INHIBITION OF NEOINTIMAL PROLIFERATION IN RABBITS AFTER VASCULAR INJURY BY A SINGLE TREATMENT WITH A PROTEIN ADDUCT OF NITRIC-OXIDE

Endothelium-derived relaxing factor is important for vascular homeosta sis and possesses qualities that may modulate vascular injury, includi ng vasodilation, platelet inhibition, and inhibition of smooth muscle proliferation, S-nitroso-serum albumin is a naturally occurring adduct of nitric oxide (NO) with a prolonged biologic half-life and is a pot ent vasodilator and platelet inhibitor. Given the avidity of serum alb umin for subendothelial matrix and the antiproliferative effects of NO , we investigated the effects of locally delivered S-nitroso-bovine se rum 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 ves sels producing a 26-fold increase in local concentration compared with uninjured vessels (P = 0.029), pS-NO-BSA significantly reduced the in timal/medial ratio (P = 0.038) and did so in conjunction with elevatio ns in platelet (P < 0.001) and vascular cGMP content (P less than or e qual to 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 am ount of displaceable NO delivered and the extent of inhibition of neoi ntimal proliferation at 2 wk (P less than or equal to 0.001). Local ad ministration of a stable protein S-nitrosothiol inhibits intimal proli feration and platelet deposition after vascular arterial balloon injur y, This strategy for the local delivery of a long-lived NO adduct has potential for preventing restenosis after angioplasty.