Ryanodine wastes oxygen consumption for Ca2+ handling in the dog heart. A new pathological heart model.

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Abstract
Ryanodine (RYA) at a low concentration (several tens of nM) is known to selectively bind to Ca2+ release channels in sarcoplasmic reticulum (SR) and to fix them open. The present study was designed to investigate the effects of the selective change in Ca2+ release channel activity on cardiac mechanoenergetics as a model of Ca(2+)-leaky SR observed in pathological hearts. We analyzed the negative inotropic effect of RYA at a low concentration (up to 30 +/- 13 nM) on left ventricular (LV) mechanoenergetics using frameworks of LV Emax (a contractility index) and the myocardial oxygen consumption (LV VO2)-systolic pressure-volume area (PVA) (a measure of total mechanical energy) relation in 11 isolated, blood-perfused dog hearts. RYA significantly decreased Emax by 42%, whereas PVA-independent VO2 remained disproportionately high (93% of control). This oxygen-wasting effect of RYA was quite different from ordinary inotropic drugs, which alter Emax and PVA-independent VO2 proportionally. The present result suggests that RYA suppresses force generation of cardiac muscle for a given amount of total sequestered Ca2+ by SR in a similar way to myocardial ischemia and stunning. We speculate about the underlying mechanism that RYA makes SR leaky for Ca2+ and thereby wastes energy for Ca2+ handling by SR.