The mechanism of early contractile failure of isolated rat ventricular myocytes subjected to complete metabolic inhibition.

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Abstract
Twitch shortening of isolated rat ventricular myocytes was measured on exposure to complete metabolic blockade (2 mM-cyanide in the presence of 10 mM-2-deoxyglucose). Under these conditions twitch shortening declines of undetectable levels over 1-15 min. This ''early'' contractile failure is followed by the development of a maintained contracture. Contractures induced by caffeine (20 mM) were similar in amplitude before and after ''early'' contractile failure. This result suggests that ''early'' contractile failure is not due to depletion of Ca2+ from the sarcoplasmic reticulum. The action potential shortened as the twitch magnitude declined during ''early'' contractile failure, raising the possibility of a causal link. Voltage-clamp experiments show that an enormous increase in K+ conductance (> 20-fold) occurs during the period of ''early'' contractile failure, and presumably underlies the action potential shortening. If the K+ conductance changes are inhibited by replacement of intracellular K+ with N-methyl glucosamine and inclusion of 2 mM-tolbutamide in intra- and extracellular solutions, good voltage control can be achieved. Under these conditions, ''early'' contractile failure did not occur on exposure to complete metabolic blockade and neither Ca2+ current nor the twitch were completely abolished until a maintained contracture had begun to occur. Injection of ATP following ''early'' contractile failure could partially restore the twitch and prolong the foreshortened action potential. These results are consistent with the hypothesis that ''early'' contractile failure occurring under non-voltage-clamped conditions is due principally to failure of activation of the Ca2+ current because of the shortening of the action potential. Although a decline in the availability of Ca2+ current also occurs, action potential shortening results mainly from increased conductance through ATP-sensitive K+ channels which are activated by a fall of intracellular [ATP]. Contractile failure arises not because of a primary alteration, or defect, in the coupling of excitation to contraction, but because the cell membrane is effectively clamped at a potential close to the K+ equilibrium potential.