EMBOLECTOMY CATHETER INJURY--EFFECTS OF DRUG THERAPY

取栓导管损伤——药物治疗的影响

• 批准号: 2223173
• 负责人: DENNIS B MCNAMARA
• 金额: $ 25.01万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2223173
• 关键词: angiogenesis; aorta; arginine; combination chemotherapy; cyclic GMP; dexamethasone; enzyme activity; heparin; hyperplasia; immunocytochemistry; in situ hybridization; injury; laboratory rabbit; light microscopy; nitric oxide; nonhuman therapy evaluation; northern blottings; peptide hormone analog; prostacyclins; protein kinase; scanning electron microscopy; somatostatin; vascular endothelium; vasodilators; western blottings

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.

因内膜增生而导致血管壁的狭窄是一个 动脉重建程序后的问题。 没有单一治疗 可用可减弱内膜增生和恢复的可用 新内皮功能，前列环素（PGI2）和 内皮衍生的放松因子（EDRF/一氧化氮）形成， 在气球导管损伤之后。 要检验的假设是 通过初步实验确定的组合疗法将更多 有效地产生这种归一化，而不是当前确定的 治疗。 可以预测，这种归一化将在 24周的研究将促进长期通畅。 治疗 测试是：地塞米松和血管肽，一种生长抑素类似物； 地塞米松和肝素；生长抑素和肝素。 新的初步数据 表明一氧化氮的前体L-精氨酸（L-Arg）抑制 内膜增生。 因此，L-ARG与血管肽或 将使用肝素或地塞米松。 气球导管损伤将是 在胸主动脉和小动脉中产生。 兔子会 受伤后2,4,8和24周处死。 控件将是假的 操作。 将分析基底和刺激的PGI2形成。 EDRF 形成将被测定，采用内皮依赖和独立的形成 血管扩张剂和一氧化氮形成的抑制剂（L-硝化精氨酸 甲酯）。 内皮再生和内膜增生将是 通过免疫组织化学，扫描电子显微镜和光测定 显微镜。 此外，降低表达和/或降低的假设 环状GMP依赖性蛋白激酶（G-激酶）的活性是相关的 受损伤诱导的内膜增生和内膜抑制剂 增强EDRF形成的增生将增加表达 将测试G激酶的R活性。 这项研究将提供更清晰的 理解内膜增生形成的相互关系作用 新的内皮，以及由PGI2和EDRF形成 新内皮细胞。 这项研究可能导致治疗的发展 可以减少或消除并发症的方式 气球导管血管成形术并提高船只的通畅性 尝试的血运重建。