EFFECT OF ENDOTHELIN-1 INFUSION ON THE DEVELOPMENT OF INTIMAL HYPERPLASIA AFTER BALLOON CATHETER INJURY

Previous studies have shown endothelin-1 (ET-1) to be mitogenic for smooth-muscle cells. We explored in vivo the ability of high ET-1 levels to worsen angioplasty restenosis. Left carotid artery balloon endothelial denudation was performed on 14 rats. ET-1 was delivered via osmotic pump at a rate of 5 pmol/kg/min. Intimal development and plasma ET-1 levels were assessed at 2 weeks. Blood pressure and heart rate were measured throughout the study. For analysis, the animals were divided into three groups based on ET-1 levels at harvest: control, 4.3 = 0.5 pmol/ml (n = 6); low ET-1, 5.2 +/- 0.9 pmol/ml (n = 4); and high ET-1, 23.1 +/- 5.9 pmol/ml (n = 4). Although ET-1 infusion caused blood pressure elevation in both ET-1 groups, this was more marked and prolonged in the group with a high ET-1 level at study conclusion. Evaluation of the intimal:medial area ratio showed a marked increase in intimal thickness in the high ET-1 group versus control (1.13 +/- 0.23 versus 0.35 +/- 0.11; p<0.05). We conclude that ET-1 infusion in responsive animals can cause worsening of the intimal hyperplastic response after mechanical injury. Further study is required to elucidate whether this is entirely caused by a direct effect of ET-1 on smooth-muscle cell mitogenesis or is also by the hemodynamic effects of ET-1-induced hypertension, or an effect of another mediator released in response to the ET-1 (e.g., angiotensin II).