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 r elation between left ventricular myocardial oxygen consumption per beat (VO 2) and systolic pressure-volume area (PVA, a total mechanical energy per be at) is obtained from a curved end-systolic pressure-volume relation as in t he blood-perfused preparation. The ordinate VO2 intercept of the VO2-PVA re lation is composed of VO2 for total Ca2+ handling in the excitation-contrac tion coupling and basal metabolism. The VO2 for total Ca2+ handling is main ly consumed by sarcoplasmic reticulum (SR) Ca2+-ATPase. The aim of the pres ent study was to investigate, in terms of left ventricular mechanoenergetic s, how an inhibition of SR Ca2+-ATPase by cyclopiazonic acid (CPA; 4 mu mol /l) affects Ca2+ handling mechanisms in the excised Langendorff-perfused ra t whole-heart preparation. The short-term (for 3 to 6 min after onset of th e infusion) CPA infusion de-creased VO2 proportionally to the decrease in P VA, The long-term (for 9 to 12 min after the short-term CPA infusion) CPA i nfusion gradually increased VO2 almost to the control level with an increas e in PVA, The increases in both VO2 and PVA during this infusion were compl etely abolished by a Na+/Ca2+ exchanger inhibitor, 3 ' ,4 ' -dichlorobenzam il, indicating the contribution of Na+/Ca2+ exchanger to the increases in V O2 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 i nfusion. All these results suggest the possibility of the contribution of g reater energy-wasting Ca2+ extrusion processes (such as Na+/K+-ATPase coupl ed to the Na+/Ca2+ exchanger; its stoichiometry is 1 ATP:1 Ca2+) to the lar ger oxygen cost of left ventricular contractility.