Thermodynamic limitation for Ca2+ handling contributes to decreased contractile reserve in rat hearts.
The free energy release from ATP hydrolysis (|DeltaG approximately p|) is decreased by inhibiting the creatine kinase (CK) reaction, which may limit the thermodynamic driving force for the sarcoplasmic reticulum (SR) Ca2+ pumps and thereby cause a decrease in contractile reserve. To determine whether a decrease in |DeltaG approximately p| results in decreased contractile reserve by impairing Ca2+ handling, we measured left ventricular pressure and cytosolic Ca2+concentration ([Ca2+]c; by indo 1 fluorescence) in isolated perfused rat hearts, with >95% inhibition of CK with 90 micromol iodoacetamide. Iodoacetamide did not directly alter SR Ca2+-ATPase activity, baseline left ventricular developed pressure, or baseline [Ca2+]c. When perfusate Ca2+ concentration was increased from 1.2 to 3.3 mM, LV developed pressure increased from 67 +/- 6 to 119 +/- 8 mmHg in control hearts (P < 0.05) but did not significantly increase in CK-inhibited hearts. Similarly, the amplitude of the [Ca2+]c transient increased from 548 +/- 54 to 852 +/- 140 nM in control hearts (P < 0.05) but did not significantly increase in CK-inhibited hearts. We conclude that decreased |DeltaG approximately p| limits intracellular Ca2+ handling and thereby limits contractile reserve.
Tian
R
R
Nuclear Magnetic Resonance Laboratory for Physiological Chemistry, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Halow
J M
JM
Meyer
M
M
Dillmann
W H
WH
Figueredo
V M
VM
Ingwall
J S
JS
Camacho
S A
SA
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003402:Creatine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007460:Iodoacetamide / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000502:physiology*; D009994:Osmolar Concentration; D010477:Perfusion; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology; D013816:Thermodynamics; D016277:Ventricular Function, Left / Q000502:physiology
D004791:Enzyme Inhibitors; D003402:Creatine Kinase; D000252:Calcium-Transporting ATPases; D002118:Calcium; D007460:Iodoacetamide