Effect of chronic endothelin blockade on PKC isoform distribution in mesenteric arteries from diabetic rats.
Hemodynamic changes, including increased vasoconstriction and reduced blood flow have been detected in both human diabetic patients and in animal models of diabetes. We previously demonstrated that the endothelin (ET) system was upregulated and involved in mediating the exaggerated vasoconstrictor responses in superior mesenteric artery (SMA) from diabetic rats. Chronic treatment of diabetic rats with the dual endothelin receptor antagonist, bosentan abolished the enhanced contractile responses in diabetic SMA. The biological actions of ET-1 have been shown to be coupled to the hydrolysis of phosphotidylinositol 4,5-biphosphate and phosphotidylcholine and the subsequent production of diacylglycerol (DAG). DAG is an activator of the classical and novel isoforms of PKC. Increases in PKC activity, associated with translocation of specific PKC isoforms from the cytosol to the membrane, have been implicated in the vasoconstrictor effect of ET-1. The goal of the present study was to determine whether chronic treatment of diabetic rats with bosentan influences the activation of specific PKC isoforms in SMA from diabetic rats. Elevated levels of PKCbeta2 in both the cytosol and membrane fractions and PKCepsilon in the membrane fraction were detected in SMA from diabetic rats. However, neither the levels nor the distribution between the cytosol and membrane fractions of any of these PKC isoforms were affected by the treatment of the diabetic rats with bosentan. These observations indicate that bosentan improves vascular reactivity in STZ-diabetic rats by mechanisms other than correction of increased activities of PKC isoforms.
Jiang
Jihong
J
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Zhang
Lili
L
Macleod
Kathleen M
KM
McNeill
John H
JH
D000818:Animals; D000077300:Bosentan; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology*; D065128:Endothelin Receptor Antagonists; D004790:Enzyme Induction / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D017538:Mesenteric Artery, Superior / Q000201:enzymology*; D011493:Protein Kinase C / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology; D013449:Sulfonamides / Q000494:pharmacology
D065128:Endothelin Receptor Antagonists; D007527:Isoenzymes; D013449:Sulfonamides; D011493:Protein Kinase C; D000077300:Bosentan