Mechanisms of vascular preservation by a novel NO donor following rat carotid artery intimal injury.
We studied the effects of a novel organic nitric oxide (NO) donor, 4-hydroxymethyl-furazan-3-carboxylic acid-2-oxide (CAS-1609), in a rat carotid artery intimal injury model. The NO donor, CAS-1609, or its non-NO-donating control compound, 4-hydroxymethyl-furazan-3-carboxylic acid (C-93-4845), was infused intravenously at 30 micrograms/day. Seven days after injury, carotid artery rings contracted only 56 +/- 6 mg to NG-nitro-L-arginine methyl ester in C-93-4845-treated rats, compared with 120 +/- 17 mg in CAS-1609-treated rats (P < 0.02), indicating a preservation of endogenous NO release. Improved responses to the endothelium-dependent dilator, acetylcholine, also occurred in injured arteries treated with CAS-1609. Morphometric analysis of injured carotid arteries given the inactive compound showed marked intimal thickening with an intimal-to-medial ratio (I/M) of 0.76 +/- 0.02, compared with a significantly lower I/M of 0.32 +/- 0.04 (P < 0.01) in injured carotid arteries given CAS-1609. Additionally, CAS-1609 was found to have a concentration-dependent stimulatory effect on cultured rat aortic endothelial cell proliferation (P < 0.01) but and inhibitory effect on platelet-derived growth factor-BB (10 ng/ml)-stimulated rat aortic smooth muscle cell proliferation (P < 0.01). This is the first study to demonstrate that NO plays a dual role in vascular cell proliferation, stimulating endothelial cells but inhibiting smooth muscle cell proliferation. This dual effect of NO on cell proliferation is associated with an in vivo reduction in neointimal thickening and an acceleration of endothelial recovery determined by both anatomic and functional methods.
Guo
J P
JP
Department of Physiology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
Panday
M M
MM
Consigny
P M
PM
Lefer
A M
AM
D000818:Animals; D002339:Carotid Arteries / Q000187:drug effects* / Q000503:physiopathology; D020212:Carotid Artery Injuries; D002455:Cell Division / Q000187:drug effects; D004730:Endothelium, Vascular / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009569:Nitric Oxide / Q000502:physiology*; D010069:Oxadiazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000293:injuries* / Q000473:pathology; D014665:Vasodilator Agents / Q000494:pharmacology*; D014949:Wounds, Nonpenetrating / Q000473:pathology / Q000503:physiopathology
C094475:4-hydroxynethyl-furoxan-3-carboxamide; D010069:Oxadiazoles; D014665:Vasodilator Agents; D009569:Nitric Oxide