[Role of endothelin in the hypertrophic remodeling of small arteries induced by exogenous norepinephrine].
In a subset of hypertensive patients, activity of the sympathetic nervous system (SNS) is enhanced. Hypertension is also associated with an adaptative process where small arteries (lumen < 300 microns) are subjected to structural changes (eutrophic or hypertrophic remodeling). Since, it has been shown that norepinephrine (NE) can induced proliferation of vascular smooth muscle 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 micrograms/kg/min alone or in combination with LU135252 30 mg/kg/d (ET-receptor antagonist, affinity ETA/ETB approximately equal to 100) for 2 weeks. Blood pressure was measured intra-arterially in conscious rats prior to sacrifice. Geometric parameters of the basilar artery were determined in pressurized and perfused conditions with calcium free Krebs solution. Plasma NE and arterial mesenteric ET levels were determined by HPLC and RIA respectively. Blood pressured was not altered following exogenous administration of NE for 2 weeks. 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 significant augmentation of the basilar artery cross-sectional area (CSA). Co-administration of LU135252 with NE prevented partially the increase of M/L while the elevation of CSA was completely blunted. Plasma levels of NE were significantly and similarly elevated in groups receiving NE but, interestingly, mesenteric ET levels were not modified by any treatment. These results suggest that chronic NE administration induced an hypertrophic inward remodeling of small arteries independently from blood pressure, which required the participation of ET as an obligatory intermediate. Furthermore, the local production of ET is probably enhanced transiently in the first days of NE administration and come back to control level at 2 weeks. Thus, early therapy initiation with an ET-receptor antagonist prevents vascular remodeling in conditions of SNS hyperactivity, which may contribute to lower risks of end-organ damage.
Dao
H H
HH
Faculté de pharmacie, université de Montréal, Québec, Canada.
McMartens
F
F
Zaor
A
A
de Champlain
J
J
Moreau
P
P
D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D016232:Endothelins / Q000502:physiology*; D006133:Growth Substances / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects; D006984:Hypertrophy / Q000139:chemically induced; D009638:Norepinephrine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D016232:Endothelins; D006133:Growth Substances; D009638:Norepinephrine