title: Protein kinase C inhibition ameliorates functional endothelial insulin resistance and vascular smooth muscle cell hypersensitivity to insulin in diabetic hypertensive rats.
abstract: OBJECTIVE
  Insulin resistance, diabetes, and hypertension are considered elements of metabolic syndrome which is associated with vascular dysfunction. We investigated whether inhibition of protein kinase C (PKC) would affect vascular function in diabetic hypertensive (DH) rats.
  
  
  METHODS
  A combination of type 2 diabetes and arterial hypertension was produced in male Sprague Dawley rats by intrauterine protein deprivation (IUPD) followed by high salt diet. At the age of 32 weeks, DH rats were treated for 2 weeks with the angiotensin-converting enzyme inhibitor captopril (Capto, 30 mg/kg), PKC inhibitor ruboxistaurin (RBX, 50 mg/kg) or vehicle (n = 8 per group) and blood pressure was monitored using telemetry. At the end of experiments, femoral arteries were dissected, and vascular reactivity was evaluated with isovolumic myography.
  
  
  RESULTS
  The IUPD followed by high salt diet resulted in significant elevation of plasma glucose, plasma insulin, and blood pressure. Endothelium-dependent vascular relaxation in response to acetylcholine was blunted while vascular contraction in response to phenylephrine was enhanced in the DH rats. Neither Capto nor RBX restored endothelium-dependent vascular relaxation while both suppressed vascular contraction. Ex-vivo incubation of femoral arteries from control rats with insulin induced dose-response vasorelaxation while insulin failed to induce vasorelaxation in the DH rat arteries. In the control arteries treated with endothelial nitric oxide synthase inhibitor L-NAME, insulin induced vasoconstriction that was exacerbated in DH rats. Capto and RBX partially inhibited insulin-stimulated vascular contraction.
  
  
  CONCLUSIONS
  These findings suggest that PKC inhibition ameliorates functional endothelial insulin resistance and smooth muscle cell hypersensitivity to insulin, but does not restore acetylcholine-activated endothelium-dependent vasodilation in DH rats.
authors.affiliation: Department of Biomedical Engineering, Cellular and Integrative Physiology, Surgery, and Indiana Center for Vascular Biology and Medicine, Indiana University Purdue University, Indianapolis, IN 46202, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Lu
authors.forename: James S
authors.initials: JS
authors.lastname: Bean
authors.forename: Ghassan S
authors.initials: GS
authors.lastname: Kassab
authors.forename: Mark D
authors.initials: MD
authors.lastname: Rekhter
mesh_terms: D000704:Analysis of Variance; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology; D005263:Femoral Artery / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D008297:Male; D008301:Maleimides / Q000494:pharmacology*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D009213:Myography; D011488:Protein Deficiency / Q000150:complications / Q000196:embryology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary; D013686:Telemetry; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001786:Blood Glucose; D007211:Indoles; D007328:Insulin; D008301:Maleimides; D047428:Protein Kinase Inhibitors; D017673:Sodium Chloride, Dietary; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C099154:ruboxistaurin; D002216:Captopril; D011493:Protein Kinase C