The pharmacology of three inwardly rectifying potassium channels in neonatal rat cardiac myocytes
The aim of the present study was to investigate the pharmacology of three inwardly rectifying K+-channels in neonatal rat cardiac myocytes, IKAch, IKI, IKAtp- using whole cell voltage clamp techniques. Cells were held at -50mV. A previous study has shown that clotrimazole, an antimycotic agent, and cetiedil, an antisickling agent are potent against the IKACch in atrial myocytes. Structural analogues of these compounds were tested on the three inward rectifiers. UCL1880, an analogue of clotrimazole was found to be potent on the G-protein gated channel, IKACh (with an IC50 of 0.18μM). Concentrations which caused an almost maximum block of this current were relatively ineffective on the IK1 and IKATP. UCL1495, an analogue of cetiedil, had an IC50 of 0.46μM against the Gprotein gated current. It was ineffective on the IK1 and the IKATP current. Both of the compounds exhibited use-dependence but not voltage dependence. Glibenclamide, a sulphonylurea, was tested on IKATP and IKACh as it has been suggested that the adenosine activation of IKACh includes the activation of IKATP. Glibenclamide was found to be far more effective on the IKATP The concentrations which were effective on IKAtp did not block the IKACh or the IK1. Barium was also tested on these three channels to see if there was any selectivity in its action. It had IC50 values of 34.9μM on IKACh, 16.8μM on IK1 and 164.5μM on IKATP. The block on IKAch was voltage dependent, increasing at negative potentials, with an IC 5o of 3.8μM at -120mV. UCL 1880 and UCL 1495 are selective for IKACh and may be used as pharmacological tools to compare and contrast other G-protein gated currents to the native atrial channel.