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 longterm patency of vein grafts, but the clinical use of many experimental drugs is limited by systemic toxicity. To determine whether this goal can be achieved by low-dose targeted drug administration, we constructed a polymeric system delivering verapamil and evaluated the effects on local and downstream vein graft morphology, neointimal smooth muscle cell proliferation, and vasomotor function.


METHODS
Ethylene-vinyl acetate polymeric delivery systems were constructed, containing 2% verapamil by weight. These are flexible, biocompatible, and nonbiodegradable matrices, delivering the drug at a rate of 10 micrograms/day. The autologous external jugular vein was used to create a carotid artery bypass graft in hypercholesterolemic (n = 22) rabbits. Verapamil-containing matrices (n = 12) or plain polymers (control, n = 10) were wrapped around the proximal third of the veins after reperfusion. Graft vasomotor function was evaluated and was also compared with function of an additional group of normocholesterolemic vein grafts (n = 8).


RESULTS
Twenty-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 mm2 versus 2.34 +/- 0.9 mm2, all p < 0.01) under verapamil matrices compared with control grafts. Neointimal smooth muscle cell content was reduced from 45.4% to 28.2%, and net neointimal smooth muscle cell thickness was reduced by 47% (30 microns vs 15.8 microns, both p < 0.01). Verapamil-treated segments distal to the matrices also showed significantly lower neointimal smooth muscle cell density and increased lumen size. Sensitivity to serotoin and vasomotor responses to serotonin, norepinephrine, and sodium nitroprusside in distal segments were significantly lower in verapamil-treated grafts than in controls.


CONCLUSIONS
Periadventitial controlled administration of verapamil below 1% of the systemic dose effectively inhibits myointimal hyperplasia in vein grafts. Local polymeric drug delivery may be readily applicable to coronary revascularization operations.
Brauner
R
R
Division of Cardiothoracic Surgery, University of California at Los Angeles School of Medicine, USA.
Laks
H
H
Drinkwater
D C
DC
Chaudhuri
G
G
Shvarts
O
O
Drake
T
T
Bhuta
S
S
Mishaly
D
D
Fishbein
I
I
Golomb
G
G
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D002455:Cell Division / Q000187:drug effects; D001026:Coronary Artery Bypass; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems; D006937:Hypercholesterolemia / Q000601:surgery; D007601:Jugular Veins / Q000166:cytology / Q000187:drug effects / Q000637:transplantation; D008854:Microscopy, Electron; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D011145:Polyvinyls; D011817:Rabbits; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects; D014700:Verapamil / Q000008:administration & dosage*
D002121:Calcium Channel Blockers; D011145:Polyvinyls; C016438:ethylenevinylacetate copolymer; D014700:Verapamil