Abstract-The effect of MgADP on the sarcomere length (SL) dependence of tension generation was investigated using skinned rat ventricular trabeculae. Increasing SL from 1.9 to 2.3 m decreased the muscle width by Ϸ11% and shifted the midpoint of the pCa-tension relationship (pCa 50 ) leftward by about 0.2 pCa units. MgADP (0.1, 1, and 5 mmol/L) augmented maximal and submaximal Ca 2ϩ -activated tension and concomitantly diminished the SL-dependent shift of pCa 50 in a concentration-dependent manner. In contrast, pimobendan, a Ca 2ϩ sensitizer, which promotes Ca 2ϩ binding to troponin C (TnC), exhibited no effect on the SL-dependent shift of pCa 50 , suggesting that TnC does not participate in the modulation of SL-dependent tension generation by MgADP. At a SL of 1.9 m, osmotic compression, produced by 5% wt/vol dextran (molecular weight Ϸ464 000), reduced the muscle width by Ϸ13% and shifted pCa 50 leftward to a similar degree as that observed when increasing SL to 2.3 m. This favors the idea that a decrease in the interfilament lattice spacing is the primary mechanism for SL-dependent tension generation. MgADP (5 mmol/L) markedly attenuated the dextran-induced shift of pCa 50 , and the degree of attenuation was similar to that observed in a study of varying SL. The actomyosin-ADP complex (AM.ADP) induced by exogenous MgADP has been reported to cooperatively promote myosin attachment to the thin filament. We hereby conclude that the increase in the number of force-generating crossbridges on a decrease in the lattice spacing is masked by the cooperative effect of AM.ADP, resulting in depressed SL-dependent tension generation. The full text of this article is available at http://www.circresaha.org. This intrinsic ability of the heart to alter cardiac output forms the basis for the Frank-Starling law of the heart. It is well established that twitch tension and Ca 2ϩ responsiveness in cardiac muscle preparations are enhanced as muscle length (ie, sarcomere length [SL]) is increased within the normal physiological range (SL from Ϸ1.8 to Ϸ2.3 m). 1-5 Although a number of studies have been conducted to account for the SL dependence of tension generation in living myocardium, its mechanism has not been completely elucidated. 6 However, at the myofilament level, there is an increasing amount of evidence suggesting that the SL dependence is primarily due to a change in the interfilament lattice spacing that accompanies the SL change. 7-9 A possible consequence of the decreased lattice spacing is an increase in the probability of myosin attachment to the thin filament, resulting in an increase in the number of force-generating crossbridges. 7,10,11 Ishiwata and Oosawa 12 proposed a model based on the Ca 2ϩ -dependent flexibility of the thin filament, in which they assumed that (1) the muscle volume (ie, the lattice volume) remains constant on a change in SL and that (2) there is a critical distance between the thick and thin filaments for tension generation. This model quantitatively explains both the stretch-induced increas...

The mechanisms of the slower time courses of Ca2+ transients (CaT) and contraction in diabetic (diabetes mellitus, DM) myocardium were studied. The aequorin method was applied to papillary muscles of streptozotocin-induced DM and control rats. The time courses of CaT and tension of twitch in DM were slower than those in control, although the magnitudes of the CaT and contraction were identical. The dependence of CaT decay time and relaxation time on developed tension in DM and control rats differed. The length-tension relation in twitch and the pCa-tension relation in tetanus were identical in the two groups. The magnitude of extra Ca2+ (transient increase in intracellular Ca2+ concentration induced by a quick release in tetanus) was identical in both groups. pCa-tension relations of skinned trabeculae at different sarcomere lengths were nearly identical. The cross-bridge cycling rate (CCR) in DM was slower than that in control. These results indicate that the tension-dependent change in the Ca2+ affinity of troponin C in DM myocardium functions as in control myocardium. The slower time courses of CaT and tension in DM myocardium are caused by slower Ca2+ uptake by the sarcoplasmic reticulum and the slower CCR.

We investigated the effect of acidosis on the sarcomere length (SL) dependence of tension generation, in comparison with the effect of inorganic phosphate (Pi), in rat skinned ventricular trabeculae. The shift of the mid‐point of the pCa‐tension relationship associated with an increase in SL from 1.9 to 2.3 μm (ΔpCa50) was studied. Decreasing pH from 7.0 to 6.2 lowered maximal and submaximal Ca2+‐activated tension and increased ΔpCa50 in a pH‐dependent manner (from 0.21 ± 0.01 to 0.30 ± 0.01 pCa units). The addition of Pi (20 mm) decreased maximal tension and enhanced the SL dependence, both to a similar degree as observed when decreasing pH to 6.2 (ΔpCa50 increased from 0.20 ± 0.01 to 0.29 ± 0.01 pCa units). Further experiments were performed using 6 % (w/v) Dextran T‐500 (molecular weight ∼500 000) to osmotically reduce interfilament lattice spacing (SL, 1.9 μm). Compared with that at pH 7.0, in the absence of Pi the increase in the Ca2+ sensitivity of tension induced by osmotic compression was enhanced at pH 6.2 (0.18 ± 0.01 vs. 0.25 ± 0.01 pCa units) or in the presence of 20 mm Pi (0.17 ± 0.01 vs. 0.24 ± 0.01 pCa units). H+, as well as Pi, has been reported to decrease the number of strongly binding cross‐bridges, which reduces the co‐operative activation of the thin filament and increases the pool of detached cross‐bridges available for interaction with actin. It is therefore considered that during acidosis, the degree of increase in the number of force‐generating cross‐bridges upon reduction of interfilament lattice spacing is enhanced, resulting in greater SL dependence of tension generation. Our results suggest that the Frank‐Starling mechanism may be enhanced when tension development is suppressed due to increased H+ and/or Pi under conditions of myocardial ischaemia or hypoxia.

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