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Positive Inotropic Effects of Low dATP/ATP Ratios on Mechanics and Kinetics of Porcine Cardiac Muscle

Brenda Schoffstall ^* , Amanda Clark  and P. Bryant Chase ^*  

^* Program in Molecular Biophysics, Department of Biological Science, and Department of Chemical & Biomedical Engineering, Florida State University, Tallahassee, Florida

Correspondence: Address reprint requests to P. Bryant Chase, PhD, F.A.H.A. Dept. of Biological Science, Florida State University, Biology Unit One, Tallahassee, FL. 32306. Tel.: 850-644-0056; Fax: 850-644-0481; E-mail: chase{at}bio.fsu.edu.

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 Ca²⁺ (pCa 4.5), isometric force increased linearly with dATP/ATP ratio, but at submaximal Ca²⁺ (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 Ca²⁺ 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.

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