HS mediates the vasodilator effect of endothelin-1 in the cerebral circulation.

HS is an endogenous gasotransmitter that increases cerebral blood flow. In the cerebral vascular endothelium, HS is produced by cystathionine δ-lyase (CSE). Endothelin-1 (ET-1) has constrictor and dilator influences on the cerebral circulation. The mechanism of the vasodilation caused by ET-1 may involve endothelium-derived factors. We hypothesize that ET-1-elicited dilation of pial arterioles requires an elevation of HS production in the cerebral vascular endothelium. We investigated the effects of ET-1 on CSE-catalyzed brain HS production and pial arteriolar diameter using cranial windows in newborn pigs in vivo. HS was measured in periarachnoid cerebrospinal fluid. ET-1 (10-10 M) caused an elevation of HS that was reduced by the CSE inhibitors propargylglycine (PPG) and β-cyano-l-alanine (BCA). Low doses of ET-1 (10-10 M) produced vasodilation of pial arterioles that was blocked PPG and BCA, suggesting the importance of HS influences. The vasodilator effects of HS may require activation of smooth muscle cell membrane ATP-sensitive K (K) channels and large-conductance Ca-activated K (BK) channels. The K inhibitor glibenclamide and the BK inhibitor paxilline blocked CSE/HS-dependent dilation of pial arterioles to ET-1. In contrast, the vasoconstrictor response of pial arterioles to 10 M ET-1 was not modulated by PPG, BCA, glibenclamide, or paxilline and, therefore, was independent of CSE/HS influences. Pial arteriolar constriction response to higher levels of ET-1 was independent of CSE/HS and K/BK channel activation. These data suggest that HS is an endothelium-derived factor that mediates the vasodilator effects of ET-1 in the cerebral circulation via a mechanism that involves activation of K and BK channels in vascular smooth muscle. NEW & NOTEWORTHY Disorders of the cerebral circulation in newborn infants may lead to lifelong neurological disabilities. We report that vasoactive peptide endothelin-1 exhibits vasodilator properties in the neonatal cerebral circulation by stimulating production of HS, an endothelium-derived messenger with vasodilator properties. The ability of endothelin-1 to stimulate brain production of HS may counteract the reduction in cerebral blood flow and prevent the cerebral vascular dysfunction caused by stroke, asphyxia, cerebral hypoxia, ischemia, and vasospasm.