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Vasospasm is a complication of cardiological procedures such as balloon angioplasty and may be related to vascular oxidant stress. Although nitric oxide donor drugs are often administered to prevent vasospasm, the response to these drugs in balloon-injured arteries has not been studied. Pig coronary arteries were balloon-injured in vitro and relaxations to nitric oxide (NO)-donating and NO-independent vasodilators studied. Generation of superoxide in response to injury was assayed using dihydroethidium. NO formation on addition of the NO donor drugs was studied using an amperometric sensor. Expression of nitrotyrosine, a peroxynitrite marker, was probed using immunocytochemistry. In vitro injury enhanced sensitivity to the NO donors SNAP and SpermineNONOate but blunted the response to isoprenaline or chromakalim. With both donors, NO formation was significantly enhanced in the presence of an injured vessel. Vascular superoxide generation was also increased throughout the vessel wall and a small increase in nitrotyrosine was detected in the injured vessel media following addition of SNAP. In conclusion, injured vessels were more sensitive to NO donors and this appears to be due to enhanced NO generation by the donor molecule. Increased formation of peroxynitrite within the injured vessel may contribute to the enhanced relaxation in injured vessels. [ABSTRACT FROM AUTHOR]

Abstract: There is now clear evidence for a contributory role of inflammatory processes to restenosis following vascular balloon injury and stent implantation. The aim of the present study was to study the effects of TNFα, administered locally in vivo immediately following balloon angioplasty, on the leukocyte adhesive response and extent of neointimal formation in a rabbit model of subclavian artery injury. Initial in vitro studies were performed with normal isolated artery rings to assess the vascular adhesive response to TNFα or IL-1β. Pre-incubation with either cytokine prior to addition of 51Cr-labelled leukocytes enhanced the adhesion of leukocytes to the artery in both a time- and concentration-dependent manner. Although both cytokines induced an increase in the expression of the adhesion molecules ICAM-1 and VCAM-1, only antibodies to ICAM-1 blocked the enhanced adhesion induced by the cytokines. In artery segments retrieved from rabbits that had previously undergone subclavian artery angioplasty either 24h or 8 days previously, there was an injury-induced increase in adhesion of leukocytes assessed ex vivo. In segments obtained from rabbits that received a 15min local infusion of TNFα (2ng/min) to the injured artery immediately after the angioplasty procedure, leukocyte adhesion assessed ex vivo was further significantly enhanced. The pro-adhesive effect of TNFα was associated with an increased expression of both ICAM-1 and VCAM-1. However, TNFα administration did not alter the extent of neointimal formation observed 8 days after injury. These findings suggest that while TNFα may play a role following vascular injury, it does not act alone to induce neointimal formation. Thus anti-inflammatory strategies targeted at multiple cytokines may be more appropriate than targeting a single cytokine to reduce the response to vascular injury. [Copyright &y& Elsevier]

Objective: The aim of the current study was to examine neointima formation in balloon injured left subclavian artery of rabbits subjected to two different methods of leukocyte depletion at the time of injury. Methods: Angioplasty of the left subclavian artery was performed in leukopenic male New Zealand White rabbits. Depletion of circulating leukocytes was induced by either mustine hydrochloride or an antibody against leukocyte common antigen (anti-LCA) before angioplasty. Left and right subclavian arteries were removed 28 days after injury for morphological analysis and measurement of neointimal size. At the same time, leukocytes were isolated from autologous rabbit blood for 51Cr-labelling for assessment of leukocyte adhesion to injured and non-injured artery segments. Results: Leukopenia decreased neointima formation in injured arteries (neointimal area was 0.09±0.03 mm2 in mustine-treated arteries, n = 8, vs. 0.56±0.07 mm2 in control arteries, n = 7; P<0.001 and 0.07±0.01 mm2 in anti-LCA treated arteries, n = 9, vs. 0.22±0.04 mm2 in non immune serum-treated arteries, n = 9; P<0.001). Adventitial fibrosis was also significantly (P<0.05) decreased by both leukopenic interventions. Neither medial nor adventitial area was modified in any of the groups. No differences in leukocyte adhesion were observed between injured and non-injured arteries in any of the experimental groups at the 28 day time point. Conclusion: These results suggest that leukocytes play a major role in the development of two of the major characteristics of the response to balloon injury, namely formation of neointima and adventitial fibrosis, that currently limit the success of clinical angioplasty. Elucidation of the fine mechanisms involved in leukocyte-mediated injury may lead to the discovery of novel therapeutic targets for the prevention of restenosis. [ABSTRACT FROM PUBLISHER]