Propofol decreases myofilament Ca 2+ sensitivity via a protein kinase C-, nitric oxide synthase-dependent pathway in diabetic cardiomyocytes

Abstract

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 (TnI) phosphorylation were assessed in [ 32P]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 TnI phosphorylation was greater (32 ± 6%) in diabetic myofibrils compared with normal. Propofol reduced actomyosin adenosine triphosphatase activity by 17 ± 7% and increased TnI phosphorylation in diabetic myofibrils. PKC inhibition prevented the propofol-induced increase in TnI phosphorylation and decrease in shortening. Expression of PKC-α, PKC-δ, PKC-ε, 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 TnI 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. © 2006 American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.