Published online before print April 18, 2002, doi: 10.1161/01.RES.0000018625.25212.1E
© 2002 American Heart Association, Inc.
Cellular Biology |
Hydroxyl Radical-Induced Acute Diastolic Dysfunction Is Due to Calcium Overload via Reverse-Mode Na+-Ca2+ Exchange
From Georg-August-Universität Göttingen Universitätsklinik (O.Z., A.E.M., P.V.N., G. Hensmann, H.K., K.M., G. Hasenfuss, P.M.L.J.), Abteilung Kardiologie und Pneumologie, Göttingen, Germany; and the Institute of Molecular Cardiobiology (P.M.L.J.), School of Medicine, Johns Hopkins University, Baltimore, Md.
Correspondence to Paul M.L. Janssen, PhD, Johns Hopkins University, Institute of Molecular Cardiology, Ross 844, 720 Rutland Ave, Baltimore, MD 21205. E-mail pjanssen{at}jhmi.edu
Hydroxyl radicals (OH) are involved in the development of reperfusion injury and myocardial failure. In the acute phase of the OH-mediated diastolic dysfunction, increased intracellular Ca2+ levels and alterations of myofilaments may play a role, but the relative contribution of these systems to myocardial dysfunction is unknown. Intact contracting cardiac trabeculae from rabbits were exposed to OH, resulting in an increase in diastolic force (Fdia) by 540%. Skinned fiber experiments revealed that OH-exposed preparations were sensitized for Ca2+ (EC50: 3.27±0.24x10-6 versus 2.69±0.15x10-6 mol/L; P<0.05), whereas maximal force development was unaltered. Western blots showed a proteolytic degradation of troponin T (TnT) with intact troponin I (TnI). Blocking of calpain I by MDL-28.170 inhibited both TnT-proteolysis and Ca2+ sensitization, but failed to prevent the acute diastolic dysfunction in the intact preparation. The OH-induced diastolic dysfunction was similar in preparations with intact (540±93%) and pharmacologically blocked sarcoplasmic reticulum (539±77%), and was also similar in presence of the L-type Ca2+-channel antagonist verapamil. In sharp contrast, inhibition of the reverse-mode sodium-calcium exchange by KB-R7943 preserved diastolic function completely. Additional experiments were performed in rat myocardium; the rise in diastolic force was comparable to rabbit myocardium, but Ca2+ sensitivity was unchanged and maximal force development was reduced. This was associated with a degradation of TnI, but not TnT. Electron microscopic analysis revealed that OH did not cause irreversible membrane damage. We conclude that OH-induced acute diastolic dysfunction is caused by Ca2+ influx via reverse mode of the sodium-calcium exchanger. Degradation of troponins appears to be species-dependent but does not contribute to the acute diastolic dysfunction.
Key Words: diastolic dysfunction • oxidant stress • calcium handling • myofilament • contractility
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