Ryanodine wastes oxygen consumption for Ca2+ handling in the dog heart. A new pathological heart model.
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.
Department of Cardiovascular Dynamics, National Cardiovascular Center, Osaka, Japan.
T
T
Takasago
Y
Y
Goto
O
O
Kawaguchi
K
K
Hata
A
A
Saeki
T
T
Nishioka
H
H
Suga
D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology*; D002122:Calcium Chloride / Q000494:pharmacology; D002395:Catecholamines / Q000097:blood; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects*; D012433:Ryanodine / Q000494:pharmacology*
D015220:Calcium Channels; D002395:Catecholamines; D012433:Ryanodine; D002122:Calcium Chloride; D002118:Calcium