Roles of cyclic AMP and Ca2+-activated K+ channels in endothelium-independent relaxation by urocortin in the rat coronary artery

Objective: Urocortin possesses cardioprotectivc 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 Ca2+-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 Ca2+-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 Ca2+-activated K+ channel blocker), glibenclamide (ATP-sensitive K+ channel blocker), or BaCl2 (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 4. Conclusion: Urocortin relaxed the rat coronary artery in substantial part via activation of the vascular Ca2+-activated K+ channels and this effect appears to be primarily Mediated through PKA-dependent intracellular mechanisms. (C) 2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.