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

Matthew Robert Nangle, Mary Anne Cotter, Norman E Cameron

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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-l,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 log(10) 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. (C) 2003 Elsevier B.V. All rights reserved.

Original languageEnglish
Pages (from-to)99-106
Number of pages7
JournalEuropean Journal of Pharmacology
Volume475
Issue number1-3
DOIs
Publication statusPublished - 2003

Keywords

  • protein kinase C
  • diabetes mellitus
  • endothelium
  • smooth muscle
  • NANC (non-adrenergic
  • non-cholinergic) nerve
  • nitric oxide (NO)
  • aorta
  • corpus cavernosum
  • ENDOTHELIUM-DEPENDENT RELAXATION
  • NITRIC-OXIDE SYNTHASE
  • SMOOTH-MUSCLE
  • BLOOD-FLOW
  • RATS
  • DYSFUNCTION
  • MELLITUS
  • GLUCOSE
  • VASODILATION
  • CONTRACTION

Cite this

Protein kinase C beta inhibition and aorta and corpus cavernosum function in streptozotocin-diabetic mice. / Nangle, Matthew Robert; Cotter, Mary Anne; Cameron, Norman E.

In: European Journal of Pharmacology, Vol. 475, No. 1-3, 2003, p. 99-106.

Research output: Contribution to journalArticle

Nangle, Matthew Robert ; Cotter, Mary Anne ; Cameron, Norman E. / Protein kinase C beta inhibition and aorta and corpus cavernosum function in streptozotocin-diabetic mice. In: European Journal of Pharmacology. 2003 ; Vol. 475, No. 1-3. pp. 99-106.
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N2 - 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-l,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 log(10) 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. (C) 2003 Elsevier B.V. All rights reserved.

AB - 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-l,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 log(10) 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. (C) 2003 Elsevier B.V. All rights reserved.

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KW - aorta

KW - corpus cavernosum

KW - ENDOTHELIUM-DEPENDENT RELAXATION

KW - NITRIC-OXIDE SYNTHASE

KW - SMOOTH-MUSCLE

KW - BLOOD-FLOW

KW - RATS

KW - DYSFUNCTION

KW - MELLITUS

KW - GLUCOSE

KW - VASODILATION

KW - CONTRACTION

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DO - 10.1016/S0014-2999(03)02113-7

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VL - 475

SP - 99

EP - 106

JO - European Journal of Pharmacology

JF - European Journal of Pharmacology

SN - 0014-2999

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