The effects of 5-hydroxytryptamine 5-HT2 receptor antagonists on nerve conduction velocity and endoneurial perfusion in diabetic rats.
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 5HT2 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.
Cameron
Norman E
NE
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD Aberdeen, Scotland, UK. n.e.cameron@abdn.ac.uk
Cotter
Mary A
MA
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009431:Neural Conduction / Q000187:drug effects* / Q000502:physiology; D010525:Peripheral Nerves / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044348:Receptors, Serotonin, 5-HT2 / Q000502:physiology; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists