Oxygen wasting for Ca2+ extrusion activated by partial inhibition of sarcoplasmic reticulum Ca2+-ATPase by cyclopiazonic acid in rat left ventricles

In the excised Langendorff-perfused rat whole-heart preparation, a linear relation between left ventricular myocardial oxygen consumption per beat (VO2) and systolic pressure-volume area (PVA, a total mechanical energy per beat) is obtained from a curved end-systolic pressure-volume relation as in the blood-perfused preparation. The ordinate VO2 intercept of the VO2-PVA relation is composed of VO2 for total Ca2+ handling in the excitation-contraction coupling and basal metabolism. The VO2 for total Ca2+ handling is mainly consumed by sarcoplasmic reticulum (SR) Ca2+-ATPase. The aim of the present study was to investigate, in terms of left ventricular mechanoenergetics, how an inhibition of SR Ca2+-ATPase by cyclopiazonic acid (CPA; 4 mu mol/l) affects Ca2+ handling mechanisms in the excised Langendorff-perfused rat whole-heart preparation. The short-term (for 3 to 6 min after onset of the infusion) CPA infusion de-creased VO2 proportionally to the decrease in PVA, The long-term (for 9 to 12 min after the short-term CPA infusion) CPA infusion gradually increased VO2 almost to the control level with an increase in PVA, The increases in both VO2 and PVA during this infusion were completely abolished by a Na+/Ca2+ exchanger inhibitor, 3 ' ,4 ' -dichlorobenzamil, indicating the contribution of Na+/Ca2+ exchanger to the increases in VO2 and PVA, The O-2 cost Of left ventricular contractility during the long-term CPA infusion was significantly higher than during the short-term CPA infusion. All these results suggest the possibility of the contribution of greater energy-wasting Ca2+ extrusion processes (such as Na+/K+-ATPase coupled to the Na+/Ca2+ exchanger; its stoichiometry is 1 ATP:1 Ca2+) to the larger oxygen cost of left ventricular contractility.