Force-velocity and power-load curves in rat skinned cardiac myocytes.

Myocardial performance in mammals depends upon factors that include the architecture of the ventricles, after-load against which the heart must work, and the contractile state of the myocardium. The capacity of the heart to perform external work is essential for moving blood throughout the circulatory system but little is known about the mechanisms that regulate this important physiological variable. In this study we present results from a single myocyte preparation in which we have investigated factors regulating the rate of work production, or power output, of mammalian myocardium. The velocity of muscle shortening is a primary determinant of myocardial power output, i.e. the product of force and velocity, and is thought to be limited by the rate of detachment of myosin cross-bridges from actin. Several factors that affect cross-bridge detachment, and thus the velocity of shortening, have been investigated by characterizing the force-velocity relationships of a variety of cardiac muscle preparations. Force-velocity relationships from both intact (Sonnenblick, 1962; De Clerk et al. 1977; Chiu et al. 1987; de Tombe & ter Keurs, 1990) and skinned (Maughan et al. 1978; Pagani & Julian, 1984; Sweitzer & Moss, 1993) myocardial preparations exhibit the expected decrease in shortening velocity as the load on the muscle is increased. Furthermore, the time course of muscle shortening against constant load has been observed to be curvilinear in cardiac muscle preparations, continually slowing as shortening proceeds (Maughan et al. 1978; Brenner, 1980, 1986; Daniels et al. 1984; Chiu et al. 1987; Sweitzer & Moss, 1993). One objective of the present study was to assess the time course (i.e. linear or non-linear behaviour) of isotonic shortening using a skinned single myocyte preparation having low end compliance at the points of attachment to the apparatus. This preparation offers several advantages for such a study. First, skinning allows experimental control of the level of Ca2+ activation during isotonic shortening. Second, the use of single myocytes allows precise characterization of contractile and regulatory protein content, as well as important physical variables (for example, sarcomere length) during activation. In this way, accurate myofibrillar protein structure-function analysis can be achieved. Third, skinned myocytes are free of extracellular viscoelastic elements that may give rise to restoring forces during shortening and contribute to non-linear length traces previously observed during shortening of myocardial preparations under force clamp conditions. Last, single myocytes reduce the diffusion distances for ATP and ADP, which decreases the likelihood of concentration gradients arising between the muscle core and surrounding solution. The second major objective of this study was to assess the load dependence of power output in skinned cardiac myocyte preparations. Changes in load and/or contractility are known to affect cardiac power output during normal physiological phenomena such as exercise and pathological conditions such as hypertension and heart failure. Since Ca2+ is a likely regulator of myocardial power output and intracellular Ca2+ varies on a beat-to-beat basis, we also assessed the effects of Ca2+ on load dependence of power output. The words force and load are used interchangeably throughout the manuscript, and tension refers to force per muscle cross-section. This work has been described in part in abstract form (McDonald et al. 1996a, b).