Perivascular Delivery Of A Nitric Oxide Donor Inhibits Neointimal Hyperplasia In Vein Grafts Implanted In The Arterial Circulation

Abstract

The periadventitial delivery of nitric oxide donor produces a reduction of neointimal hyperplasia in veins implanted in the arterial circulation. The mechanism of action is not entirely clear, but the reduction cannot be explained on the basis of decreased cell proliferation alone. Other possibilities are modulation of protein synthesis of vascular smooth muscle cells and production of extracellular matrix components.

Beneficial effect of a short-acting NO donor for the prevention of neointimal hyperplasia

“…Previous studies have augmented NO levels, however, these alternative means of NO supplementation have not made it to the clinical arena due to several limitations. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]35] Systemic administration of NO is rapidly inactivated by hemoglobin in the circulating blood resulting in limited bioavailability. To overcome this limitation, larger doses of the NO donor must be administered systemically; however, these larger doses can produce adverse systemic hemodynamic and hemostatic effects, thereby precluding administration of biologically effective doses of NO.…”

“…[12,25,27] Chaux et al delivered SPER/NO in a biodegradable polymer to the external surface of vein grafts in hypercholesterolemic rabbits and found a 41% reduction in vein graft hyperplasia at 28 days. [23] Masters et al delivered a NO-releasing hydrogel covalently modified with a S-nitrocysteine and showed 75% inhibition of neointimal hyperplasia at 14 days in the rat carotid artery injury model. [35] Our periadventitial therapy resulted in greater than 90% inhibition of neointimal hyperplasia.…”

“…While Kaul et al and Chaux et al demonstrated efficacy with periadventital delivery of SPER/NO, SPER/NO dissociates into NO and spermine, the latter of which has biologically active properties that may not be beneficial to the vasculature. [23,25,39] Despite the significant efficacy of our therapies, some limitations exist. Most polymers, despite the rapid improvements in their safety profile, still carry some adverse reactions.…”

“…All animal procedures were performed in accordance with principles outlined in the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication 85- 23,1996) and approved by the Northwestern University Animal Care and Use Committee. Adult male Sprague-Dawley rats (Harlan, Indianapolis, IN) weighing 350-400 grams were anesthetized with inhaled isofluorane (0.5-2%).…”

“…This has been demonstrated in numerous animal models which have utilized varying NO delivery methods including inhalational NO, delivery of the substrate L-arginine, delivery of NO-donors systemically or locally, gene therapy with endothelial NO synthase (eNOS) or inducible NO synthase (iNOS), and polymer-based approaches of NO-donor delivery. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] All of these therapies have demonstrated varying degrees of success, yet none have been used in the clinical arena due to significant side effects, safety concerns, complexity of administration and, sometimes, lack of significant and durable effect.…”