Roles of cyclic AMP and Ca2+-activated K+ channels in endothelium-independent relaxation by urocortin in the rat coronary artery.
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.
Huang
Yu
Y
Department of Physiology, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China. yu-huang@cuhk.edu.hk
Chan
Franky Leung
FL
Lau
Chi-Wai
CW
Tsang
Suk-Ying
SY
Chen
Zhen-Yu
ZY
He
Guo-Wei
GW
Yao
Xiaoqiang
X
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*
D024681:Potassium Channels, Calcium-Activated; D054832:Urocortins; D014665:Vasodilator Agents; D003346:Corticotropin-Releasing Hormone; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases