Extracellular Ca2+ is obligatory for ouabain-induced potentiation of cardiac basal energy expenditure.
1. The method of action of cardiac glycosides is commonly explained by the 'pump-inhibition hypothesis': inhibition of the Na+/K+-ATPase allows [Na+]i to rise, eventually reversing Na+/Ca2+ exchange. The resulting influx of Ca2+o increases [Ca2+]i, thereby activating intracellular Ca2+-dependent ATPases and, hence, energy demand. This sequence has been presumed to occur during diastole as well as systole. However, it has been reported that dihydro-ouabain-induced potentiation of heat production by quiescent ventricular trabeculae persists in the absence of Ca2+o. This implies that the pump-inhibition hypothesis is inapplicable during diastole. 2. We tested this implication by: (i). measuring the rate of oxygen consumption (Vo2) of arrested guinea-pig whole-hearts; (ii). measuring[Ca2+]i in quiescent ventricular trabeculae; and (iii). mathematical modelling using software (Oxsoft Heart, Oxford Software, Oxford, UK) based on DiFrancesco-Noble formalism. 3. Upon induction of arrest, whole heart Vo2 fell to one-quarter of its 'beating' value. Subsequent perfusion with ouabain (20 micromol/L), in the presence of Ca2+o, increased Vo2 fourfold. This increase was prevented by withholding Ca2+o. Comparable results were obtained in quiescent trabeculae: ouabain increased [Ca2+]i only if Ca2+o was present. Mathematical modelling readily simulated these experimental results. 4. We conclude that influx of Ca2+o is mandatory for potentiation of cardiac basal metabolism by cardiac glycosides.
Guild
S-J
SJ
Department of Physiology, Faculty of Medical, University of Auckland, Auckland, New Zealand.
Ward
M-L
ML
Cooper
P J
PJ
Hanley
P J
PJ
Loiselle
D S
DS
D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D010042:Ouabain / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D011189:Potassium Chloride / Q000494:pharmacology
D002316:Cardiotonic Agents; D010042:Ouabain; D011189:Potassium Chloride; D002118:Calcium