Sustained high O2 use for Ca2+ handling in rat ventricular slices under decreased free shortening after ryanodine.

摘要

We hypothesized that O2 wasting of Ca2+ handling in the excitation-contraction coupling in ryanodine-treated failing hearts might derive from an increased external Ca2+ extrusion via Na+/Ca2+ exchanger and futile Ca2+ cycling via sarcoplasmic reticulum (SR) Ca2+-ATPase. We tested this hypothesis by mechanoenergetic studies using rat left ventricular slices. After the slices were treated with ryanodine (0.1 microM), 1-Hz free shortening significantly decreased by 78-85%, whereas the observed O2 consumption (VO2) required for total Ca2+ handling, increased from 0.79 to 1.13 ml O2 x min(-1) x 100 g x LV(-1) (155.6% of control). We reconfirmed that cyclopiazonic acid (10 microM), a blocker of SR Ca2+-ATPase, decreased VO2 by 75-80% in normal slices. However, 100 microM of cyclopiazonic acid was needed to inhibit the VO2 by 80% after ryanodine treatment. Blockade of a sarcolemmal Na+/Ca2+ exchanger by KB-R7943 (10 microM) significantly decreased VO2 by 45% after ryanodine treatment without significant effects on normal slices. Our results indicated that the VO2 increase following ryanodine treatment was derived from a net change of an increased external Ca2+ extrusion via Na+/Ca2+ exchanger and futile Ca2+ cycling via SR Ca2+-ATPase.