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Am J Physiol Heart Circ Physiol 277: H2212-H2221, 1999;
0363-6135/99 $5.00
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Vol. 277, Issue 6, H2212-H2221, December 1999

Functional role of ionic regulation of Na+/Ca2+ exchange assessed in transgenic mouse hearts

Krista Maxwell1, Jason Scott1, Alexander Omelchenko1, Anton Lukas1, Liyan Lu2, Yujuan Lu2, Mark Hnatowich1, Kenneth D. Philipson2, and Larry V. Hryshko1

1 Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, University of Manitoba, Winnipeg, Manitoba, Canada R2H 2A6; and 2 Cardiovascular Research Laboratory and Departments of Physiology and Medicine, University of California, Los Angeles, California 90095

Na+/Ca2+ exchange is the primary mechanism mediating Ca2+ efflux from cardiac myocytes during diastole and, thus, can prominently influence contractile force. In addition to transporting Na+ and Ca2+, the exchanger is also regulated by these ions. Although structure-function studies have identified protein regions of the exchanger subserving these regulatory processes, their physiological importance is unknown. In this study, we examined the electrophysiological and mechanical consequences of cardiospecific overexpression of the canine cardiac exchanger NCX1.1 and a deletion mutant of NCX1.1 (Delta 680-685), devoid of intracellular Na+ (Na+i)- and Ca2+ (Ca2+i)- dependent regulatory properties, in transgenic mice. Using the giant excised patch-clamp technique, normal ionic regulation was observed in membrane patches from cardiomyocytes isolated from control and transgenic mice overexpressing NCX1.1. In contrast, ionic regulation was nearly abolished in mice overexpressing Delta 680-685, indicating that the native regulatory processes could be overwhelmed by expression of the transgene. To address the physiological consequences of ionic regulation of the Na+/Ca2+ exchanger, we examined postrest force development in papillary muscles from NCX1.1 and Delta 680-685 transgenic mice. Postrest potentiation was found to be substantially greater in Delta 680-685 than in NCX1.1 transgenic mice, supporting the notion that ionic regulation of Na+/Ca2+ exchange plays a significant functional role in cardiac contractile properties.

giant excised patch; sodium-calcium exchange; ionic regulation; postrest potentiation


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