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 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 (kTR) increased with dATP at all Ca2+ levels. kTR 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. lament activation and kinetic shortening of the actomyosin cross-bridge cycle.