Propofol decreases myofilament Ca2+ sensitivity via a protein kinase C-, nitric oxide synthase-dependent pathway in diabetic cardiomyocytes

Published on May 1, 2006in Anesthesiology6.42
· DOI :10.1097/00000542-200605000-00014
Peter J. Wickley7
Estimated H-index: 7
Toshiya Shiga12
Estimated H-index: 12
+ 1 AuthorsDerek S. Damron24
Estimated H-index: 24
Background: The authors' objective was to assess the role of protein kinase C (PKC) and nitric oxide synthase (NOS) in mediating the effects of propofol on diabetic cardiomyocyte contractility, intracellular free Ca 2+ concentration ([Ca 2+ ] i ), and myofilament Ca 2+ sensitivity. Methods: Freshly isolated ventricular myocytes were obtained from normal and diabetic rat hearts. [Ca 2+ ] i and cell shortening were simultaneously measured in electrically stimulated, ventricular myocytes using fura-2 and video-edge detection, respectively. Actomyosin adenosine triphosphatase activity and troponin I (Tnl) phosphorylation were assessed in [ 32 P]orthophosphate-labeled myofibrils. Western blot analysis was used to assess expression of PKC and NOS. Results: Propofol (10 μM) decreased peak shortening by 47 ± 6% with little effect on peak [Ca 2+ ] i (92 ± 5% of control) in diabetic myocytes. Maximal actomyosin adenosine triphosphatase activity was reduced by 43 ± 7% and Tnl phosphorylation was greater (32 ± 6%) in diabetic myofibrils compared with normal. Propofol reduced actomyosin adenosine triphosphatase activity by 17 ± 7% and increased Tnl phosphorylation in diabetic myofibrils. PKC inhibition prevented the propofol-induced increase in Tnl phosphorylation and decrease in shortening. Expression of PKC-α, PKC-δ, PKC-e, and constitutive NOS were up-regulated and inducible NOS was expressed in diabetic cardiomyocytes. NOS inhibition attenuated the propofol-induced decrease in shortening. Conclusion: Myofilament Ca 2+ sensitivity and, to a lesser extent, peak [Ca 2+ ] i are decreased in diabetic cardiomyocytes. Increases in PKC and NOS expression in combination with Tnl phosphorylation seem to contribute to the decrease in [Ca 2+ ] i and myofilament Ca 2+ sensitivity. Propofol decreases [Ca 2+ ] i and shortening via a PKC-, NOS-dependent pathway.
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