H₂S mediates the vasodilator effect of endothelin-1 in the cerebral circulation

H₂S is an endogenous gasotransmitter that increases cerebral blood flow. In the cerebral vascular endothelium, H₂S 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 H₂S production in the cerebral vascular endothelium. We investigated the effects of ET-1 on CSE-catalyzed brain H₂S production and pial arteriolar diameter using cranial windows in newborn pigs in vivo. H₂S was measured in periarachnoid cerebrospinal fluid. ET-1 (10^-12-10^-8 M) caused an elevation of H₂S that was reduced by the CSE inhibitors propargylglycine (PPG) and β-cyano-l-alanine (BCA). Low doses of ET-1 (10^-12-10^-11 M) produced vasodilation of pial arterioles that was blocked PPG and BCA, suggesting the importance of H₂S influences. The vasodilator effects of H₂S may require activation of smooth muscle cell membrane ATP-sensitive K⁺ (K_ATP) channels and large-conductance Ca²⁺-activated K⁺ (BK) channels. The K_ATP inhibitor glibenclamide and the BK inhibitor paxilline blocked CSE/H₂S-dependent dilation of pial arterioles to ET-1. In contrast, the vasoconstrictor response of pial arterioles to 10^-8 M ET-1 was not modulated by PPG, BCA, glibenclamide, or paxilline and, therefore, was independent of CSE/H₂S influences. Pial arteriolar constriction response to higher levels of ET-1 was independent of CSE/H₂S and K_ATP/BK_Ca channel activation. These data suggest that H₂S 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_ATP 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 H₂S, an endothelium-derived messenger with vasodilator properties. The ability of endothelin-1 to stimulate brain production of H₂S may counteract the reduction in cerebral blood flow and prevent the cerebral vascular dysfunction caused by stroke, asphyxia, cerebral hypoxia, ischemia, and vasospasm.