Large-conductance
calcium-activated
potassium (K(Ca)) channels regulate the physiological functions of many tissues, including cerebrovascular smooth muscle.
l-Glutamic acid (
glutamate) is the principal excitatory
neurotransmitter in the central nervous system, and
oxygen tension is a dominant local regulator of vascular tone. In vivo,
glutamate and
hypoxia dilate newborn pig cerebral arterioles, and both dilations are blocked by inhibition of
carbon monoxide (CO) production. CO dilates cerebral arterioles by activating K(Ca) channels. Therefore, the present study was designed to investigate the effects of
glutamate and
hypoxia on cerebral CO production and the role of K(Ca) channels in the cerebral arteriolar dilations to
glutamate and
hypoxia. In the presence of
iberiotoxin or
paxilline that block dilation to the K(Ca) channel opener,
NS-1619, neither CO nor
glutamate dilated pial arterioles. Conversely, neither
paxilline nor
iberiotoxin inhibited dilation to acute severe or moderate prolonged
hypoxia. Both
glutamate and
hypoxia increased cerebrospinal fluid (CSF) CO concentration.
Iberiotoxin that blocked dilation to
glutamate did not attenuate the increase in CSF CO. The
guanylyl cyclase inhibitor,
1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ), which blocked dilation to
sodium nitroprusside, did not inhibit dilation to
hypoxia. These data suggest that dilation of newborn pig pial arterioles to
glutamate is mediated by activation of K(Ca) channels, consistent with the intermediary signal being CO. Surprisingly, although 1)
heme oxygenase (HO) inhibition attenuates dilation to
hypoxia, 2)
hypoxia increases CSF CO concentration, and 3) K(Ca) channel antagonists block dilation to CO, neither K(Ca) channel blockers nor ODQ altered dilation to
hypoxia, suggesting the contribution of the HO/CO system to
hypoxia-induced dilation is not by stimulating vascular smooth muscle K(Ca) channels or
guanylyl cyclase.