CONTROLLED PERIADVENTITIAL ADMINISTRATION OF VERAPAMIL INHIBITS NEOINTIMAL SMOOTH-MUSCLE CELL-PROLIFERATION AND AMELIORATES VASOMOTOR ABNORMALITIES IN EXPERIMENTAL VEIN BYPASS GRAFTS

Objective: Inhibition of early myointimal proliferation may improve lo ng-term patency of vein grafts, but the clinical use of many experimen tal drugs is limited by systemic toxicity, To determine whether this g oal can be achieved by low-dose targeted drug administration, we const ructed a polymeric system delivering verapamil and evaluated the effec ts on local and downstream vein graft morphology, neointimal smooth mu scle cell proliferation, and vasomotor function. Methods: Ethylene-vin yl acetate polymeric delivery systems were constructed, containing 2% verapamil by weight, These are flexible, biocompatible, and nonbiodegr adable matrices, delivering the drug at a rate of 10 mu g/day. The aut ologous external jugular vein was used to create a carotid artery bypa ss graft in hypercholesterolemic (n = 22) rabbits, Verapamil-containin g matrices (n = 12) or plain polymers (control, n = 10) were wrapped a round the proximal third of the veins after reperfusion, Graft vasomot or function was evaluated and was also compared with function of an ad ditional group of normocholesterolemic vein grafts (n = 8), Results: T wenty-eight days after grafting, intimal index (intima/media thickness ratio) was 31% lower, neointima/original lumen surface ratio was 26% lower, and residual luminal area was 71% greater (4.00 +/- 1.2 mm(2) v ersus 2.34 +/- 0.9 mm(2), all p < 0.01) under verapamil matrices compa red with control grafts, Neointimal smooth muscle cell content was red uced from 45.4% to 28.2%, and net neointimal smooth muscle cell thickn ess was reduced by 47% (30 mu m vs 15.8 mu m, both p < 0.01), Verapami l-treated segments distal to the matrices also showed significantly lo wer neointimal smooth muscle cell density and increased lumen size, Se nsitivity to serotonin and vasomotor responses to serotonin, norepinep hrine, and sodium nitroprusside in distal segments were significantly lower ire verapamil-treated grafts than in controls, Conclusions: Peri adventitial controlled administration of verapamil below 1% of the sys temic dose effectively inhibits myointimal hyperplasia in vein grafts, Local polymeric drug delivery may be readily applicable to coronary r evascularization operations.