Analysis of the relationship between myoplasmic ionized calcium and contractile function in guinea pig intact hearts
Analysis of the phase-plane relationship between myoplasmic calcium concentration ([Ca2+ ]) and left ventricular pressure (LVP) using morphologic indices and dynamic modeling should enable a better understanding of Ca 2+ -contraction coupling. We simultaneously measured [Ca2+ ], using fluorescent techniques, and LVP in guinea pig intact hearts. We developed novel indices based on the morphology and timing of [Ca2+ ] and LVP transients, and phase-plane diagrams (LVP vs. [Ca2+ ]). We adapted a four-state model based on interactions between actin and myosin i.e. cross-bridge kinetics, and Ca2+ handling by myofilament regulatory protein troponin C (TnC) to interpret the cyclic relationship between [Ca2+ ] and LVP. We investigated changes in morphologic indices and model rate constants from control (1) after 30 min 37°C global ischemia, (2) during 17°C perfusion, (3) after 240 min 17°C global ischemia, and (4) during inotropic intervention before and after 30 min 37°C global ischemia. On 30 minutes of reperfusion after 37°C ischemia, morphologic indices revealed dissociation in Ca2+ -contraction coupling and inefficient Ca2+ utilization by myofilaments for generating force. Changes in model rate constants suggest reduced cooperativity in cross-bridge association and Ca2+ binding to TnC after 37°C ischemia. Morphologic indices revealed that 17°C perfusion resulted in slower heart rates, myoplasmic Ca2+ loading, and diastolic contracture. Optimized model rate constants indicated slower association and dissociation of Ca2+ and TnC. The model predicted slowed cross-bridge kinetics that might account for observed diastolic contracture. Morphologic indices and model predicted parameters both indicate better preservation of contractile apparatus after long-term cold ischemia compared to short-term warm ischemia. Beta-adrenoceptor agonists, dopamine and dobutamine, have positive inotropic and chronotropic effects; however, the model predicted loss of myofilament Ca2+ sensitivity despite increased [Ca2+ ] before ischemia. After ischemia, dopamine improved, and dobutamine reduced myofilament Ca2+ sensitivity. Morphologic indices suggest that digoxin improved Ca2+ -contraction coupling efficiency before and after ischemia; however the model predicted improved cross-bridge kinetics and Ca 2+ sensitivity after, but not before ischemia. Levosimendan sensitized the myofilaments to Ca2+ after, but not before ischemia. Comprehensive studies of morphologic indices and modeled rate constants provide useful insight into alterations in myocardial Ca2+ handling in response to pharmacologic and pathologic interventions.
Rhodes, Samhita Shahane, "Analysis of the relationship between myoplasmic ionized calcium and contractile function in guinea pig intact hearts" (2003). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI3093149.