title: YC-1, a benzyl indazole derivative, stimulates vascular cGMP and inhibits neointima formation.
abstract: The pathobiologic process of arterial stenosis following balloon angioplasty continues to be an enigmatic problem in clinical settings. This research project investigates the ability of YC-1, a benzyl indazole derivative that sensitizes sGC/cGMP, to stimulate endogenous cGMP and attenuate balloon injury-induced neointima (NI) formation in the rat carotid artery. Northern and Western blot analyses revealed enhanced acute expression of iNOS and inducible heme oxygenase (HO-1) mRNA and protein in the injured artery. The contralateral uninjured artery also demonstrated acute HO-1 mRNA and protein induction without detectable iNOS expression. Perivascular application of YC-1 immediately following injury significantly stimulated acute vessel wall cGMP compared to untreated controls. YC-1 treated sections demonstrated significant reduction in NI area (-74%), NI area/medial wall area (-72%), and NI thickness (-76%) 2 weeks post-injury. These results directly implicate YC-1 as a potent new therapeutic agent capable of reducing post-angioplasty stenosis through endogenous CO- and/or NO-mediated, cGMP-dependent processes.
authors: Department of Medicine, Veterans Affairs Medical Center, Houston, Texas, 77030, USA.
authors: D A
authors: DA
authors: Tulis
authors: W
authors: W
authors: Durante
authors: K J
authors: KJ
authors: Peyton
authors: G B
authors: GB
authors: Chapman
authors: A J
authors: AJ
authors: Evans
authors: A I
authors: AI
authors: Schafer
mesh_terms: D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D020212:Carotid Artery Injuries / Q000209:etiology / Q000517:prevention & control; D016893:Carotid Stenosis / Q000503:physiopathology / Q000628:therapy; D006152:Cyclic GMP / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics; D051547:Heme Oxygenase-1; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012008:Recurrence; D014158:Transcription, Genetic / Q000187:drug effects; D017539:Tunica Intima / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*
chemical_list: D007191:Indazoles; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D006152:Cyclic GMP