Early inhibition of myointimal proliferation by angiopeptin after balloon catheter injury in the rabbit.
OBJECTIVE
Coronary artery restenosis after percutaneous transluminal angioplasty occurs in more than 40% of patients. Angiopeptin, a stable synthetic octapeptide analogue of somatostatin, attenuates accelerated coronary artery myointimal thickening in rabbit cardiac allografts and myointimal thickening after arterial injury. In this study the temporal relationship between the angiopeptin treatment schedule and efficacy was explored. The relationship between inhibition of myointimal thickening by angiopeptin and inhibition of vascular cell proliferation was also examined.


METHODS
The aorta and the common and external iliac arteries of the rabbit underwent balloon injury. Angiopeptin (2 to 200 micrograms/kg/day) was administered for 1 day before injury and for 1, 5, and 21 days after injury. Morphometric studies were performed to determine measurement of intimal thickening. Inhibition of vascular cell proliferation by angiopeptin was evaluated by tritiated thymidine incorporation into the balloon-injured rabbit aorta. Thymidine was either administered intraperitoneally or added ex vivo to aorta segments of rabbits treated with angiopeptin (2, 20, or 200 micrograms/kg/day) from 1 day before injury until sacrifice 72 hours later.


RESULTS
Administration of angiopeptin (2 to 200 micrograms/kg/day) significantly reduced intimal thickening by approximately 50% in all three vessels when evaluated 3 weeks after injury. This inhibitory effect was unrelated to duration of treatment and dose. Treatment initiated at the time of injury was found to be effective, but delaying treatment for 8, 18, or 27 hours abrogated the inhibitory effect of angiopeptin on myointimal thickening. Angiopeptin treatment significantly decreased thymidine-labeled nuclei of smooth muscle cells in vitro. Angiopeptin treatment similarly inhibited thymidine uptake in vitro by balloon-injured aorta segments.


CONCLUSIONS
Angiopeptin significantly inhibits myointimal thickening by inhibiting 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 abrogates the inhibitory effects of angiopeptin. This speaks to the importance of early events immediately after vascular tissue injury, suggesting that angiopeptin inhibits the expression of early genes causally related to the vascular injury response and thereby triggering vascular cell proliferation.
Foegh
M L
ML
Department of Surgery, Georgetown University Medical Center, Washington, DC 20007.
Asotra
S
S
Conte
J V
JV
Howell
M
M
Kagan
E
E
Verma
K
K
Ramwell
P W
PW
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D002404:Catheterization / Q000009:adverse effects*; D002455:Cell Division / Q000187:drug effects; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D007083:Iliac Artery / Q000166:cytology / Q000187:drug effects / Q000293:injuries; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic; D011817:Rabbits; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014316:Tritium; D017539:Tunica Intima / Q000166:cytology / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism
D009842:Oligopeptides; D010456:Peptides, Cyclic; C060347:lanreotide; D014316:Tritium; D013004:Somatostatin; D013936:Thymidine