Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts

B. L. Hamman, J. A. Bittl, W. E. Jacobus, P. D. Allen, R. S. Spencer, R. Tian, J. S. Ingwall

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112 Scopus citations

Abstract

To define the relation between phosphoryl transfer via creatine kinase (CK) and the ability of the intact beating heart to do work, we chemically inhibited CK activity and then measured cardiac performance under physiological and acute stress conditions. Isolated perfused rat hearts were exposed to iodoacetamide (IA) and subjected to one of three cardiac stresses: hypercalcemic (Ca2+ = 3 mM) buffer perfusion (n = 7), norepinephrine (2 μmol/min) infusion (n = 6), or hypoxic buffer perfusion (n = 5). IA decreased CK activity to near zero, measured in intact hearts by 31P magnetization transfer, and to 2% of control CK activity, measured in myocardial homogenates. The CK isoenzyme profile was unchanged, suggesting nonselective IA inhibition of all isoenzymes. Mitochondria isolated from IA- treated hearts had normal ADP:O ratios, state 3 respiratory rates, and unchanged acceptor and respiratory control ratios. Neither actomyosin adenosinetriphosphatase nor adenylate kinase activities were changed. After IA exposure, end-diastolic pressure, left ventricular developed pressure, and heart rate were unchanged for at least 30 min at physiological perfusion pressures, but large changes were observed during stress conditions. The increase in left ventricular developed pressure induced by hypercalcemic perfusion and by norepinephrine infusion decreased by 39 and 54%, respectively. During hypoxia, the rate of phosphocreatine depletion was decreased by 57%, left ventricular developed pressure declined, and end- diastolic pressure increased faster than in controls. These results show that inhibition of CK to <2% of control activity by IA reduced contractile reserve by ~50%. We conclude that CK activity is essential for the expression of the full dynamic range of myocardial performance.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume269
Issue number3 38-3
StatePublished - 1995
Externally publishedYes

Keywords

  • adenylate kinase

ASJC Scopus subject areas

  • Physiology

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    Hamman, B. L., Bittl, J. A., Jacobus, W. E., Allen, P. D., Spencer, R. S., Tian, R., & Ingwall, J. S. (1995). Inhibition of the creatine kinase reaction decreases the contractile reserve of isolated rat hearts. American Journal of Physiology - Heart and Circulatory Physiology, 269(3 38-3).