title: Differential effects of cystathionine-γ-lyase-dependent vasodilatory H2S in periadventitial vasoregulation of rat and mouse aortas.
abstract: BACKGROUND
  Hydrogen sulfide (H(2)S) is a potent vasodilator. However, the complex mechanisms of vasoregulation by H(2)S are not fully understood. We tested the hypotheses that (1) H(2)S exerts vasodilatory effects by opening KCNQ-type voltage-dependent (K(v)) K(+) channels and (2) that H(2)S-producing cystathionine-γ-lyase (CSE) in perivascular adipose tissue plays a major role in this pathway.
  
  
  RESULTS
  Wire myography of rat and mouse aortas was used. NaHS and 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (ADTOH) were used as H(2)S donors. KCNQ-type K(v) channels were blocked by XE991. 4-Propargylglycine (PPG) and ß-cyano-l-alanine (BCA), or 2-(aminooxy)-acetic acid (AOAA) were used as inhibitors of CSE or cystathionine-ß-synthase (CBS), respectively. NaHS and ADTOH produced strong vasorelaxation in rat and mouse aortas, which were abolished by KCNQ channel inhibition with XE991. Perivascular adipose tissue (PVAT) exerted an anticontractile effect in these arteries. CSE inhibition by PPG and BCA reduced this effect in aortas from rats but not from mice. CBS inhibition with AOAA did not inhibit the anticontractile effects of PVAT. XE991, however, almost completely suppressed the anticontractile effects of PVAT in both species. Exogenous l-cysteine, substrate for the endogenous production of H(2)S, induced vasorelaxation only at concentrations >5 mmol/l, an effect unchanged by CSE inhibition.
  
  
  CONCLUSIONS
  Our results demonstrate potent vasorelaxant effects of H(2)S donors in large arteries of both rats and mice, in which XE991-sensitive KCNQ-type channel opening play a pivotal role. CSE-H(2)S seems to modulate the effect of adipocyte-derived relaxing factor in rat but not in mouse aorta. The present study provides novel insight into the interaction of CSE-H(2)S and perivascular adipose tissue. Furthermore, with additional technical advances, a future clinical approach targeting vascular H(2)S/KCNQ pathways to influence states of vascular dysfunction may be possible.
authors.affiliation: Medical Clinic for Nephrology and Internal Intensive Care, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Carolin
authors.initials: C
authors.lastname: Köhn
authors.forename: Johanna
authors.initials: J
authors.lastname: Schleifenbaum
authors.forename: István András
authors.initials: IA
authors.lastname: Szijártó
authors.forename: Lajos
authors.initials: L
authors.lastname: Markó
authors.forename: Galyna
authors.initials: G
authors.lastname: Dubrovska
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Maik
authors.initials: M
authors.lastname: Gollasch
mesh_terms: D000393:Air Pollutants / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000201:enzymology*; D003542:Cystathionine gamma-Lyase / Q000378:metabolism*; D003545:Cysteine / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D015640:Ion Channel Gating / Q000187:drug effects; D051656:KCNQ Potassium Channels / Q000378:metabolism; D008297:Male; D051379:Mice; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000393:Air Pollutants; D051656:KCNQ Potassium Channels; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; D003542:Cystathionine gamma-Lyase; D003545:Cysteine; D006862:Hydrogen Sulfide