2-Deoxyadenosine triphosphate restores the contractile function of cardiac myofibril from adult dogs with naturally occurring dilated cardiomyopathy.
Dilated cardiomyopathy (DCM) is a major type of heart failure resulting from loss of systolic function. Naturally occurring canine DCM is a widely accepted experimental paradigm for studying human DCM. 2-Deoxyadenosine triphosphate (dATP) can be used by myosin and is a superior energy substrate over ATP for cross-bridge formation and increased systolic function. The objective of this study was to evaluate the beneficial effect of dATP on contractile function of cardiac myofibrils from dogs with naturally occurring DCM. We measured actomyosin NTPase activity and contraction/relaxation properties of isolated myofibrils from nonfailing (NF) and DCM canine hearts. NTPase assays indicated replacement of ATP with dATP significantly increased myofilament activity in both NF and DCM samples. dATP significantly improved maximal tension of DCM myofibrils to the NF sample level. dATP also restored Ca(2+) sensitivity of tension that was reduced in DCM samples. Similarly, dATP increased the kinetics of contractile activation (kACT), with no impact on the rate of cross-bridge tension redevelopment (kTR). Thus, the activation kinetics (kACT/kTR) that were reduced in DCM samples were restored for dATP to NF sample levels. dATP had little effect on relaxation. The rate of early slow-phase relaxation was slightly reduced with dATP, but its duration was not, nor was the fast-phase relaxation or times to 50 and 90% relaxation. Our findings suggest that myosin utilization of dATP improves cardiac myofibril contractile properties of naturally occurring DCM canine samples, restoring them to NF levels, without compromising relaxation. This suggests elevation of cardiac dATP is a promising approach for the treatment of DCM.
Department of Bioengineering, University of Washington, Seattle, Washington;
Yuanhua
Y
Cheng
Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada; and.
Kaley A
KA
Hogarth
Department of Clinical Studies, University of Guelph, Guelph, Ontario, Canada.
M Lynne
ML
O'Sullivan
Department of Bioengineering, University of Washington, Seattle, Washington;
Michael
M
Regnier
Centre for Cardiovascular Investigations, Department of Biomedical Sciences, University of Guelph, Guelph, Ontario, Canada; and gpyle@uoguelph.ca.
W Glen
WG
Pyle
D000205:Actomyosin / Q000378:metabolism; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003838:Deoxyadenine Nucleotides / Q000494:pharmacology*; D004195:Disease Models, Animal; D004285:Dogs; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D007700:Kinetics; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009210:Myofibrils / Q000187:drug effects* / Q000378:metabolism; D009218:Myosins / Q000378:metabolism*; D010766:Phosphorylation; D020127:Recovery of Function
D002316:Cardiotonic Agents; D003838:Deoxyadenine Nucleotides; D000205:Actomyosin; D009218:Myosins; C026600:2'-deoxyadenosine triphosphate
contraction; relaxation