Analysis of the relationship between myoplasmic ionized calcium and contractile function in guinea pig intact hearts
Abstract
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.
Recommended Citation
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.
https://epublications.marquette.edu/dissertations/AAI3093149