MODELING THE MECHANISM OF METABOLIC OSCILLATIONS IN ISCHEMIC CARDIAC MYOCYTES.

Malgorzata Kotulska (1), and Saleet Jafri (2)

(1) Faculty of Basic Problems of Technology, Wroclaw University of Technology, Wroclaw, Poland.

(2) School of Computational Sciences, George Mason University, Manassas, VA, USA.

During a heart attack the heart is deprived of energy substrate and oxygen due to blockage of the coronary circulation. Substrate-deprived ventricular myocytes exhibit oscillatory activation of sarcolemmal ATP-sensitive potassium current (Ik,ATP) which can give rise to cardiac arrhythmias. Correlation between oscillations of the sarcolemmal Ik,ATP, NADH,and inner mitochondrial membrane (IMM) potential suggests that the phenomenon may originate in the mitochondrial metabolism. Experiments with IMM ion channels show that the periodic behavior can be suppressed by blocking the family of inner membrane anion channels (IMAC).

We have developed a computational model that suggests a possible mechanism of the oscillatory behavior. The model is based on a system of ordinary differential equations that involves regulation of the low-conductance IMAC by Mg2+ and pH. Other important features of the model include the phosphate carrier, the F1F0-ATPase, the electron transport chain, and the interaction of Mg2+ and inorganic phosphate in the mitochondrial matrix. The model produces mitochondrial matrix pH oscillations, which accompany IMM potential and Pi oscillations and were observed on experiments carried out on isolated mitochondria. This provides additional evidence that the observed limit cycle behavior probably originates in mitochondria and differs from well-known glycolytic oscillations.