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Ischemia-reperfusion injury changes the dynamics of Ca²⁺-contraction coupling due to inotropic drugs in isolated hearts

Departments of ¹Anesthesiology and ²Physiology, and ³Cardiovascular Research Center, Medical College of Wisconsin; ⁴Department of Biomedical Engineering, Marquette University; and ⁵Veterans Affairs Medical Center, Milwaukee, Wisconsin

Submitted 9 March 2005 ; accepted in final form 8 November 2005

Positive inotropic drugs may attenuate or exacerbate the deleterious effects of ischemia and reperfusion (IR) injury on excitation-contraction coupling in hearts. We 1) quantified the phase-space relationship between simultaneously measured myoplasmic Ca²⁺ concentration ([Ca²⁺]) and isovolumetric left ventricular pressure (LVP) using indexes of loop area, orientation, and position; and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca²⁺] and rate of LVP development in intact hearts during administration of positive inotropic drugs before and after global IR injury. Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer solution (37°C, 1.25 mM CaCl₂). [Ca²⁺] was measured ratiometrically by indo 1 fluorescence by using a fiber-optic probe placed at the left ventricular free wall. LVP was measured by using a saline-filled latex balloon and transducer. Drugs were infused for 2 min, 30 min before, and for 2 min, 30 min after 30-min global ischemia. IR injury worsened Ca²⁺-contraction coupling, as seen from decreased orientation and repositioning of the loop rightward and downward and reduced cooperativity of contraction and relaxation with or without drugs. Dobutamine (4 µM) worsened, whereas dopamine (8 µM) improved Ca²⁺-contraction coupling before and after IR injury. Dobutamine and dopamine improved cooperativity of contraction and relaxation after IR injury, whereas only dopamine increased cooperativity of relaxation before IR injury. Digoxin (1 µM) improved Ca²⁺-contraction coupling and cooperativity of contraction after but not before ischemia. Levosimendan (1 µM) did not alter Ca²⁺-contraction coupling or cooperativity, despite producing concomitant increases in contractility, relaxation, and Ca²⁺ flux before and after ischemia. Dynamic indexes based on LVP-[Ca²⁺] diagrams (area, shape, position) can be used to identify and measure alterations in Ca²⁺-contraction coupling during administration of positive inotropic drugs in isolated hearts before and after IR injury.

phase-space diagrams; cooperativity; guinea pigs; linear model