Heterogeneity and function of K(ATP) channels in canine hearts

Abstract

Background: The concept that pore-forming Kir6.2 and regulatory SUR2A subunits form cardiac ATP-sensitive potassium (K(ATP)) channels is challenged by recent reports that SUR1 is predominant in mouse atrial K(ATP) channels.

Objective: To assess SUR subunit composition of K(ATP) channels and consequence of K(ATP) activation for action potential duration (APD) in dog hearts.

Methods: Patch-clamp techniques were used on isolated dog cardiomyocytes to investigate K(ATP) channel properties. Dynamic current clamp, by injection of a linear K(+) conductance to simulate activation of the native current, was used to study the consequences of K(ATP) activation on APD.

Results: Metabolic inhibitor (MI)-activated current was not significantly different from pinacidil (SUR2A-specific)-activated current, and both currents were larger than diazoxide (SUR1-specific)-activated current in both the atrium and the ventricle. Mean K(ATP) conductance (activated by MI) did not differ significantly between chambers, although, within the ventricle, both MI-induced and pinacidil-induced currents tended to decrease from the epicardium to the endocardium. Dynamic current-clamp results indicate that myocytes with longer baseline APDs are more susceptible to injected K(ATP) current, a result reproduced in silico by using a canine action potential model (Hund-Rudy) to simulate epicardial and endocardial myocytes.

Conclusions: Even a small fraction of K(ATP) activation significantly shortens APD in a manner that depends on existing heterogeneity in K(ATP) current and APD.

Keywords: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; ANOVA; AP; APD; ATP-sensitive potassium; ATP-sensitive potassium channel; Action potential duration; CL; Canine; Diazoxide; EGTA; Endo; Epi; HEPES; I(Kr); I(Ks); I(to); K(ATP); K(ATP-INJ); MI; Metabolic inhibition; Mid; Model simulation; Myocyte; Patch-clamp technique; Pinacidil; Sulfonylurea receptor; action potential; action potential duration; analysis of variance; cycle length; endocardial/endocardium; epicardial/epicardium; ethylene glycol-bis(2-aminoethylether)-N,N,N′,N′-tetraacetic acid; metabolic inhibitor; mid-myocardial/mid-myocardium; rapid delayed rectifier current; simulated ATP-sensitive potassium current; slow delayed rectifier current; transient outward current.