Recent studies have shown that
calcium antagonists exert an antiatherogenic effect in animals fed
cholesterol. Vein graft intimal
hyperplasia is believed to be an early event in atherosclerotic lesion formation, which is a significant cause of graft failure. Altered vasoreactivity has also been postulated in the etiology of vein graft failure. Therefore this study examined the effect of
verapamil treatment on the development of intimal
hyperplasia and the vasoreactivity of experimental vein bypass grafts. The right external jugular vein was grafted into the right carotid artery of 30 male New Zealand white rabbits fed normal rabbit chow. The left external jugular vein was used as the control vein. Fifteen animals received
verapamil (1.25 mg/day for 28 days) via the femoral vein by means of an osmotic pump. In 15 control animals the pump contained saline. Plasma
verapamil concentration was 50.9 +/- 13.2 ng/mL (x +/- SEM), a dose that showed no effect on either blood pressure, total serum
cholesterol, or in vitro platelet aggregation to
ADP. Fourteen of fifteen grafts were patent in each group, for a patency rate of 93%. Histologic examination using computer morphometry showed significant reduction of intimal
hyperplasia at the proximal, middle, and distal graft segments (p less than 0.05). In addition in vitro isometric tension studies of the vein grafts and control veins showed that
verapamil causes enhanced reactivity of both vein grafts and control veins in response to
norepinephrine and
histamine (p less than 0.05). Reactivity of vein grafts to
serotonin was unaltered. While none of the normal veins in the control group responded to
serotonin, normal veins treated with
verapamil contracted readily in response to
serotonin. Endothelial-dependent relaxation to
acetylcholine was absent in both control and
verapamil-treated vein grafts, while normal veins from both groups responded to the same extent to
acetylcholine. Because we could not demonstrate any difference in platelet or endothelium function between untreated and
verapamil-treated animals, we examined the direct effect of
verapamil on smooth muscle.
Verapamil significantly inhibited [3H]-
thymidine incorporation into
DNA in vascular smooth muscle cells in culture in a dose-dependent manner.
Verapamil treatment significantly reduces intimal
hyperplasia in experimental vein grafts and inhibits smooth muscle cell proliferation in culture. Furthermore the enhanced reactivity to
norepinephrine and
histamine in the
verapamil-treated vessels has no detrimental effect on the patency rate at 4 weeks. Thus by inhibiting intimal
hyperplasia,
calcium antagonists may improve the long-term patency of vein bypass grafts.