title: Modeling transmural heterogeneity of K(ATP) current in rabbit ventricular myocytes.
abstract: To investigate the mechanisms regulating excitation-metabolic coupling in rabbit epicardial, midmyocardial, and endocardial ventricular myocytes we extended the LabHEART model (Puglisi JL and Bers DM. Am J Physiol Cell Physiol 281: C2049-C2060, 2001). We incorporated equations for Ca(2+) and Mg(2+) buffering by ATP and ADP, equations for nucleotide regulation of ATP-sensitive K(+) channel and L-type Ca(2+) channel, Na(+)-K(+)-ATPase, and sarcolemmal and sarcoplasmic Ca(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 min of ischemia, the three regions were characterized by different I(Na), I(to), I(Kr), I(Ks), and I(Kp) channel properties. The results indicate that the ATP-sensitive K(+) channel is activated by the smallest reduction in ATP in epicardial cells and largest in endocardial cells when cytosolic ADP, AMP, PCr, Cr, P(i), total Mg(2+), Na(+), K(+), Ca(2+), and pH diastolic levels are normal. The model predicts that only K(ATP) ionophore (Kir6.2 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 K(ATP) channel opening through metabolic interactions with the endogenous PI cascade (PIP(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.
authors.affiliation: Dept of Bioengineering, PFBH 241, University of California San Diego, La Jolla, CA 92093-0412, USA. amihaylo@bioeng.ucsd.edu
authors.forename: Anushka
authors.initials: A
authors.lastname: Michailova
authors.forename: William
authors.initials: W
authors.lastname: Lorentz
authors.forename: Andrew
authors.initials: A
authors.lastname: McCulloch
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000200:Action Potentials; D000244:Adenosine Diphosphate / Q000378:metabolism; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D003198:Computer Simulation; D003401:Creatine / Q000378:metabolism; D004699:Endocardium / Q000378:metabolism; D006352:Heart Ventricles / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating; D008274:Magnesium / Q000378:metabolism; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000201:enzymology / Q000378:metabolism*; D010496:Pericardium / Q000378:metabolism; D010725:Phosphocreatine / Q000378:metabolism; D011188:Potassium / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011817:Rabbits; D011955:Receptors, Drug / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000244:Adenosine Diphosphate; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D002118:Calcium; D020746:Calcium Channels, L-Type; D003401:Creatine; D008274:Magnesium; D010725:Phosphocreatine; D011188:Potassium; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000254:Sodium-Potassium-Exchanging ATPase; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel