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Propofol decreases myofilament Ca2+ sensitivity via a protein kinase C-, nitric oxide synthase-dependent pathway in
Peter J Wickley1, Toshiya Shiga, Paul A Murray
1Kent State University, Kent, Ohio, USA.
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 Ca2+ concentration ([Ca2+]i), and myofilament Ca2+ sensitivity.
Methods:
Freshly isolated ventricular myocytes were obtained from normal and diabetic rat hearts. [Ca2+]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 microM) decreased peak shortening by 47 +/- 6% with little effect on peak [Ca2+]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-alpha, PKC-delta, PKC-epsilon, 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 Ca2+ sensitivity and, to a lesser extent, peak [Ca2+]i are decreased in diabetic cardiomyocytes. Increases in PKC and NOS expression in combination with TnI phosphorylation seem to contribute to the decrease in [Ca2+]i and myofilament Ca2+ sensitivity. Propofol decreases [Ca2+]i and shortening via a PKC-, NOS-dependent pathway.
Insights
Propofol impairs diabetic heart function by reducing calcium sensitivity via protein kinase C and nitric oxide synthase pathways. This study clarifies propofol
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Diabetic cardiomyopathy is associated with altered cardiomyocyte function.
- Protein kinase C (PKC) and nitric oxide synthase (NOS) are implicated in cardiac regulation.
Purpose of the Study:
- To investigate the roles of PKC and NOS in propofol's effects on diabetic cardiomyocyte contractility.
- To assess propofol's impact on intracellular calcium ([Ca2+]i) and myofilament calcium sensitivity in diabetes.
Main Methods:
- Isolated ventricular myocytes from normal and diabetic rats were used.
- Cell shortening, [Ca2+]i, and actomyosin ATPase activity were measured.
- PKC and NOS expression, and troponin I (TnI) phosphorylation were analyzed.
Main Results:
- Propofol reduced contractility and actomyosin ATPase activity in diabetic myocytes.
- Diabetic myocytes showed increased TnI phosphorylation and altered PKC/NOS expression.
- PKC and NOS inhibition partially reversed propofol's negative effects.
Conclusions:
- Propofol impairs diabetic cardiomyocyte function through PKC- and NOS-dependent mechanisms.
- Reduced myofilament calcium sensitivity and [Ca2+]i contribute to these effects.
- Altered PKC/NOS expression and TnI phosphorylation are key in diabetic hearts.
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