Inhibition of the creatine kinase reaction decreases the
contractile reserve of the isolated rat heart.
Hamman, Baron L., John A. Bittl, William E. Jacobus, Paul D. Allen,
Richard S. Spencer, Rong Tian, and Joanne S. Ingwall.
NMR Laboratory for Physiological Chemistry, the Departments of
Medicine and Anesthesiology, Brigham and Women's Hospital and Harvard
Medical School, Boston, Massachusetts 02115, and Department of
Medicine, The Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205
APStracts 2:0144H, 1995.
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 [mu]moles/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 III respiratory rates, and
unchanged acceptor and respiratory control ratios. Neither actomyosin
ATPase 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
physiologic 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%, and 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 about 50%. We conclude that CK activity is essential for the
expression of the full dynamic range of myocardial performance.
Received 14 March 1994; accepted in final form 16 March 1995.
APS Manuscript Number H238-4.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 19 April 1995.