The effects of 5-hydroxytryptamine 5-HT2 receptor antagonists on nerve conduction velocity and endoneurial perfusion in diabetic rats

Norman E Cameron, Mary Anne Cotter

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Reduced peripheral nerve perfusion participates in the aetiology of diabetic neuropathy. 5-Hydroxtryptamine causes vasa nervorum vasoconstriction and platelet aggregation, which are enhanced by diabetes. To assess whether these mechanisms could contribute to neuropathy, the effects of 5-hydroxytryptamine 5-HT2 receptor antagonist treatment were examined in streptozotocin-induced diabetic rats.

One study determined the dose-response relationship for AT1015 (N-[2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate). Two weeks AT1015 treatment after 6 weeks of diabetes dose-dependently corrected 19.7%, 54.1%, and 15.7% deficits in sciatic nerve motor conduction velocity and blood flow, and saphenous nerve sensory conduction: ED50 values were 0.52, 0.74 and 0.15 mg/kg(-1)/day(-1), respectively.

In a second study, high-dose AT1015 (3 mg/kg(-1)/day(-1)) actions were compared with those of the 5HT(2) receptor antagonists, ritanserin (10 mg/kg(-1)/day(-1)) and sarpogrelate (100 mg/kg(-1)/day(-1)), and the anti-platelet phosphodiesterase III inhibitor, cilostazol (100 mg/kg(-1)/day(-1)). Two weeks treatment with these drugs produced a marked correction (82.6-99.7%) of a 19.8% sciatic motor conduction deficit in diabetic rats. Similarly, 44.7% and 14.9% reductions in sciatic endoneurial blood flow and saphenous sensory conduction velocity were completely reversed. Thus, 5-HT2 receptor antagonists had marked beneficial effects in experimental diabetic neuropathy, and AT1015 appears suitable for further evaluation in clinical trials.

Original languageEnglish
Pages (from-to)607-614
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume367
Issue number6
DOIs
Publication statusPublished - 2003

Keywords

  • neuropathy
  • diabetic rat
  • serotonin
  • 5HT(2) receptors
  • nerve conduction
  • blood flow
  • ALDOSE REDUCTASE INHIBITION
  • PERIPHERAL-NERVE
  • BLOOD-FLOW
  • NITRIC-OXIDE
  • OXYGEN-TENSION
  • SCIATIC-NERVE
  • NEUROPATHY
  • RESPONSES
  • ARTERIES
  • DEFICITS

Cite this

The effects of 5-hydroxytryptamine 5-HT2 receptor antagonists on nerve conduction velocity and endoneurial perfusion in diabetic rats. / Cameron, Norman E; Cotter, Mary Anne.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 367, No. 6, 2003, p. 607-614.

Research output: Contribution to journalArticle

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N2 - Reduced peripheral nerve perfusion participates in the aetiology of diabetic neuropathy. 5-Hydroxtryptamine causes vasa nervorum vasoconstriction and platelet aggregation, which are enhanced by diabetes. To assess whether these mechanisms could contribute to neuropathy, the effects of 5-hydroxytryptamine 5-HT2 receptor antagonist treatment were examined in streptozotocin-induced diabetic rats.One study determined the dose-response relationship for AT1015 (N-[2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate). Two weeks AT1015 treatment after 6 weeks of diabetes dose-dependently corrected 19.7%, 54.1%, and 15.7% deficits in sciatic nerve motor conduction velocity and blood flow, and saphenous nerve sensory conduction: ED50 values were 0.52, 0.74 and 0.15 mg/kg(-1)/day(-1), respectively.In a second study, high-dose AT1015 (3 mg/kg(-1)/day(-1)) actions were compared with those of the 5HT(2) receptor antagonists, ritanserin (10 mg/kg(-1)/day(-1)) and sarpogrelate (100 mg/kg(-1)/day(-1)), and the anti-platelet phosphodiesterase III inhibitor, cilostazol (100 mg/kg(-1)/day(-1)). Two weeks treatment with these drugs produced a marked correction (82.6-99.7%) of a 19.8% sciatic motor conduction deficit in diabetic rats. Similarly, 44.7% and 14.9% reductions in sciatic endoneurial blood flow and saphenous sensory conduction velocity were completely reversed. Thus, 5-HT2 receptor antagonists had marked beneficial effects in experimental diabetic neuropathy, and AT1015 appears suitable for further evaluation in clinical trials.

AB - Reduced peripheral nerve perfusion participates in the aetiology of diabetic neuropathy. 5-Hydroxtryptamine causes vasa nervorum vasoconstriction and platelet aggregation, which are enhanced by diabetes. To assess whether these mechanisms could contribute to neuropathy, the effects of 5-hydroxytryptamine 5-HT2 receptor antagonist treatment were examined in streptozotocin-induced diabetic rats.One study determined the dose-response relationship for AT1015 (N-[2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate). Two weeks AT1015 treatment after 6 weeks of diabetes dose-dependently corrected 19.7%, 54.1%, and 15.7% deficits in sciatic nerve motor conduction velocity and blood flow, and saphenous nerve sensory conduction: ED50 values were 0.52, 0.74 and 0.15 mg/kg(-1)/day(-1), respectively.In a second study, high-dose AT1015 (3 mg/kg(-1)/day(-1)) actions were compared with those of the 5HT(2) receptor antagonists, ritanserin (10 mg/kg(-1)/day(-1)) and sarpogrelate (100 mg/kg(-1)/day(-1)), and the anti-platelet phosphodiesterase III inhibitor, cilostazol (100 mg/kg(-1)/day(-1)). Two weeks treatment with these drugs produced a marked correction (82.6-99.7%) of a 19.8% sciatic motor conduction deficit in diabetic rats. Similarly, 44.7% and 14.9% reductions in sciatic endoneurial blood flow and saphenous sensory conduction velocity were completely reversed. Thus, 5-HT2 receptor antagonists had marked beneficial effects in experimental diabetic neuropathy, and AT1015 appears suitable for further evaluation in clinical trials.

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KW - OXYGEN-TENSION

KW - SCIATIC-NERVE

KW - NEUROPATHY

KW - RESPONSES

KW - ARTERIES

KW - DEFICITS

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SP - 607

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JO - Naunyn-Schmiedeberg's Archives of Pharmacology

JF - Naunyn-Schmiedeberg's Archives of Pharmacology

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