Endothelial and neural regulation of skin microvascular blood flow in patients with diabetic peripheral neuropathy: effect of treatment with the isoform-specific protein kinase C beta inhibitor, ruboxistaurin.
OBJECTIVE
This article aims to study the effects of ruboxistaurin (RBX) on skin microvascular blood flow (SkBF) and evaluate the relationship between endothelial and neural control of SkBF in patients with diabetic peripheral neuropathy (DPN).


METHODS
We studied 11 placebo- and 9 RBX (32 mg/day)-treated patients who participated in a 1-year, double-masked, randomized, Phase 3 study of RBX for treatment of DPN sensory symptoms. Patients had type 1 or type 2 diabetes, a detectable sural sensory nerve action potential, and Neuropathy Total Symptom Score-6 (NTSS-6) >6 points. SkBF was measured by laser Doppler velocimetry, combined with iontophoresis of acetylcholine and sodium nitroprusside, at baseline, 3 months, and 1 year. Sensory symptoms and electrophysiology were also evaluated during the study. The relationship between endothelial and neural control of SkBF at baseline was assessed using linear regression.


RESULTS
No significant differences (RBX vs. placebo) were demonstrable for post-iontophoresis SkBF [fold increase from basal state (1 year): endothelium-dependent, 3.6 vs. 8.6; endothelium-independent, 3.7 vs. 2.0; C fiber-mediated, 1.7 vs. 2.0; P>.05] or sensory symptoms [NTSS-6 total score (1 year): 7.7 vs. 6.0 points; P=.4]. There were also no significant between-group differences in nerve conduction parameters, except for placebo peroneal nerve conduction velocity, which demonstrated a statistically significant improvement of unknown clinical importance (Z=2.1; P=.034). At baseline, C fiber-mediated vasodilatation correlated well with endothelium-dependent vasodilation (r=.7, P<.01) but not with endothelium-independent vasodilatation (r=-.1, P=.7).


CONCLUSIONS
RBX demonstrated no effect on SkBF or sensory symptoms after 1 year in this cohort. The correlation between C fiber-mediated and endothelium-dependent SkBF at baseline suggests that improving endothelial function could affect the microcirculation not only locally but also via the neurovascular arcade.
Brooks
Belinda
B
Diabetes Centre, Royal Prince Alfred Hospital, and Discipline of Medicine, The University of Sydney, Sydney, New South Wales, Australia. belinda@email.cs.nsw.gov.au
Delaney-Robinson
Carol
C
Molyneaux
Lynda
L
Yue
Dennis K
DK
D000328:Adult; D001783:Blood Flow Velocity / Q000187:drug effects*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology; D004594:Electrophysiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008297:Male; D008301:Maleimides / Q000627:therapeutic use*; D008833:Microcirculation / Q000187:drug effects*; D008875:Middle Aged; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D064546:Protein Kinase C beta; D012044:Regression Analysis; D012867:Skin / Q000098:blood supply* / Q000294:innervation
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta