Submitted on March 9, 2005
Accepted on November 8, 2005
Ischemia reperfusion injury changes the dynamics of Ca2+-contraction coupling due to inotropic drugs in isolated hearts
Samhita S. Rhodes1*, Kristina M. Ropella2, Amadou K.S. Camara1, Qun Chen1, Matthias L. Riess3, Paul S. Pagel4, and David F. Stowe5
1 Department of Anesthesiology Research, Medical College of Wisconsin, Milwaukee, WI, USA
2 Department of Biomedical Engineering, Marquette University, Milwaukee, WI, USA
3 Department of Anesthesiology Research, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI, USA
4 Department of Anesthesiology Research, Medical College of Wisconsin, Milwaukee, WI, USA; Department of Cardiovascular Research Center, Medical College of Wisconsin, Milwaukee, WI, USA; VA Medical Center, Milwaukee, WI, USA
5 Department of Anesthesiology Research, Medical College of Wisconsin, Milwaukee, WI, USA; VA Medical Center, Milwaukee, WI, USA
* To whom correspondence should be addressed. E-mail: srhodes{at}mcw.edu.
Objective: 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+] and isovolumetric left ventricular pressure (LVP) using indices of loop area, orientation, and position, and 2) quantified cooperativity by linearly modeling the phase-space relationship between [Ca2+] and dLVP/dt in intact hearts during administration of positive inotropic drugs before and after global IR injury. Methods: Unpaced, isolated guinea pig hearts were perfused at a constant pressure with Krebs-Ringer's solution (37 °C, 1.25 mM CaCl2). [Ca2+] was measured ratiometrically by indo-1 fluorescence using a fiber optic probe placed at the LV free wall. LVP was measured 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. Results: 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. Conclusion: Dynamic indices 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.
