kinase nor PI3 kinase altered HO-2 catalytic activity. Conversely, inhibition of calmodulin with calmidazolium chloride blocked glutamate stimulation of CO production and reduced HO-2 catalytic activity. These data suggest that glutamate may activate NOS producing NO that leads to CO synthesis via a cGMP dependent elevation of HO-2 catalytic activity. These results are consistent with the findings in vivo that either HO or NOS inhibition blocks cerebrovascular dilation to glutamate in piglets.
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