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(Circulation Research. 1997;80:688-698.)
© 1997 American Heart Association, Inc.

Articles

Inhibition of Myocardial Crossbridge Cycling by Hypoxic Endothelial Cells

A Potential Mechanism for Matching Oxygen Supply and Demand?

Ajay M. Shah, Alexandre Mebazaa, Zhao-Kang Yang, Giovanni Cuda, Edward B. Lankford, Chris B. Pepper, Steven J. Sollott, James R. Sellers, James L. Robotham, , Edward G. Lakatta

From the Department of Cardiology (A.M.S., Z.-K.Y., C.B.P.), University of Wales College of Medicine, Cardiff, UK; Laboratory of Cardiovascular Science (A.M.S., A.M., S.J.S., E.G.L.), Gerontology Research Center/National Institute on Aging, National Institutes of Health, Baltimore, Md; Pulmonary Anesthesia Laboratory (A.M., J.L.R.), Johns Hopkins Medical Institutions, Baltimore, Md; Laboratory of Molecular Cardiology (G.C., J.R.S.), National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md; Cardiovascular Section (E.B.L.), University of Pennsylvania School of Medicine, Philadelphia; and Department of Anesthesiology (A.M.), Lariboisiere Hospital, Paris, France.

Correspondence to Ajay M. Shah, MD MRCP, Department of Cardiology, University of Wales College of Medicine, Heath Park, Cardiff CF4 4XN, UK. E-mail shaham2{at}cf.ac.uk

Abstract Previous studies have shown that cardiac endothelial cells release substances that influence myocardial contraction. Since PO₂ is an important stimulus that modulates endothelial function, we investigated the effects of acute moderate hypoxia and reoxygenation on the release of cardioactive factors by endothelial cells. Endothelial cells cultured from several vascular beds were superfused with normoxic (equilibrated with room air; PO₂, 160 mm Hg) or hypoxic (PO₂, 40 to 50 mm Hg) physiological buffer solution, and the superfusates were reequilibrated to a PO₂ of 160 mm Hg and then tested for their effects on various myocardial assays. Endothelial cell viability and buffer ionic composition were unaltered after the superfusion procedures. The superfusates of hypoxic endothelial cells induced rapid, potent, reversible inhibition of isolated cardiac myocyte contraction without reducing cytosolic Ca²⁺ transients. This activity was not lost after heating (95°C) and was present in low molecular weight (M_r, <500) superfusate fractions. Hypoxic endothelial superfusate reduced unloaded shortening velocity of human skinned soleus muscle fibers. It markedly depressed in vitro actin motility over cardiac myosin and reduced the rate of actin-activated cardiac myosin ATPase activity but had no effect on corresponding smooth muscle myosin assays. Reoxygenation of hypoxic endothelial cells resulted in loss of this inhibitory activity. These data indicate that cultured endothelial cells respond to acute moderate hypoxia by releasing an unidentified substance(s) that inhibits myocardial crossbridge cycling, independent of Ca²⁺ or other second messenger signaling pathways. Such a mechanism could have important implications for the regulation of oxygen supply-demand balance in the heart and be relevant to conditions such as myocardial hibernation.

Key Words: cardiac contraction • hypoxia • endothelial cell • hibernation • myofilament

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