Time-dependent action of carbon monoxide on the newborn cerebrovascular circulation

Knecht KR, Milam S, Wilkinson DA, Fedinec AL, Leffler CW. Time-dependent action of carbon monoxide on the newborn cerebrovascular circulation. Am J Physiol Heart Circ Physiol 299: H70-H75, 2010. First published April 30, 2010; doi:10.1152/ajpheart.00258.2010.-Carbon monoxide (CO) causes cerebral arteriolar dilation in newborn pigs by the activation of large-conductance Ca2+-activated K+ channels. In adult rat cerebral and skeletal muscle arterioles, CO has been reported to produce constriction caused by the inhibition of nitric oxide (NO) synthase (NOS). We hypothesized that, in contrast to dilation to acute CO, more prolonged exposure of newborn cerebral arterioles to elevated CO produces constriction by reducing NO. In piglets with closed cranial windows, pial arteriolar responses to isoproterenol (10(-6) M), sodium nitroprusside (SNP; 10(-7) and 3 x 10(-7) M), and L-arginine ethyl ester (L-Arg; 10(-5) and 10(-4) M) were determined before and after 2 h of treatment with CO. CO (10(-7) M) caused transient dilation and had no further effects. CO (2 x 10(-7) and 10(-6) M) initially caused vasodilation, but over the 2-h exposure, pial arterioles constricted and removal of the CO caused dilation. Exposure to elevated CO (2 h) did not alter dilation to SNP or isoproterenol. Conversely, the NOS substrate L-Arg caused dilation before CO that was progressively lost over 90 min of elevated CO. If NO was held constant, CO caused dilation that was sustained for 2 h. We conclude that in neonates, cerebral arteriole responses to CO are biphasic: dilation to acute elevation with subsequent constriction from NOS inhibition after more prolonged exposure. As a result, short episodic production of CO allows function as a dilator gasotransmitter, whereas prolonged elevation can reduce NO to elevate cerebrovascular tone. The interaction between heme oxygenase/CO and NOS/NO could form a negative feedback system in the control of cerebral vascular tone.