DITPA prevents the blunted contraction-frequency relationship in myocytes from infarcted hearts.
Loss of the positive force-frequency relationship is a characteristic finding in failing hearts. The mechanisms of this change are not well understood. Myocardial infarction (MI) was induced in rabbits to produce left ventricular (LV) dysfunction. Beginning 1 day after MI, a subgroup of rabbits received diiodothyropropionic acid (DITPA) (3.75 mg x kg(-1) x day(-1) sc) for 3 wk. We measured contractions, Ca(2+) transients, action potentials, and sarcoplasmic reticulum (SR) Ca(2+) content at different stimulation rates in single LV myocytes. The shortening-frequency relationship was markedly flattened in MI myocytes compared with control myocytes. In addition, Ca(2+) transients, action potentials, and contractions were prolonged. Myocytes from DITPA-treated MI rabbits had preserved inotropic responses to increased stimulation rate and normal duration of action potentials and Ca(2+) transients. SR Ca(2+) content increased significantly when stimulation rate was increased from 0.5 to 2.0 Hz in control myocytes but did not change significantly in MI myocytes. Myocytes from DITPA-treated MI rabbits had a greater frequency-dependent increase in SR Ca(2+) content compared with the untreated MI rabbits. Thus single myocytes from infarcted rabbit hearts have frequency-dependent abnormalities of contractility, Ca(2+) cycling, and action potential repolarization. The flattened contraction-frequency relationship can be partially explained by an attenuation of the normal enhancement of SR Ca(2+) content that occurs when stimulation rate is increased. Chronic DITPA administration after MI largely prevents the development of these abnormalities.
Litwin
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Cardiovascular Division, Veterans Affairs Medical Center, and University of Utah Health Sciences Center, Salt Lake City, Utah 84132, USA. sheldon.litwin@hsc.utah.edu
Zhang
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Roberge
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Pennock
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D000200:Action Potentials; D000818:Animals; D002118:Calcium / Q000378:metabolism; D048429:Cell Size; D004104:Diiodothyronines / Q000008:administration & dosage / Q000494:pharmacology*; D004452:Echocardiography; D004558:Electric Stimulation; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D011422:Propionates / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
D004104:Diiodothyronines; D011422:Propionates; C082182:3,5-diiodothyropropionic acid; D002118:Calcium