Ca2+ handling in excitation-contraction coupling requires considerable O2 consumption (Vo 2) in cardiac contraction. We have developed an integrative method to quantify total Ca2+ handling in normal hearts. However, its direct application to failing hearts, where futile Ca2+ cycling via the Ca2+-leaky sarcoplasmic reticulum (SR) required an increased Ca2+handling Vo 2, was not legitimate. To quantify total Ca2+ handling even in such failing hearts, we combined futile Ca2+ cycling with Ca2+ handling Vo 2 and the internal Ca2+ recirculation fraction via the SR. We applied this method to the canine heart mechanoenergetics before and after intracoronary ryanodine at nanomolar concentrations. We found that total Ca2+ handling per beat was halved after the ryanodine treatment from ∼60 μmol/kg left ventricle before ryanodine. We also found that futile Ca2+ cycling via the SR increased to >1 cycle/beat after ryanodine from presumably zero before ryanodine. These results support the applicability of the present method to the failing hearts with futile Ca2+ cycling via the SR.

We studied whether intracoronary Ca administration after beta-blockade would increase the internal Ca recirculation fraction (RF) analogously to the Ca administration before beta-blockade. This was performed in excised cross-circulated canine hearts. We analyzed the exponential decay component of the postextrasystolic potentiation (PESP) following a spontaneous extrasystole. All the PESPs decayed in alternans with atrial pacing at a constant rate. We obtained the time constant (tau(e)) of the monoexponential decay component of the alternans PESP. An increment of intracoronary Ca by 1.5 mmol/l enhanced the left ventricular contractility index Emax (end-systolic maximum elastance) by 2.5 times before and after beta-blockade with propranolol. The intracoronary Ca after beta-blockade slightly but significantly increased tau(e), and hence increased RF calculated from tau(e) by RF = exp(-1/tau(e)). This was analogous to the slightly increased tau(e) and RF with Ca before beta-blockade. We speculate that the myocardial cyclic AMP-dependent phosphorylation level would not significantly alter the effect of intracoronarily administered Ca on myocardial Ca handling, in terms of tau(e) and RF.

We investigated the effects of intracoronary Ca2+ and epinephrine on the intracellular Ca2+ recirculation fraction (RF) and total Ca2+ handling in the left ventricle (LV) of the excised cross-circulated canine heart preparation. We analyzed LV postextrasystolic potentiation (PESP) following a spontaneous extrasystole that occurred sporadically under constant atrial pacing. All PESPs decayed in alternans and none decayed monotonically. We extracted an exponential decay component from the alternans PESP, determined its beat constant (taue), and calculated RF = exp(-1/taue). Increased intracoronary Ca2+ slightly increased taue and RF, but epinephrine did not change them, although both agents enhanced LV contractility 2-3 times. Neither Ca2+ nor epinephrine affected the sinusoidal decay of the alternans PESP. These results indicate that RF via the sarcoplasmic reticulum was slightly augmented by Ca2+, but not by epinephrine. We combined these RF data with LV Ca2+ handling O2 consumption data and obtained 40-110 micromol/kg as the total amount of Ca2+ handled in one cardiac cycle in the control and enhanced contractile states. These results indicate that this new LV-level approach seems to better the understanding of the Ca2+ mass dynamics responsible for the mechanoenergetics enhanced by inotropic interventions.

We investigated the effects of myocardial temperature on left ventricular (LV) mechanoenergetics in the excised, cross-circulated canine heart. We used the framework of the LV contractility ( E max)-pressure-volume area (PVA; a measure of total mechanical energy)-myocardial oxygen consumption (Vo 2) relationship. We have shown this framework to be useful to integrative analysis of the mechanoenergetics of a beating heart. In isovolumic contractions at a constant pacing rate, increasing myocardial temperature from 30 to 40°C depressed E max and increased the oxygen cost of E max, which was enhanced by dobutamine, in a linear manner. However, the slope of the Vo 2-PVA relation (reciprocal of contractile efficiency) and its Vo 2intercept remained constant. Q10values of E max, the oxygen cost of E max, and the oxygen cost of PVA were 0.4, 2.1 and 1.0, respectively, around normothermia. We conclude that the temperature-dependent processes of cross-bridge cycling and Ca2+handling integratively depress E max and augment its oxygen cost without affecting the oxygen cost of PVA as myocardial temperature increases by 10°C around normothermia.