Abstract
Temporal consequences of neurocompensation to balloon injury on endothelinergic functionality in rat contralateral carotid were evaluated. Rats underwent balloon injury in left carotid and were treated with CP-96345 (NK1 antagonist). Concentration-response curves for endothelin-1 were obtained in contralateral (right) carotid at 2, 8, 16, 30, or 45 days after surgery in the absence or presence of BQ-123 (ETA antagonist), BQ-788 (ETB antagonist), or Tempol (superoxide-dismutase mimic). Endothelin-1-induced calcium mobilization was evaluated in functional assays carried out with BQ-123, BQ-788, or Tempol. Endothelin-1-induced NADPH oxidase-driven superoxide generation was measured by lucigenin chemiluminescence assays performed with BQ-123 or BQ-788. Endothelin-1-induced contraction was increased in contralateral carotid from the sixteenth day after surgery. This response was restored in CP-96345-treated rats. Endothelium removal or BQ-123 did not change endothelin-1-induced contraction in contralateral carotid. This response was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced calcium mobilization, which was restored by BQ-788 or Tempol. Contralateral carotid exhibited an increased endothelin-1-induced lucigenin chemiluminescence, which was restored by BQ-788. We conclude that the NK1-mediated neurocompensatory response to balloon injury elicits a contractile hyperreactivity to endothelin-1 in rat contralateral carotid by enhancing the muscular ETB-mediated NADPH oxidase-driven generation of superoxide, which activates calcium channels.
Highlights
Vascular remodeling is a hallmark of many vascular disorders including atherosclerosis [1, 2]
We evaluated the endothelinergic relaxant functionality by obtaining the maximum relaxation induced by ET-1 (0.1 nmol/l) in PE (0.1 휇mol/l) precontracted E+ or E− carotid rings in the absence or presence of BQ-123 (3.0 휇mol/l) or BQ-788 (3.0 휇mol/l), added 30 min prior to ET-1 [26]
The unaltered structure from contralateral carotid wall had incorrectly supported the use of this vessel as the control parameter from ipsilateral carotid [36] until the findings provided by Accorsi-Mendonca et al [5], who described that contralateral carotid exhibits a broad muscular dysfunction resultant from a vascular bed-dependent mechanism not mediated by humoral factors but elicited by the neurocompensatory response to balloon injury [11]
Summary
Vascular remodeling is a hallmark of many vascular disorders including atherosclerosis [1, 2]. Carotid occlusive disease is a specific kind of atherosclerosis that significantly contributes to cerebrovascular accidents [3]. Balloon angioplasty is the most common intervention to restore blood flow upon arterial obstruction by atherosclerotic plaques [5,6,7]. Therapeutic efficacy of balloon angioplasty is limited by postoperative complications mainly resultant from restenosis, which markedly narrows ipsilateral (injured) artery lumen and reduces local blood flow [8, 9]. Pathophysiological mechanisms underlying restenosis have been effectively studied by the rat carotid balloon injury model, which triggers neointimal formation in close
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