No abstract

Carbon monoxide (CO) causes cerebral arteriolar dilation in newborn pigs by the activation of large-conductance Ca 2ϩ -activated K ϩ 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 Ϫ6 M), sodium nitroprusside (SNP; 10 Ϫ7 and 3 ϫ 10 Ϫ7 M), and L-arginine ethyl ester (L-Arg; 10 Ϫ5 and 10 Ϫ4 M) were determined before and after 2 h of treatment with CO. CO (10 Ϫ7 M) caused transient dilation and had no further effects. CO (2 ϫ 10 Ϫ7 and 10 Ϫ6 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. nitric oxide; neonate CARBON MONOXIDE (CO) is produced, along with biliverdin and iron, via the catabolism of heme by heme oxygenase (HO) (17). The constitutive isoform, HO-2, is highly expressed in astrocytes and the endothelium in the neonatal brain (15,16,20). CO functions as a gasotransmitter, causing dose-dependent vasodilation of cerebral arterioles in newborn pigs and adult rats (6, 16). Acute CO dilates cerebral arterioles through the activation of Ca 2ϩ -activated K ϩ (K Ca ) channels (26). The effect of CO could be age-, species-, and/or exposure time-dependent because in the adult rat skeletal muscle vasculature, prolonged exposure to CO causes vasoconstriction by the inhibition of nitric oxide (NO) synthase (NOS) (9). In adult rats, CO derived from HO-2 appears to tonically regulate cerebral vasodilation by decreasing NO production (8).The actions of CO and NO on the cerebral vasculature appear to be interrelated. NOS, isolated from the rat cerebellum, can be inhibited by CO (24), and CO has been shown to suppress NOS in rat renal arteries (21). In the newborn piglet cerebral circulation, CO causes dilation that can be blocked by treatment with inhibitors of NOS (1, 14). While it is clear the NOS/NO and HO/CO systems can interact, this interaction remains incompletely understood in either the adult or the neonatal cerebral circulat...