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Modeling the fast and slow calcium membrane channels of cardiac myocytes from voltage-clamp data
J Mol Cell Cardiol23
p-5-29
(Supplement
III) (1991)
ATP-REGULATED K+ CHANNELS PROTECT THE MYOCARDlUM REPERFlJSK3N’DAWkGE
AGAINST ISCHEMIA-
William C. Cole, Caroline D. McPherson, David P. Sontag. Department of Physiology, Division of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, MB, Canada RZH 2A6 The role of ATP-regulated K’ channels in protecting the myocardlum against ischemia - reperfusion damage was studied using glybenclamide and pinacidil to block and activate the channds, respectfvely. Electrical and mechanical activity of arterially perfused guinea-pig right ventricular walls were recorded simultaneously via intracellular microelectrodes and a force transducer. Preparations were subjected to; 1) 20 min ischemia * glybenclamide (1 & 10 NM) or (2) 30 min ischemia * pinacidil (1 & IO pM), followed by 60 min R. 20 min ischemia produced fully reversible changes in electrical and mechanical activity. Glybenclamide had no effect on activity during perfusion, but action potential duration declined only slightly and resting tension rose significantly during 20 min ischem’a and reflow led to arrhythmias and failed to restore contractile function. 30 min no-flow ischemia caused contract&e, and led to severe arrhythmias and poor recovery upon refiow in untreated preparations. Pinacidil had no (1 PM) or slight negative inotropic (10 PM) effect during perfusion, caused a faster and greater decline in APD and prevented contracture during ischemia, and complete recovery of contractile activity during reflow (10 pM; 35% at IpM). Thus glybenclamide enhances whereas pinackfil reduces myocardial damage due to ischemia-repetfusion. The results indicate that activation of ATP-regulated K’ channels and the resultant decline in action potential duration during ischemia are critical in protecting the myocardium when blood flow to the tissue is compromised. Supported by Manitoba Heart Foundation. Pinacidil was a gift of Eli Lilly Co.
p-5-30
MODELING THE FAST AND SLOW CALCIUM MEMBR&NE CHANNELS OF CARDIAC MYOCYTES FROM VOLTAGE-CLAMP DATA Jacques Beaumont, Josh Leon, Fernand A. Roberge. Institute of Biomedical Engineering, University of Montreal, Montreal, Can., H3C 351 We assume that the fast and slow calcium membrane channels of the cardiac myocyte can be represented by nonlinear conductances governed by the voltage-dependent activation (d) and inactivation (f) variables of the Hodgkin-Huxley formalism. A parameter extraction method based on optimization techniques was developed to calculate steady-state activation and inactivation characteristics and related time constants from voltage-clamp data, using only the timing and amplitude of the peak of the current waveforms. Deviations from the classical formalism are incorporated into the model as needed in the form of parameter modulation, such as voltage-shift of the The approach was characteristics. applied to various published experimental data sets: rabbit sinus node myocytes, guinea-pig ventricular myocytes, caning atria1 and Purkinje myocytes, bovine ventricular myocytes. It was found that all the data sets were incomplete with respect to the requirements of the Hodgkin-Huxley formalism, and the analysis provides clear indications regarding the additional experimental measurements needed to have more complete data sets. From this limited information we obtained a d2f representation for the slow channel and a df representation for the fast channel which, when adjustments were made for the number of channels, fit all of the data sets of all preparations.
p-5-31
A MECHANISTIC ACTION POTENTIAL MODEL OF THE GUINEA-PIG CARDIAC MYOCYTE D. Renald Lemieux, Jacques Beaumont, Fernand A. Roberge. Institute of Biomedical Engineering, Universit6 de Mont&al, MontrBal, Canada, H3C 357. For the purpose of studying drug action (e.g. the effect of catecholamines) on the electrical activity of the heart, we built a mechanistic model of the action potential of the guinea-pig ventricular myocyte. A definition of a mechanistic model would be a reasonable description of the interaction between ions and membrane We describe the movements of Na+, K* and Caf+ ions through a membrane proteins. surrounding a cylindrical cell of 13.3 m in diameter and 100 w in length, bathing in an electrolytic solution of fixed ionic concentration. The membrane currents represented mechanistically are: the K+ currents 1~1 and IK, the Na,K pump, and the by a Michaelis-Menten The sarcolenrmal Ca++- pump is represented Na-Ca exchange. Ica are formulation with a K0.5 of 1 p. The fast Ifla, and the slow and fast represented by an Hodgkin-Huxley formulation. The background Nat and Ca++ currents are governed by a fixed conductance. A three compartment model represents the movement of Ca++ ions between SR and cytoplasm. The SR contains two compartments: the terminal cisternae (0.33% of cell volume) for Cat+ release and the SR network (1.67% The resulting action potential is characterized by a of cell volume) for ca++ uptake. = 46 mV, (dV/dt),,, = 480 V/s, Vrest = -83 mV and APD90 = 225 ms. During the “max course of the action potential, [Caff]i varies between 0.1 and 1 w.
5.100
p-5-29
(Supplement
III) (1991)
ATP-REGULATED K+ CHANNELS PROTECT THE MYOCARDlUM REPERFlJSK3N’DAWkGE
AGAINST ISCHEMIA-
William C. Cole, Caroline D. McPherson, David P. Sontag. Department of Physiology, Division of Cardiovascular Sciences, St. Boniface Research Centre, University of Manitoba, Winnipeg, MB, Canada RZH 2A6 The role of ATP-regulated K’ channels in protecting the myocardlum against ischemia - reperfusion damage was studied using glybenclamide and pinacidil to block and activate the channds, respectfvely. Electrical and mechanical activity of arterially perfused guinea-pig right ventricular walls were recorded simultaneously via intracellular microelectrodes and a force transducer. Preparations were subjected to; 1) 20 min ischemia * glybenclamide (1 & 10 NM) or (2) 30 min ischemia * pinacidil (1 & IO pM), followed by 60 min R. 20 min ischemia produced fully reversible changes in electrical and mechanical activity. Glybenclamide had no effect on activity during perfusion, but action potential duration declined only slightly and resting tension rose significantly during 20 min ischem’a and reflow led to arrhythmias and failed to restore contractile function. 30 min no-flow ischemia caused contract&e, and led to severe arrhythmias and poor recovery upon refiow in untreated preparations. Pinacidil had no (1 PM) or slight negative inotropic (10 PM) effect during perfusion, caused a faster and greater decline in APD and prevented contracture during ischemia, and complete recovery of contractile activity during reflow (10 pM; 35% at IpM). Thus glybenclamide enhances whereas pinackfil reduces myocardial damage due to ischemia-repetfusion. The results indicate that activation of ATP-regulated K’ channels and the resultant decline in action potential duration during ischemia are critical in protecting the myocardium when blood flow to the tissue is compromised. Supported by Manitoba Heart Foundation. Pinacidil was a gift of Eli Lilly Co.
p-5-30
MODELING THE FAST AND SLOW CALCIUM MEMBR&NE CHANNELS OF CARDIAC MYOCYTES FROM VOLTAGE-CLAMP DATA Jacques Beaumont, Josh Leon, Fernand A. Roberge. Institute of Biomedical Engineering, University of Montreal, Montreal, Can., H3C 351 We assume that the fast and slow calcium membrane channels of the cardiac myocyte can be represented by nonlinear conductances governed by the voltage-dependent activation (d) and inactivation (f) variables of the Hodgkin-Huxley formalism. A parameter extraction method based on optimization techniques was developed to calculate steady-state activation and inactivation characteristics and related time constants from voltage-clamp data, using only the timing and amplitude of the peak of the current waveforms. Deviations from the classical formalism are incorporated into the model as needed in the form of parameter modulation, such as voltage-shift of the The approach was characteristics. applied to various published experimental data sets: rabbit sinus node myocytes, guinea-pig ventricular myocytes, caning atria1 and Purkinje myocytes, bovine ventricular myocytes. It was found that all the data sets were incomplete with respect to the requirements of the Hodgkin-Huxley formalism, and the analysis provides clear indications regarding the additional experimental measurements needed to have more complete data sets. From this limited information we obtained a d2f representation for the slow channel and a df representation for the fast channel which, when adjustments were made for the number of channels, fit all of the data sets of all preparations.
p-5-31
A MECHANISTIC ACTION POTENTIAL MODEL OF THE GUINEA-PIG CARDIAC MYOCYTE D. Renald Lemieux, Jacques Beaumont, Fernand A. Roberge. Institute of Biomedical Engineering, Universit6 de Mont&al, MontrBal, Canada, H3C 357. For the purpose of studying drug action (e.g. the effect of catecholamines) on the electrical activity of the heart, we built a mechanistic model of the action potential of the guinea-pig ventricular myocyte. A definition of a mechanistic model would be a reasonable description of the interaction between ions and membrane We describe the movements of Na+, K* and Caf+ ions through a membrane proteins. surrounding a cylindrical cell of 13.3 m in diameter and 100 w in length, bathing in an electrolytic solution of fixed ionic concentration. The membrane currents represented mechanistically are: the K+ currents 1~1 and IK, the Na,K pump, and the by a Michaelis-Menten The sarcolenrmal Ca++- pump is represented Na-Ca exchange. Ica are formulation with a K0.5 of 1 p. The fast Ifla, and the slow and fast represented by an Hodgkin-Huxley formulation. The background Nat and Ca++ currents are governed by a fixed conductance. A three compartment model represents the movement of Ca++ ions between SR and cytoplasm. The SR contains two compartments: the terminal cisternae (0.33% of cell volume) for Cat+ release and the SR network (1.67% The resulting action potential is characterized by a of cell volume) for ca++ uptake. = 46 mV, (dV/dt),,, = 480 V/s, Vrest = -83 mV and APD90 = 225 ms. During the “max course of the action potential, [Caff]i varies between 0.1 and 1 w.
5.100