Narrowing of the vascular wall as a result of intimal hyperplasia is a problem following arterial reconstruction procedures. No monotherapy is available that attenuates intimal hyperplasia and recovery of neoendothelial function, as evidenced by prostacyclin (PGI2) and endothelium-derived relaxing factor (EDRF/nitric oxide) formation, following balloon catheter injury. A hypothesis to be tested is combination therapy, identified through preliminary experiments, will more effectively produce this normalization than currently identified treatments. It is predicted this normalization will be maintained over the 24-week study and will promote long-term patency. The treatments to be tested are: dexamethasone and angiopeptin, a somatostatin analog; dexamethasone and heparin; somatostatin and heparin. New preliminary data indicate that L-arginine (L-ARG), the precursor to nitric oxide, inhibits intimal hyperplasia. Therefore, combination of L-ARG with angiopeptin or heparin or dexamethasone will be employed. Balloon catheter injury will be produced in the thoracic aorta and iliac artery. Rabbits will be sacrificed at 2,4,8, and 24 weeks following injury. Controls will be sham operated. Basal and stimulated PGI2 formation will be assayed. EDRF formation will be assayed employing endothelium-dependent and independent vasodilators and an inhibitor of nitric oxide formation (L-nitroarginine methyl ester). Endothelial regeneration and intimal hyperplasia will be assayed by immunohistochemistry, scanning electron microscopy, and light microscopy. Moreover, the hypothesis that decreased expression and/or activity of cyclic GMP dependent protein kinase (G-kinase) is associated with intimal hyperplasia induced by injury and that inhibitors of intimal hyperplasia that also augment EDRF formation will increase the expression r activity of G-kinase will be tested. This study will provide a clearer understanding of the interrelational roles of intimal hyperplasia formation of neoendothelium, and the formation of pGI2 and EDRF by the neoendothelium. This study may lead to the development of treatment modalities that will lessen or eliminate complications associated with balloon catheter angioplasty and improve patency of vessels following attempted revascularization.
