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

Shalinkumar Patel, Alexander L. Fedinec, Jiangxiong Liu, Max A. Weiss, Massroor Pourcyrous, Mimily Harsono, Elena Parfenova, Charles Leffler

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Abstract

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+ (KATP) channels and large-conductance Ca2+-activated K+ (BK) channels. The KATP 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 KATP/BKCa 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 KATP and BK channels in vascular smooth muscle. NEW & NOTEWORTHY Disorders of the cerebral circulation innewborn infants may lead to lifelong neurological disabilities. Wereport that vasoactive peptide endothelin-1 exhibits vasodilator propertiesin 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 maycounteract the reduction in cerebral blood flow and prevent thecerebral vascular dysfunction caused by stroke, asphyxia, cerebralhypoxia, ischemia, and vasospasm.

Original languageEnglish (US)
Pages (from-to)H1759-H1764
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume315
Issue number6
DOIs
StatePublished - Dec 1 2018

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Cerebrovascular Circulation
Endothelin-1
Vasodilator Agents
Cystathionine
Lyases
Arterioles
KATP Channels
Large-Conductance Calcium-Activated Potassium Channels
Endothelium
Glyburide
Vascular Endothelium
Vasodilation
Dilatation
Gasotransmitters
Calcium-Activated Potassium Channels
Asphyxia
Brain
Vasoconstrictor Agents

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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H2S mediates the vasodilator effect of endothelin-1 in the cerebral circulation. / Patel, Shalinkumar; Fedinec, Alexander L.; Liu, Jiangxiong; Weiss, Max A.; Pourcyrous, Massroor; Harsono, Mimily; Parfenova, Elena; Leffler, Charles.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 315, No. 6, 01.12.2018, p. H1759-H1764.

Research output: Contribution to journalArticle

Patel, Shalinkumar ; Fedinec, Alexander L. ; Liu, Jiangxiong ; Weiss, Max A. ; Pourcyrous, Massroor ; Harsono, Mimily ; Parfenova, Elena ; Leffler, Charles. / H2S mediates the vasodilator effect of endothelin-1 in the cerebral circulation. In: American Journal of Physiology - Heart and Circulatory Physiology. 2018 ; Vol. 315, No. 6. pp. H1759-H1764.
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AU - Patel, Shalinkumar

AU - Fedinec, Alexander L.

AU - Liu, Jiangxiong

AU - Weiss, Max A.

AU - Pourcyrous, Massroor

AU - Harsono, Mimily

AU - Parfenova, Elena

AU - Leffler, Charles

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N2 - 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+ (KATP) channels and large-conductance Ca2+-activated K+ (BK) channels. The KATP 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 KATP/BKCa 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 KATP and BK channels in vascular smooth muscle. NEW & NOTEWORTHY Disorders of the cerebral circulation innewborn infants may lead to lifelong neurological disabilities. Wereport that vasoactive peptide endothelin-1 exhibits vasodilator propertiesin 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 maycounteract the reduction in cerebral blood flow and prevent thecerebral vascular dysfunction caused by stroke, asphyxia, cerebralhypoxia, ischemia, and vasospasm.

AB - 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+ (KATP) channels and large-conductance Ca2+-activated K+ (BK) channels. The KATP 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 KATP/BKCa 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 KATP and BK channels in vascular smooth muscle. NEW & NOTEWORTHY Disorders of the cerebral circulation innewborn infants may lead to lifelong neurological disabilities. Wereport that vasoactive peptide endothelin-1 exhibits vasodilator propertiesin 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 maycounteract the reduction in cerebral blood flow and prevent thecerebral vascular dysfunction caused by stroke, asphyxia, cerebralhypoxia, ischemia, and vasospasm.

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