Protein kinase Cβ inhibition and aorta and corpus cavernosum function in streptozotocin-diabetic mice

Abstract

Increased activity of the β-isoform of protein kinase C (PKC) has been linked to the vascular and neural complications of diabetes mellitus. Treatment with the PKCβ inhibitor, ( s)-13-[(dimethylamino)methyl]-10,11,14,15-tetrahydro-4,9:16,21-dimetheno-1 H,13 H-dibenzo[ e, k]pyrrolo[3,4- h][1,4,13]oxadiazacyclohexadecene-1,3(2 H)-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 (EC 50) to phenylephrine-mediated contraction was increased by approximately 0.85 log 10 M units; LY333531 treatment completely prevented this effect. Thus, PKCβ 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.