Reversal of endothelin-1 release by stimulation of endothelial alpha2-adrenoceptor contributes to cerebral vasorelaxation.
Agonists acting on the vascular endothelium can modulate the release of a number of factors that interact with the surrounding smooth muscle cells and influence their tone. One such factor is the vasoconstricting agent endothelin-1 (ET-1), which has been implicated in several disease states, including stroke. However, very little is known about the physiological role of ET-1 in the cerebral circulation. We demonstrate that activation of alpha2-adrenoceptors in human pial artery endothelial cells reduces both constitutive and agonist-stimulated release of immunoreactive ET-1. That this has physiological relevance is supported by our demonstration that in segments of rabbit middle cerebral arteries, alpha2-adrenoceptor activation reduces the release of endothelium-derived ET-1 and causes an endothelium-dependent relaxation. The adrenoceptor-dependent relaxation was not blocked by combined addition of indomethacin and N omega-nitro-L-arginine in 25 mmol/L KCl-depolarizing physiological solution but was selectively antagonized by a subthreshold concentration of exogenous ET-1. Our data suggest that activation of endothelial alpha2-adrenoceptor would favor a decrease in ET-1 production and possibly promote vascular relaxation.
Thorin
E
E
Department of Pharmacology, University of Vermont, Burlington, USA. thorin@icm.umontreal.ca
Shreeve
S M
SM
Thorin-Trescases
N
N
Bevan
J A
JA
D000293:Adolescent; D000328:Adult; D000818:Animals; D001685:Biological Factors / Q000494:pharmacology; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000502:physiology*; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D011189:Potassium Chloride / Q000494:pharmacology; D011817:Rabbits; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D001685:Biological Factors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D010456:Peptides, Cyclic; D011942:Receptors, Adrenergic, alpha; C067410:endothelium-dependent hyperpolarization factor; D011189:Potassium Chloride; C072247:cyclo(Trp-Asp-Pro-Val-Leu)