SUrMARY1. The load bearing capacity during relaxation of ventricular cardiac muscle from various animal species was investigated.2. The effect of load on the time course of relaxation was analysed either by comparing afterloaded contractions against various loads or by imposing abrupt alterations in load (load clamps).3. In heart muscle from the mammalian species studied relaxation was sensitive to loading conditions, whereas in frog heart muscle relaxation was largely independent of the loading conditions. The mechanical properties of relaxation of cardiac muscle appear, therefore, governed by the interplay of a load-controlled and an activationcontrolled decay mechanism, the relative importance of which differs with species.4. Load-dependence may be the mechanical expression of the ratio of the number of force generating sites at any time during contraction and relaxation to the load to be carried; this mechanism would predominate in mammalian animal species with a well developed calcium sequestering sarcoplasmic reticulum. Activation-dependence would seem to predominate in animal species, such as frog, in which calcium sequestration appears to be the rate limiting step during relaxation.

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The influence of calcium concentration in the bathing solution on the force-velocity relations of the isolated, electrically excited cat papillary muscle was examined. Shortening velocity was directly measured at minimum loads by unloading or load clamping the muscle from the preload (at the length, Lmax, where maximum active tension was developed) to 0 (zero-load clamp), 2, 5, 10, and 15% of the total tension, P o . All measurements were made in the physiological length range between Lmax and 12.5% below Lmax. Increasing the calcium concentration augmented the measured maximum unloaded shortening velocity and shifted the normalized force-velocity relation when force was expressed as a fraction of P o . These observations suggest that the activating calcium has an action more complex than the binding to troponin alone.

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SUMMARY The relaxation of isolated cardiac muscles from mammals was recently shown to be sensitive to the loading conditions because the time course of relaxation could be changed by changing the load. This effect apparently is related to the amount and functional status of the sarcoplasmic reticulum. The purpose of this study was to determine whether hypoxia affected the load sensitivity of papillary muscles isolated from both rats and cats. We used three mechanical tests to establish the presence of load-sensitive relaxation. First, we superimposed records of isotonic contractions at increasing afterloads up to isometric contraction. From these records we measured the ratio (tRi) which was the time from the initiation of the contraction to the initial decay of force at each isotonic afterload, divided by the time it took for the force of an isometric contraction to relax to that same afterload. If the tRi was less than 1.0, then the muscle was load sensitive. Hypoxia caused the loss of load-sensitive relaxation in isotonically contracting rat papillary muscles since the tRi ratios were not significantly different from 1.0 at all afterloads. Both hypoxia and caffeine were required to make cat papillary muscles load insensitive. Second, during hypoxia, loads added in midcontraction did not induce early relaxation in rat papillary muscles, but still did so in cat muscles. Hypoxia plus caffeine eliminated this load-induced early relaxation in cat papillary muscles. Third, physiologically contracting muscles made hypoxic did not lengthen earlier in response to an additional load. This decrease of load sensitivity under hypoxic conditions could contribute to the relaxation abnormalities observed during regional wall motion studies. Circ Res 48: 797-803, 1981 REGIONAL and global abnormalities of relaxation in the myocardium critically affect the evaluation of left ventricular function in patients with heart disease. To date, however, the underlying mechanisms for these abnormalities have not been fully elucidated. Recent studies (Brutsaert et al., 1978a(Brutsaert et al., , 1978bLeCarpentier et al., 1979) on the nature of relaxation in mammalian cardiac muscle introduced the concept that relaxation depends on the load imposed on the relaxing muscle. This concept may provide a basis for analyzing relaxation abnormalities of the ventricles. Muscular relaxation occurs when the load imposed upon the muscle exceeds the load-bearing ability of that muscle. In this process, the sarcoplasmic reticulum (SR) sequesters calcium, inactivates the contractile process, and decreases the muscle's load-bearing ability. If at this point the load exceeds the load-bearing capacity of the muscle, then relaxation occurs. The recent studies on relaxation of cardiac muscles were performed on muscles with extensive and active sarcoplasmic reticular systems. In these studies, a midcontraction increase of the imposed load initiated early relaxation, perhaps because the SR sequestered enough calcium to lower the muscle's loadbearing ability, ...