title: Systemic hemodynamic function in humans with type 1 diabetes treated with protein kinase Cβ inhibition and renin-angiotensin system blockade: a pilot study.
abstract: The protein kinase Cβ (PKCβ) system has been implicated in the deleterious vascular responses to hyperglycemia and angiotensin II (Ang II) in experimental models of diabetes (DM). Whether these interactions are important in humans is unknown. Flow-mediated vasodilatation (FMD) was measured during clamped euglycemia and hyperglycemia, before and after randomization to PKCβ inhibition (ruboxistaurin; RBX, 32 mg daily, n = 13) or a placebo (n = 7) for 8 weeks in renin-angiotensin system (RAS) blockade-treated subjects with type 1 DM. Blood pressure responses to infused Ang II were measured before and after randomization to RBX or a placebo. The RBX and placebo groups displayed similar clinical characteristics. Before RBX, FMD declined in response to hyperglycemia (6.8% ± 2.8% to 4.9% ± 1.8%). This effect was reversed after treatment with RBX (5.6% ± 3.1% to 6.0% ± 1.6% (within-group change, p = 0.009 (ANOVA)). No changes were observed in the placebo group. Infused Ang II was associated with hypertensive responses in the RBX and placebo groups (p < 0.05 (ANOVA)), and RBX did not influence this effect. In conclusion, RBX blunted the effect of hyperglycemia on FMD, suggesting that PKCβ may modulate endothelial function in type 1 DM. The lack of effect on Ang II responses suggests that PKCβ inhibition may act through non-RAS pathways in humans with DM.
authors.affiliation: Division of Nephrology, Toronto General Hospital, University of Toronto, 585 University Ave, 8N-845, Toronto, ON M5G 2N2, Canada. david.cherney@uhn.on.ca
authors.forename: David Z I
authors.initials: DZ
authors.lastname: Cherney
authors.forename: Heather N
authors.initials: HN
authors.lastname: Reich
authors.forename: James W
authors.initials: JW
authors.lastname: Scholey
authors.forename: Vesta
authors.initials: V
authors.lastname: Lai
authors.forename: Cameron
authors.initials: C
authors.lastname: Slorach
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Bradley
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000008:administration & dosage / Q000494:pharmacology; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D015309:Glucose Clamp Technique / Q000379:methods / Q000706:statistics & numerical data; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D008297:Male; D008301:Maleimides / Q000494:pharmacology / Q000627:therapeutic use*; D010865:Pilot Projects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D064546:Protein Kinase C beta; D012084:Renin-Angiotensin System / Q000187:drug effects*
chemical_list: D000959:Antihypertensive Agents; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D000804:Angiotensin II; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta