Positive inotropic effects of low dATP/ATP ratios on mechanics and kinetics of porcine cardiac muscle.
Substitution of 2'-deoxy ATP (dATP) for ATP as substrate for actomyosin results in significant enhancement of in vitro parameters of cardiac contraction. To determine the minimal ratio of dATP/ATP (constant total NTP) that significantly enhances cardiac contractility and obtain greater understanding of how dATP substitution results in contractile enhancement, we varied dATP/ATP ratio in porcine cardiac muscle preparations. At maximum Ca(2+) (pCa 4.5), isometric force increased linearly with dATP/ATP ratio, but at submaximal Ca(2+) (pCa 5.5) this relationship was nonlinear, with the nonlinearity evident at 2-20% dATP; force increased significantly with only 10% of substrate as dATP. The rate of tension redevelopment (k(TR)) increased with dATP at all Ca(2+) levels. k(TR) increased linearly with dATP/ATP ratio at pCa 4.5 and 5.5. Unregulated actin-activated Mg-NTPase rates and actin sliding speed linearly increased with the dATP/ATP ratio (p < 0.01 at 10% dATP). Together these data suggest cardiac contractility is enhanced when only 10% of the contractile substrate is dATP. Our results imply that relatively small (but supraphysiological) levels of dATP increase the number of strongly attached, force-producing actomyosin cross-bridges, resulting in an increase in overall contractility through both thin filament activation and kinetic shortening of the actomyosin cross-bridge cycle.
Schoffstall
Brenda
B
Program in Molecular Biophysics, Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
Clark
Amanda
A
Chase
P Bryant
PB
D000199:Actins / Q000737:chemistry / Q000502:physiology; D000205:Actomyosin / Q000502:physiology; D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D001696:Biomechanical Phenomena; D002118:Calcium / Q000502:physiology*; D003838:Deoxyadenine Nucleotides / Q000378:metabolism*; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D018482:Muscle, Skeletal / Q000737:chemistry; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009218:Myosins / Q000502:physiology; D011817:Rabbits; D013552:Swine
D000199:Actins; D003838:Deoxyadenine Nucleotides; D000255:Adenosine Triphosphate; D000205:Actomyosin; D009218:Myosins; C026600:2'-deoxyadenosine triphosphate; D002118:Calcium