title: The calpain inhibitor, A-705253, corrects penile nitrergic nerve dysfunction in diabetic mice.
abstract: Calpains, a superfamily of Ca(2+)-activated proteases, are associated with an array of physiological and pathological events, including susceptibility to diabetes. Recently, increased calpain activity has been linked to reduced endothelium-derived nitric oxide-mediated vasodilatation in diabetes. However, a similar mechanism for neuronal-derived nitric oxide has not been examined. Thus, the aim was to investigate effects of the calpain inhibitor A-705253, N-(1-benzyl-2-carbamoyl-2-oxoethyl)-2-[E-2-(4-diethyl-aminomethylphenyl)ethen-1-yl]benzamide, on nitrergic neurovascular function in diabetic mice. Diabetes was induced by streptozotocin; duration was 6 weeks. Intervention A-705253 treatment (30 mg/kg/day) was given for 2 weeks following 4 weeks of untreated diabetes. After 6 weeks of diabetes, corpus cavernosa were isolated in organ baths for measurement of agonist- and electrical stimulation-evoked smooth muscle tensions. Adrenergic nerve- and phenylephrine-mediated contractions were not altered by diabetes or calpain inhibition. In contrast, maximum nitrergic nerve-mediated relaxation of phenylephrine-precontracted cavernosum was approximately 29% reduced by diabetes (P<0.001). This neurological deficit was 66% corrected by A-705253 treatment (P<0.05). Maximum nitric oxide-mediated endothelium-dependent relaxation to acetylcholine was attenuated approximately 39% by diabetes (P<0.01). Similarly, maximum endothelium-independent relaxation to the nitric oxide donor, sodium nitroprusside, was blunted approximately 23% by diabetes (P<0.001). A-705253 treatment partially improved endothelium-dependent relaxation to acetylcholine but had no effect on the deficit in response to nitroprusside. The data suggest that calpain contributes to the aetiology of diabetic nitrergic autonomic neuropathy and endothelial dysfunction, which may provide a novel therapeutic target for neurovascular complications.
authors.affiliation: School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, United Kingdom.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Nangle
authors.forename: Mary A
authors.initials: MA
authors.lastname: Cotter
authors.forename: Norman E
authors.initials: NE
authors.lastname: Cameron
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001549:Benzamides / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D002154:Calpain / Q000037:antagonists & inhibitors*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D008297:Male; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D026602:Nitrergic Neurons / Q000187:drug effects* / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D009929:Organ Size; D010413:Penis / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology; D010656:Phenylephrine / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C500488:A-705253; D001549:Benzamides; D001786:Blood Glucose; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D010656:Phenylephrine; D002154:Calpain; D000109:Acetylcholine