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Effect of Metabolic Inhibition on Couplon Behavior in Rabbit Ventricular Myocytes

Chana Chantawansri ^*, Nhi Huynh ^*, Jun Yamanaka ^*, Alan Garfinkel ^*, Scott T. Lamp ^*, Masashi Inoue , John H. B. Bridge  and Joshua I. Goldhaber ^*

^* Division of Cardiology, Cardiovascular Research Laboratories, David Geffen School of Medicine at UCLA, Los Angeles, California; and Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, Utah

Correspondence: Address reprint requests to Joshua I. Goldhaber, E-mail: jgoldhaber{at}mednet.ucla.edu.

We investigated the effect of combined inhibition of oxidative and glycolytic metabolism on L-type Ca²⁺ channels (LCCs) and Ca²⁺ spikes in isolated patch-clamped rabbit ventricular myocytes. Metabolic inhibition (MI) reduced LCC open probability, increased null probability, increased first latency, and decreased open time but left conductance unchanged. These results explain the reduction in macroscopic Ca²⁺ current observed during MI. MI also produced a gradual reduction in action potential duration at 90% repolarization (APD₉₀), a clear decline in spike probability, and an increase in spike latency and variance. These effects are consistent with the changes we observed in LCC activity. MI had no effect on the amplitude or time to peak of Ca²⁺ spikes until APD₉₀ reached 10% of control, suggesting preserved sarcoplasmic reticulum Ca²⁺ stores and ryanodine receptor (RyR) conductance in those couplons that remained functioning. Ca²⁺ spikes disappeared completely when APD₉₀ reached <2% of control, although in two cells, spikes were reactivated in a highly synchronized fashion by very short action potentials. This reactivation is probably due to the increased driving force for Ca²⁺ entry through a reduced number of LCCs that remain open during early repolarization. The enlarged single channel flux produced by rapid repolarization is apparently sufficient to trigger RyRs whose Ca²⁺ sensitivity is likely reduced by MI. We suggest that loss of coupling fidelity during MI is explained by loss of LCC activity (possibly mediated by Ca²⁺-calmodulin kinase II activity). In addition, the results are consistent with loss of RyR activity, which can be mitigated under conditions likely to enlarge the trigger.