Protein kinase C beta inhibition and aorta and corpus cavernosum function in streptozotocin-diabetic mice.
Increased activity of the beta-isoform of protein kinase C (PKC) has been linked to the vascular and neural complications of diabetes mellitus. Treatment with the PKCbeta inhibitor, (s)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1H,13H-dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecene-1,3(2H)-dione, (LY333531), improves somatic nerve function and blood flow in diabetic rats. The aim was to assess whether LY333531 treatment could prevent nitric oxide-dependent autonomic nerve and vascular dysfunction in a diabetic mouse model. Diabetes was induced by streptozotocin; duration was 4 weeks. Aorta and corpus cavernosum were isolated and mounted in organ baths and agonist or electrical stimulation-evoked nerve-mediated tension responses were examined. Maximum nitric oxide-mediated endothelium-dependent relaxation of phenylephrine-precontracted aorta and cavernosum to acetylcholine were more than 30% reduced by diabetes. LY333531 treatment (10 mg kg(-1) day(-1)) completely prevented the diabetic deficit in cavernosum, and 75% prevented the deficit in aorta. Maximum nitric oxide-dependent non-adrenergic, non-cholinergic (NANC) nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 43% reduced by diabetes; LY333531 attenuated the deficit by 44%. For diabetic aorta, but not cavernosum, sensitivity (EC50) to phenylephrine-mediated contraction was increased by approximately 0.85 log10 M units; LY333531 treatment completely prevented this effect. Thus, PKCbeta activation contributes to nitric oxide-dependent vascular and autonomic nerve dysfunction in diabetic mice and could prove suitable for further study in clinical trials of diabetic autonomic neuropathy and vasculopathy.
Nangle
Matthew R
MR
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Cotter
Mary A
MA
Cameron
Norman E
NE
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology*; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology; D010413:Penis / Q000187:drug effects / Q000201:enzymology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors* / Q000502:physiology; D064546:Protein Kinase C beta
D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; C099154:ruboxistaurin; D011493:Protein Kinase C; D064546:Protein Kinase C beta