Induction and maintenance of anesthesia typically causes myocardial depression in healthy patients presenting for cardiac surgery. Moreover, the diabetic patient presents the anesthesiologist with an even greater risk for adverse clinical outcomes during the pre-, peri- and post-operative periods due to pre-existing myocardial dysfunction associated with the disease. Intracellular free Ca2+ concentration ([Ca2+]i) and myofilament Ca2+ sensitivity are the two key factors regulating cardiomyocyte function. We previously demonstrated that the intravenous anesthetic, propofol, modifies cardiomyocyte contractile function via interactions with multiple signaling pathways. Several potential mediators may be involved including protein kinase C (PKC) and nitric oxide synthase (NOS). The overall working hypothesis of this investigation is that activation of individual PKC and/or NOS isoforms in myocardial cells mediate the cardiac contractile dysfunction observed in response to propofol and experimental diabetes.
I first tested the hypothesis that propofol stimulates PKC activation and translocation to distinct intracellular sites in cardiomyocytes where they can potentially alter [Ca2+]i and/or myofilament Ca2+ sensitivity. I then tested the hypothesis that PKC and/or NOS isoform expression was up-regulated in diabetic cardiomyocytes and whether an increase in their activity is responsible for the propofol-induced alterations in cellular signaling pathways regulating [Ca2+]i and/or myofilament Ca2+ sensitivity. Finally, I assessed the role of superoxide in regulating nitric oxide (NO) bioavailability, as well as cellular mechanisms leading to NOS activation in diabetic cardiomyocytes.
I observed that propofol stimulates translocation of PKC alpha, PKC delta, PKC epsilon and PKC zeta to distinct intracellular locations in cardiomyocytes. I also observed that [Ca2+]i and myofilament Ca2+ sensitivity is reduced in diabetic cardiomyocytes and that propofol causes a PKC- and NOS-dependent reduction in [Ca 2+]i and myofilament Ca2+ sensitivity. Propofol also prolongs cytosolic Ca2+ removal in diabetic cardiomyocytes via a PKC-dependent inhibition of the Na+/Ca2+ exchanger. Finally, NO bioavailability, eNOS phosphorylation and expression of heat shock protein 90 are decreased, while Akt phosphorylation is increased in diabetic cardiomyocytes. In diabetic rats, the decrease in cardiomyocyte NO bioavailability is rescued by intraperitoneal injection of superoxide dismutase. I suggest that increases in PKC and/or NO are important mediators of myocardial dysfunction observed in response to propofol and/or experimental diabetes.
|School:||Kent State University|
|School Location:||United States -- Ohio|
|Source:||DAI-B 78/11(E), Dissertation Abstracts International|
|Keywords:||Anesthesia, Cardiac, Diabetes, Nitric oxide, Protein kinase c|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be