Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide.

Abstract

IntroductionEndothelium-derived relaxing factor is important for vascular homeostasis and possesses qualities that may modulate vascular injury, including vasodilation, platelet inhibition, and inhibition of smooth muscle proliferation. S-nitrososerum albumin is a naturally occurring adduct of nitric oxide (NO) with a prolonged biologic half-life and is a potent vasodilator and platelet inhibitor. Given the avidity of serum albumin for subendothelial matrix and the antiproliferative effects of NO, we investigated the effects of locally delivered S-nitroso-bovine serum albumin (S-NO-BSA) and a polythiolated form of bovine serum albumin (pS-BSA) modified to carry several S-nitrosothiol groups (pS-NO-BSA) on neointimal responses in an animal model of vascular injury.Locally delivered S-NO-BSA bound preferentially to denuded rabbit femoral vessels producing a 26-fold increase in local concentration compared with uninjured vessels (P = 0.029). pS-NO-BSA significantly reduced the intimal/medial ratio (P = 0.038) and did so in conjunction with elevations in platelet (P < 0.001) and vascular cGMP content (P < 0.001). pS-NO-BSA treatment also inhibited platelet deposition (P = 0.031) after denuding injury. Comparison of BSA, S-NO-BSA, pS-NO-BSA, and control revealed a dose-response relationship between the amount of displaceable NO delivered and the extent of inhibition of neointimal proliferation at 2 wk (P < 0.001).Local administration of a stable protein S-nitrosothiol inhibits intimal proliferation and platelet deposition after vascular arterial balloon injury. This strategy for the local delivery of a long-lived NO adduct has potential for preventing restenosis after angioplasty. (J. Clin. Invest. 1995Invest. . 96:2630Invest. -2638

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.…”

“…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.…”

Vascular biology and pathobiology of the liver: Report of a single-topic symposium

“…Local or systemic administration of NO donors and transfer of genes encoding NOS attenuate vascular injury through sGC activation. 5,6 Interestingly, gene transfer of the individual sGC subunits, sGC ␣1 and ␤1, further increase NO responsiveness in vascular injury models. 7 New NO-independent pharmacologic activators of sGC, such as BAY41-2272 and BAY 58-2667, also have a remarkable ability to stimulate sGC and thus to selectively dilate blood vessels.…”

Experimental intracoronary stenting: comprehensive experience in a porcine model

“…Regarding these aspects, the authors like to call the present porcine model as an ideal experimental set-up not only for the test of novel, intracoronary stent devices, but also for the study of adjuvant therapeutic strategies, such as (i) inhibition of neointimal proliferation by a protein adduct of nitric oxide (Marks et al 1995) or an endothelin receptor antagonist (Ferrer et al 1995); (ii) endovascular irradiation via low-dose radioactive stents (Hehrlein et al 1995); and (iiil acceleration of stent endothelialization by local delivery of growth factors (Van Belle et al 1997 …”