Role of endothelin receptor antagonist in preventing small arteries hypertrophy induced by exogenous administration of norepinephrine

In a subset of hypertensive patients, activity of the sympathetic nervous s ystem (SNS) is enhanced. Hypertension is also associated with an adaptative process where small arteries (lumen < 300 mu m) are subjected to structura l changes (eutrophic or hypertrophic remodeling). Since, it has been shown that norepinephrine (NE) can induced proliferation of vascular smooth muscl e cells, the purpose of the present study was to determine the effect of a chronic treatment with NE, mimicking hyperactivity of SNS, on small artery structure. The role of endothelin (ET) in the process was also evaluated. To achieve these goals, control rats were compared with rats receiving NE 2 .5 mu g/kg/min alone or in combination with LU135252 30 mg/kg/d (ET-recepto r antagonist, affinity ETA/ETB congruent to 100) for 2 weeks. Blood pressur e was measured intra-arterially in conscious rats prior to sacrifice. Geome tric parameters of the basilar artery were determined in pressurized and pe rfused conditions with calcium free Krebs solution. Plasma NE and arterial mesenteric ET levels were determined by HPLC and RIA respectively. Blood pr essured was not altered following exogenous administration of NE for 2 week s. However, media thickness increased while the lumen diameter was reduced at the level of the basilar artery, leading to elevated media : lumen ratio (p < 0.05). This morphological alteration was associated with a significan t augmentation of the basilar artery cross-sectional area (CSA). Go-adminis tration of LU135252 with NE prevented partially the increase of M/L while t he elevation of CSA was completely blunted. Plasma levels of NE were signif icantly and similarly elevated in groups receiving NE but, interestingly, m esenteric ET levels were not modified by any treatment. These results suggest that chronic NE administration induced an hypertrophi c inward remodeling of small arteries independently from blood pressure, wh ich required the participation of ET as an obligatory intermediate. Further more, the local production of ET is probably enhanced transiently in the fi rst days of NE administration and come back to control level at 2 weeks, Th us, early therapy initiation with an ET-receptor antagonist prevents vascul ar remodeling in conditions of SNS hyperactivity, which may contribute to l ower risks of end-organ damage.