Modeling transmural heterogeneity of [K.sub.ATP] current in rabbit ventricular myocytes

To investigate the mechanisms regulating excitation-metabolic coupling in rabbit epicardial, midmyocardial, and endocardial ventricular myocytes we extended the LabHEART model (Puglisi JL and Bets DM. Am J Physiol Cell Physiol 281: C2049-C2060, 2001). We incorporated equations for [Ca.sup.2+] and [Mg.sup.2+] buffering by ATP and ADP, equations for nucleotide regulation of ATP-sensitive [K.sup.+] channel and L-type [Ca.sup.2+] channel, [Na.sup.+]-[K.sup.+]-ATPase, and sarcolemmal and sarcoplasmic [Ca.sup.2+]-ATPases, and equations describing the basic pathways (creatine and adenylate kinase reactions) known to communicate the flux changes generated by intracellular ATPases. Under normal conditions and during 20 rain of ischemia, the three regions were characterized by different [I.sub.Na],[I.sub.to], [I.sub.Kr][I.sub.Ks] and [I.sub.Kp] channel properties. The results indicate that the ATP-sensitive [K.sup.+] channel is activated by the smallest reduction in ATP in epicardial cells and largest in endocardial cells when cytosolic ADP, AMP, PCr, Cr, [P.sub.i], total [Mg.sup.2+], [Na.sup.+], [K.sup.+], [Ca.sup.2+], and pH diastolic levels are normal. The model predicts that only [K.sub.ATP] ionophore (Kit6.2 subunit) and not the regulatory subunit (SUR2A) might differ from endocardium to epicardium. The analysis suggests that during ischemia, the inhomogeneous accumulation of the metabolites in the tissue sublayers may alter in a very irregular manner the KATP channel opening through metabolic interactions with the endogenous PI cascade (PI[P.sub.2], PIP) that in turn may cause differential action potential shortening among the ventricular myocyte subtypes. The model predictions are in qualitative agreement with experimental data measured under normal and ischemic conditions in rabbit ventricular myocytes. ATP-sensitive [K.sup.+] channel; creatine and adenylate kinase reactions; phosphatidylinositol phosphates; heart; mathematical model