YC-1, a benzyl indazole derivative, stimulates vascular cGMP and inhibits neointima formation.
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.
Tulis
D A
DA
Department of Medicine, Veterans Affairs Medical Center, Houston, Texas, 77030, USA.
Durante
W
W
Peyton
K J
KJ
Chapman
G B
GB
Evans
A J
AJ
Schafer
A I
AI
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*
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