title: Roles of cyclic AMP and Ca2+-activated K+ channels in endothelium-independent relaxation by urocortin in the rat coronary artery.
abstract: OBJECTIVE
  Urocortin possesses cardioprotective properties against the damaging effects of ischemia/reperfusion injury. Our previous study demonstrated that urocortin can induce both endothelium-dependent and -independent coronary relaxation. However, the mechanisms thereby urocortin triggers endothelium-independent relaxation have not been investigated. The present study aimed to examine the role of cyclic AMP and Ca(2+)-activated K(+) channels in the relaxant response to urocortin in the isolated endothelium-denuded rat left anterior descending coronary arteries.
  
  
  METHODS
  Changes in vessel tension were measured by using a force transducer built in a Multi Myograph System.
  
  
  RESULTS
  In 9,11-dideoxy-11alpha,9alpha-epoxy-methanoprostaglandin F(2alpha) (U46619)-contracted rings, urocortin-induced relaxation (pD(2): 8.40+/-0.04) was significantly reduced by cyclic AMP-dependent protein kinase (PKA) inhibitors, Rp-cAMPS triethylamine (Rp-cAMPS) and KT 5720. Treatment with the large-conductance Ca(2+)-activated K(+) channel blockers, iberiotoxin or tetraethylammonium ions (TEA(+)) attenuated urocortin-induced relaxation; this effect was abolished in the presence of 200 nmol/l KT 5720. In contrast, apamin (small-conductance Ca(2+)-activated K(+) channel blocker), glibenclamide (ATP-sensitive K(+) channel blocker), or BaCl(2) (inwardly rectifier K(+) channel blocker) had no effect. Urocortin-induced relaxation was reduced in rings contracted with increasing concentrations of extracellular K(+) (35 and 50 mmol/l). Treatment with TEA(+) or Rp-cAMPS inhibited the relaxant effect of urocortin in 35 mmol/l K(+)-contracted rings. Combined treatment with TEA(+) and Rp-cAMPS had no additional effect. Similarly, forskolin produced significantly less relaxant response in 50 mmol/l K(+)-contracted than U46619-contracted rings. Forskolin-induced relaxation was attenuated by pretreatment with 3 mmol/l TEA(+).
  
  
  CONCLUSIONS
  Urocortin relaxed the rat coronary artery in substantial part via activation of the vascular Ca(2+)-activated K(+) channels and this effect appears to be primarily mediated through PKA-dependent intracellular mechanisms.
authors.affiliation: Department of Physiology, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. yu-huang@cuhk.edu.hk
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Franky Leung
authors.initials: FL
authors.lastname: Chan
authors.forename: Chi-Wai
authors.initials: CW
authors.lastname: Lau
authors.forename: Suk-Ying
authors.initials: SY
authors.lastname: Tsang
authors.forename: Zhen-Yu
authors.initials: ZY
authors.lastname: Chen
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: He
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Yao
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D003346:Corticotropin-Releasing Hormone / Q000494:pharmacology*; D000242:Cyclic AMP / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D054832:Urocortins; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D024681:Potassium Channels, Calcium-Activated; D054832:Urocortins; D014665:Vasodilator Agents; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases