R oles of cyclic AMP and Ca -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 21 1 examine the role of cyclic AMP and Ca -activated K channels in the relaxant response to urocortin in the isolated endotheliumdenuded 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-11a,9a-epoxy-methanoprostaglandin F (U46619)-contracted rings, 2a urocortin-induced relaxation (pD : 8.4060.04) was significantly reduced by cyclic AMP-dependent protein kinase (PKA) inhibitors, 2 21 1 Rp-cAMPS triethylamine (Rp-cAMPS) and KT 5720. Treatment with the large-conductance Ca -activated K channel blockers, 1 iberiotoxin or tetraethylammonium ions (TEA ) attenuated urocortin-induced relaxation; this effect was abolished in the presence of 200 21 1 1 nmol / l KT 5720. In contrast, apamin (small-conductance Ca -activated K channel blocker), glibenclamide (ATP-sensitive K channel 1 blocker), or BaCl (inwardly rectifier K channel blocker) had no effect. Urocortin-induced relaxation was reduced in rings contracted 2 1 1 with increasing concentrations of extracellular K (35 and 50 mmol / l). Treatment with TEA or Rp-cAMPS inhibited the relaxant effect 1 1 of urocortin in 35 mmol / l K -contracted rings. Combined treatment with TEA and Rp-cAMPS had no additional effect. Similarly, 1 forskolin produced significantly less relaxant response in 50 mmol / l K -contracted than U46619-contracted rings. Forskolin-induced 1 relaxation was attenuated by pretreatment with 3 mmol / l TEA . Conclusion: Urocortin relaxed the rat coronary artery in substantial part 21 1 via activation of the vascular Ca -activated K channels and this effect appears to be primarily mediated through PKA-dependent intracellular mechanisms.  2003 European Society of Cardiology. Published by Elsevier Science B.V. All rights reserved.