Norepinephrine-induced aortic hyperplasia and extracellular matrix deposition are endothelin-dependent.
BACKGROUND
Sympathetic hyperactivity is observed in several disease states and may contribute to cardiovascular hypertrophic remodeling. Endothelin has been suggested to be a mediator of hypertrophy.


OBJECTIVE
To examine the involvement of endothelin in maintaining the growth response induced by exogenous norepinephrine.


METHODS
Rats were treated with norepinephrine (2.5 microg/Kg per min subcutaneously) for 2 and 4 weeks, alone or in association with the selective endothelin-A (ETA) receptor antagonist, darusentan (LU135252, 30 mg/Kg per day orally) for weeks 3 and 4.


RESULTS
Increases in medial cell number and accumulation of collagen and elastin characterized norepinephrine-induced aortic remodeling. These effects occurred without marked changes of mean arterial pressure, but may be related to enhanced pressure variability in addition to direct effects of norepinephrine. Inhibition of ETA receptors by darusentan reversed aortic alterations produced by infusion of norepinephrine. Evaluation of medial apoptosis did not reveal any significant change in any group at 4 weeks.


CONCLUSIONS
Antagonism of ETA receptors effectively and rapidly reversed norepinephrine-induced aortic structural and compositional changes, suggesting a central role of endothelin in mediating this response. Thus, ETA receptor antagonists may help to regress large artery remodeling in conditions of increased circulating catecholamine concentrations.
Dao
H H
HH
Faculty of Pharmacy and bDepartment of Physiology, Faculty of Medicine, University of Montreal, Canada.
Lemay
J
J
de Champlain
J
J
deBlois
D
D
Moreau
P
P
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001158:Arteries / Q000502:physiology; D002452:Cell Count; D003094:Collagen / Q000378:metabolism; D004549:Elastin / Q000378:metabolism; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D005109:Extracellular Matrix / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D006965:Hyperplasia; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D009638:Norepinephrine / Q000494:pharmacology*; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010666:Phenylpropionates; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan; D003094:Collagen; D004549:Elastin; D009638:Norepinephrine