High calcium and dobutamine positive inotropy in the perfused mouse heart: myofilament calcium responsiveness, energetic economy, and effects of protein kinase C inhibition.
BACKGROUND
In perfused hearts, high calcium-induced inotropy results in less developed pressure relative to myocardial oxygen consumption compared to the beta-adrenergic agonist dobutamine. Calcium handling is an important determinant of myocardial oxygen consumption. Therefore, we hypothesized that this phenomenon was due to reduced myofilament responsiveness to calcium, related to protein kinase C activation.


RESULTS
Developed pressure was significantly higher with dobutamine compared to high perfusate calcium of 3.5 mM (73 +/- 10 vs 63 +/- 10 mmHg, p < 0.05), though peak systolic intracellular calcium was not significantly different, suggesting reduced myofilament responsiveness to intracellular calcium with high perfusate calcium. The ratio of developed pressure to myocardial oxygen consumption, an index of economy of contraction, was significantly increased with dobutamine compared to high perfusate calcium (1.35 +/- 0.15 vs 1.15 +/- 0.15 mmHg/micromoles/min/g dry wt, p < 0.05), suggesting energetic inefficiency with high perfusate calcium. The specific protein kinase C inhibitor, chelerythrine, significantly attenuated the expected increase in developed pressure when increasing perfusate calcium from 2.5 to 3.5 mM (3.5 mM: 64 +/- 8 vs 3.5 mM + chelerythrine: 55 +/- 5 mmHg, p < 0.05), though had no effects on dobutamine, or lower levels of perfusate calcium (1.5 to 2.5 mM).


CONCLUSIONS
By measuring intracellular calcium, developed pressures and myocardial oxygen consumption in perfused mouse hearts, these results demonstrate that high perfusate calcium positive inotropy compared to dobutamine results in reduced myofilament responsiveness to intracellular calcium, which is associated with energetic inefficiency and evidence of protein kinase C activation.
MacGowan
G A
GA
Cardiovascular Institute, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA. macgowanga@msx.upmc.edu
Du
C
C
Koretsky
A P
AP
D008841:Actin Cytoskeleton / Q000378:metabolism*; D000470:Alkaloids; D000818:Animals; D053119:Benzophenanthridines; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004280:Dobutamine / Q000494:pharmacology*; D004734:Energy Metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D008297:Male; D051379:Mice; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D009924:Organ Culture Techniques; D010101:Oxygen Consumption; D010617:Phenanthridines / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*
D000470:Alkaloids; D053119:Benzophenanthridines; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D010617:Phenanthridines; D004280:Dobutamine; C016299:chelerythrine; D011493:Protein Kinase C; D002118:Calcium