EFFECT OF BDM, VERAPAMIL, AND CARDIAC WORK ON MITOCHONDRIAL-MEMBRANE POTENTIAL IN PERFUSED RAT HEARTS

The biochemical link providing effective coordination between the mito chondrial ATP synthetic machinery and the contractile apparatus follow ing transitions in cardiac work remains enigmatic. Studies were design ed to determine whether activation of the actomyosin adenosinetriphosp hatase (ATPase) is a necessary part of the signaling mechanism to the mitochondrial ATP synthase or whether a rise in cytosolic free Ca2+ is sufficient to activate the synthase. With the use of Langendorff-perf used rat hearts, cardiac work was varied via changes in perfusion pres sure and by the inclusion of a beta-adrenergic agent. Furthermore, 2,3 -butanedione monoxime and verapamil were used to vary independently ei ther the activity of the actomyosin ATPase or the level of cytosolic f ree Ca2+. Determinations of the in vivo mitochondrial membrane potenti al [Delta psi(m); see Walt et al. Am. J. Physiol. 265 (Heart Circ. Phy siol. 34): H445-H452, 1993] and its vectorial displacement during work transitions provide valuable information concerning direct activation of the ATP synthase and proton movement through the membrane domain o f the synthase. Increased cardiac work in the presence of the beta-adr energic agent resulted in a decrease in Delta psi(m) Addition of 2,3-b utanedione monoxime decreased cardiac work but did not change Delta ps i(m). The inclusion of verapamil resulted in similar decreases in card iac work. However, Delta psi(m) reversed back to a value observed unde r control, low-work conditions. These results in conjunction with data regarding levels of high-energy phosphates, free Mg2+, and adenosine 3',5'-cyclic monophosphate suggest a Ca2+-mediated increase in the act ivity of the ATP synthase.