EARLY INHIBITION OF MYOINTIMAL PROLIFERATION BY ANGIOPEPTIN AFTER BALLOON CATHETER INJURY IN THE RABBIT

Purpose: Coronary artery restenosis after percutaneous transluminal an gioplasty occurs in more than 40% of patients. Angiopeptin, a stable s ynthetic octapeptide analogue of somatostatin, attenuates accelerated coronary artery myointimal thickening in rabbit cardiac allografts and myointimal thickening after arterial injury. In this study the tempor al relationship between the angiopeptin treatment schedule and efficac y was explored. The relationship between inhibition of myointimal thic kening by angiopeptin and inhibition of vascular cell proliferation wa s also examined. Methods: The aorta and the common and external iliac arteries of the rabbit underwent balloon injury. Angiopeptin (2 to 200 mu g/kg/day) was administered for 1 day before injury and for 1, 5, a nd 21 days after injury. Morphometric studies were performed to determ ine measurement of intimal thickening. Inhibition of vascular cell pro liferation by angiopeptin was evaluated by tritiated thymidine incorpo ration into the balloon-injured rabbit aorta. Thymidine was either adm inistered intraperitoneally or added ex vivo to aorta segments of rabb its treated with angiopeptin (2, 20, or 200 mu g/kg/day) from 1 day be fore injury until sacrifice 72 hours later. Results: Administration of angiopeptin (2 to 200 mu g/kg/day) significantly reduced intimal thic kening by approximately 50% in all three vessels when evaluated 3 week s after injury. This inhibitory effect was unrelated to duration of tr eatment and dose. Treatment initiated at the time of injury was found to be effective, but delaying treatment for 8, 18, or 27 hours abrogat ed the inhibitory effect of angiopeptin on myointimal thickening. Angi opeptin treatment significantly decreased thymidine-labeled nuclei of smooth muscle cells in vitro. Angiopeptin treatment similarly inhibite d thymidine uptake in vitro by balloon-injured aorta segments. Conclus ion: Angiopeptin significantly inhibits myointimal thickening by inhib iting vascular cell proliferation. Administration of angiopeptin for 2 days is as efficacious as 3 weeks treatment in inhibiting myointimal thickening. Delaying treatment for as little as 8 hours after injury a brogates the inhibitory effects of angiopeptin. This speaks to the imp ortance of early events immediately after vascular tissue injury, sugg esting that angiopeptin inhibits the expression of early genes causall y related to the vascular injury response and thereby triggering vascu lar cell proliferation.