The Effects Of Urocortin On Cardiac Sarcolemmal ATP-sensitive K～+ Channels And L-type Ca～(2+) Channels

Urocortin (UCN) is a newly found cardioprotective peptide. It belongs to CRP family and binds with CRFR2 which is expressed in the cardiovascular system. UCN has a number of cardiac pathophysiological properties, such as causing a gradual decrease in the average blood pressure and an increase in heart rate, cardiac output and coronary blood flow in a dose-dependent way. And UCN can also protect neonatal rat cardiac myocytes in vitro when administered before hypoxia or at the point of reoxygenation and protect the adult rat heart ex vivo where UCN reduces the infarct size of a perfused intact rat heart exposed to regional ischemia. At present there are more and more reports about the mechanisms of cardioprotection of UCN. Many references show that MAPK signaling pathway exerts a major role in the cardioprotection of UCN against ischemia or hypoxia. Other mechanisms include the increased expression of HSP90 induced by UCN, the activation of PKB/Akt signaling pathway and the protection of mitochondria.In recent years the relationship between UCN and ion channels has become a key point in the experimental research. There is evidence showing that UCN can activate Ca²⁺-sensitive K⁺ channels in guinea-pig gastric antrum smooth muscle cells and rat coronary artery and it can also relax rat pulmonary arteries via stimulation of Ba²⁺-sensitive K⁺ channels. It has been reported that sarcKATP and L-type Ca²⁺ channels play an important role in the developmentand prognosis of I/R. However, effects of UCN on the cardiac sarcKATP channels and L-type Ca²⁺ channels are still unknown. In this study, we investigated the effects of UCN on single adult rat cardiac myocytes by using whole-cell patch clamp technique. sarcKATP channels are dominantly closed on the normal adult rat cardiac myocytes where we could hardly record any sarcKATP currents. Pinacidil, the KATP channel specific opener, caused a large number of sarcKATP channels open so that obvious outward potassium currents were recorded. The currents were totally abolished by glibenclamide, the KATP specific blocker. UCN administration resulted in a similar outward potassium current with a weaker potency. The effects of UCN are concentration-dependent. Furthermore, we found that UCN could increase sarcKATP currents activated by hypoxia in a concentration-dependent manner and CRFR2 inhibitor could abolish this UCN's effect. In addition, we discovered that the mechanisms might involve mitoKATP modulation and the activation of adenosine, PKA and PKC signaling way. Finally, we also investigated the effects of UCN on L-type Ca²⁺ channels and found that UCN could reduce L-type Ca²⁺ currents in a concentration-dependent way.In a word, this is the first study on the electrophysiological effects of UCN on cardiac myocytes. UCN could open sarcKATP channels and inhibit L-type Ca²⁺ channels on the cardiac myocytes. These results indicate that UCN might have some characteristics of traditional KATP channel openers and L-type Ca²⁺ channel blockers and supply a strong evidence for the potential clinical therapeutic role of UCN.