Differential sensitivity of atrial and ventricular KATP channels to metabolic inhibition

Objective: The aim is to compare the activation of ATP-sensitive potassium channels (KATP channels) in intact and metabolically impaired atrial and ventricular myocytes. Methods: The KATP channel current is measured by whole cell and gramicidin-perforated patch clamp recordings in 164 cultured neonate rat cardiomyocytes. Results: In whole cell recordings with 84 μmol/l ADP in pipette, spontaneous activity is significantly higher in atrium than ventricle, and EC50 for the KATP channel opener diazoxide is 0.13 μmol/l (atrium) versus 3.1 μmol/l (ventricle). With an ATP-regenerating system in pipette, EC50 for diazoxide is 19.7 μmol/l (atrium) versus 54.9 μmol/l (ventricle). In gramicidin-perforated patch recordings, atrial myocytes respond significantly to 100 nmol/l of the mitochondrial protonophore CCCP, while ventricular myocytes do not. EC50 for diazoxide is 129 μmol/l (atrium) versus <2500 μmol/l (ventricle) for myocytes exposed to CCCP, and 676 versus <2500 μmol/l, respectively, without CCCP. Conclusions: (1) KATP channels are significantly more sensitive to metabolic inhibition in atrial than ventricular myocytes. (2) Sensitivity of atrium versus ventricle to the channel opener diazoxide increases from 3:1 to ≥24:1 with ADP or metabolic inhibition. If extended to intact hearts, the results would predict a higher atrial sensitivity to ischemia, and a high sensitivity of the ischemic atrium to KATP channel opener