Load-insensitive relaxation caused by hypoxia in mammalian cardiac muscle.

Abstract

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, ...

The influence of pressure overload left ventricular hypertrophy on diastolic properties during hypoxia in isovolumically contracting rat hearts.

“…In isolated heart muscle experiments (Chuck et al, 1981), myocardial muscle relaxation during hypoxia appears to be load independent, and appears to be related primarily to differences in force inactivation itself; that is, the processes influencing the dissipation of force-generating crossbridge attachment (Chuck et al, 1981;LeCarpentier et al, 1982;661 Brutsaert et al, 1984). The biochemical processes that influence the rate and extent of force inactivation and final resting cardiac tone are incompletely understood, but appear to depend in part on the ATP-dependent rate and capacity of calcium sequestration by the sarcoplasmic reticulum (Nayler et al, 1979;Lewis et al, 1979;LeCarpentier et al, 1979LeCarpentier et al, , 1982Grossman and Barry, 1980;Brutsaert et al, 1984).…”

Diltiazem and left ventricular hypertrophy in renovascular hypertensive rats.

“…Quantification of the effects of loading on load dependence of relaxation was done according to the method proposed by Chuck et al 22 with the ratio of time to relaxation. If this ratio was below 1.0, the relaxation was termed load-sensitive; if this ratio was equal to 1.0, relaxation was termed loadinsensitive., 23 ' 24 Data Calculation and Statistical Analysis Cardiac output and coronary blood flow were computed from the radioactivity in tissues and blood samples according to standard formulas.…”

What global diastolic function is, what it is not, and how to measure it

“…There are three prominent factors in this decline in force: calcium reuptake, deactivation of cross-bridge binding sites, and detachment of cross bridges themselves. If calcium reuptake is slowed, for example in ischemia or hypoxia, then the rate of relaxation is reduced (13,15). Altered deactivation of cross-bridge binding sites, for example due to phosphorylation or mutation of troponin complexes, is also associated with slow relaxation (73,81,118).…”