2-deoxy-ATP enhances contractility of rat cardiac muscle

To investigate the kinetic parameters of the crossbridge cycle that regulat e force and shortening in cardiac muscle, we compared the mechanical proper ties of cardiac trabeculae with either ATP or 2-deoxy-ATP (dATP) as the sub strate for contraction. Comparisons were made in trabeculae from untreated rats (predominantly V1 myosin) and those treated with propylthiouracil (PTU ; V3 myosin). Steady-state hydrolytic activity of cardiac heavy meromyosin (HMM) showed that PTU treatment resulted in >40% reduction of ATPase activi ty, dATPase activity was >50% elevated above ATPase activity in HMM from bo th untreated and PTU-treated rats. V-max of actin-activated hydrolytic acti vity was also >50% greater with dATP, whereas the K-m for dATP was similar to that for ATP. This indicates that dATP increased the rate of crossbridge cycling in cardiac muscle. Increases in hydrolytic activity were parallele d by increases of 30% to 80% in isometric force (F-max), rate of tension re development (k(u)), and unloaded shortening velocity (V-u) in trabeculae fr om both untreated and PTU-treated rats (at maximal Ca2+ activation), and F- actin sliding speed in an in vitro motility assay (V-f). These results cont rast with the effect of dATP in rabbit psoas and soleus fibers, where F-max is unchanged even though k(u), V-u, and V-f are increased. The substantial enhancement of mechanical performance with dATP in cardiac muscle suggests that it may be a better substrate for contractility than ATP and warrants exploration of ribonucleotide reductase as a target for therapy in heart fa ilure.