To determine the importance of angiotensin converting enzyme (ACE) activity in the development of arterial proliferative lesions in a primate model, the response to vascular injury was studied in ...five baboons treated with oral cilazapril (20 mg/kg/day) and in five untreated control animals. Each animal underwent three procedures: 1) carotid artery endarterectomy, 2) balloon catheter deendothelialization of the superficial femoral artery, and 3) surgical placement of bilateral aorto-iliac expanded polytetrafluoroethylene (Gore-Tex) vascular grafts. Cilazapril therapy was initiated 1 week preoperatively and continued throughout the study interval. At 1 and 3 weeks postoperatively, plasma ACE activity was inhibited by more than 96% versus control values. After animals were killed at 3 months, injured vessel and graft segments were evaluated morphometrically. Although the response between animals was variable, average cross-sectional areas of neointima did not differ between the cilazapril-treated and control groups at sites of carotid endarterectomy (0.26 +/- 0.12 versus 0.34 +/- 0.17 mm2, respectively; p greater than 0.5), femoral artery ballooning (0.15 +/- 0.08 versus 0.11 +/- 0.01 mm2; p greater than 0.5), or at graft anastomoses (1.86 +/- 0.50 versus 1.72 +/- 0.50 mm2; p greater than 0.5). Thus, cilazapril did not reduce intimal thickening over 3 months in these primate arterial injury models. However, a possible beneficial effect of cilazapril, which might be apparent at earlier time points or with larger animal groups, cannot be excluded.
Angiotensin converting enzyme inhibition markedly suppresses neointima formation in response to balloon catheter-induced vascular injury of the rat carotid artery. To determine whether this effect ...was mediated through the vasoactive peptide angiotensin II (Ang II), two approaches were followed. First, the balloon model was used to compare the effects of continuous infusion of Ang II, with and without concurrent converting enzyme inhibition by cilazapril; second, the effects of the orally active nonpeptidic Ang II receptor antagonist DuP 753 were analyzed. Morphometric analysis was performed at 14 days after balloon injury. Animals that received continuous infusion of Ang II (0.3 micrograms/min/rat) were found to have significantly greater neointima formation in response to balloon injury than controls. Animals treated with cilazapril (10 mg/kg/day) had markedly reduced neointima formation, but in animals receiving infusion of Ang II, treatment with cilazapril did not suppress development of neointimal lesions. In the second group of experiments, DuP 753 (10 mg/kg twice daily) was as effective to prevent neointima formation as cilazapril. These data support the conclusions that converting enzyme inhibition prevents neointima formation after vascular injury through inhibition of Ang II generation.
Vascular endothelial growth factor was infused into rat carotid arteries for 3 minutes immediately after endothelial denudation by balloon injury. Endothelial proliferation was determined by ...immunohistochemical labelling of proliferating cell nuclear antigen using Häutchen preparations. The proliferation index, or number of proliferating cells/total cells, measured at 25.5 or 30 hours was markedly increased after infusion of vascular endothelial growth factor. In addition, the total number of proliferating cells increased with increasing doses up to 100μg total dose per infusion. These data indicate that infusion of vascular endothelial growth factor increases endothelial cell proliferation after mechanical denudation injury of the vascular wall.
The glycoprotein hormone erythropoietin plays a major role in regulating erythropoiesis and deficiencies of erythropoietin result in anemia. Detailed studies of the hormone and attempts at ...replacement therapy have been difficult due to the scarcity of purified material. We used a cloned human erythropoietin gene to develop stably transfected mammalian cell lines that secrete large amounts of the hormone with potent biological activity. These cell lines were produced by cotransfection of mammalian cells with a plasmid containing a selectable marker and plasmid costructions containing a cloned human erythropoietin gene inserted next to a strong promoter. The protein secreted by these cells stimulated the proliferation and differentiation of erythroid progenitor cells and, with increased selection, several of these cell lines secrete up to 80 mg of the protein per liter of supernatant. Hybridization analysis of DNA from human chromosomes isolated by high resolution dual laser sorting provides evidence that the gene for human erythropoietin is located on human chromosome 7.
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