Tirapelli Carlos R, Casolari Débora A, Montezano Augusto C, Yogi Alvaro, Tostes Rita C, Legros Eurode, D'Orléans-Juste Pedro, Lanchote Vera L, Uyemura Sérgio A, de Oliveira Ana M
Department of Pharmacology, Faculty of Medicine of Ribeirão Preto, University of Sao Paulo, Sao Paulo, Sao Paulo, Brazil.
J Pharmacol Exp Ther. 2006 Aug;318(2):819-27. doi: 10.1124/jpet.106.103010. Epub 2006 May 1.
We investigated the mechanisms involved in the enhancement of endothelin (ET)-1 vascular reactivity induced by ethanol consumption. Ethanol intake for 2, 6, and 10 weeks enhanced the ET-1-induced contractile response of endothelium-intact but not endothelium-denuded rat carotid rings independently of the treatment duration. Conversely, phenylephrine-induced contraction was not affected by ethanol intake. The contraction induced by IRL1620 [succinyl-(Glu(9),Ala(11,15))-ET-1-(8-21)], a selective ET(B) agonist, was increased after treatment with ethanol in endothelium-intact but not in endothelium-denuded carotid rings. Moreover, ET-1- and IRL1620-induced relaxation was reduced in endothelium-intact phenylephrine-precontracted rings from ethanol-treated rats. Acetylcholine-induced relaxation was not affected by ethanol treatment. N(G)-Nitro-l-arginine methyl ester, 1H-[1,2,4]-oxadiazolo[4,3-a]quinoxalin-1-one, indomethacin, and tetraethylammonium reduced the relaxation induced by IRL1620 in carotid glands from control but not ethanol-treated rats. The mRNA levels for ET(A) and ET(B) receptors were not altered by ethanol consumption. However, ethanol treatment reduced the protein expression of ET(B) receptors. Furthermore, immunohistochemical assays showed reduced immunostaining for endothelial ET(B) receptors after treatment with ethanol. We conclude that ethanol consumption enhances ET-1-induced contraction in the rat carotid and that this response is not different among the three periods of treatment used in this study. Finally, the potentiation of ET-1-induced vascular reactivity is probably caused by reduced expression of relaxing endothelial ET(B) receptors.
我们研究了饮酒增强内皮素（ET）-1血管反应性的相关机制。2周、6周和10周的乙醇摄入增强了ET-1诱导的完整内皮而非去内皮大鼠颈动脉环的收缩反应，且与处理持续时间无关。相反，苯肾上腺素诱导的收缩不受乙醇摄入的影响。选择性ET(B)激动剂IRL1620 [琥珀酰-(Glu(9),Ala(11,15))-ET-1-(8 - 21)]诱导的收缩在乙醇处理后的完整内皮颈动脉环中增加，而去内皮颈动脉环中未增加。此外，在乙醇处理大鼠的完整内皮、苯肾上腺素预收缩的环中，ET-1和IRL1620诱导的舒张减弱。乙酰胆碱诱导的舒张不受乙醇处理的影响。N(G)-硝基-L-精氨酸甲酯、1H-[1,2,4]-恶二唑并[4,3-a]喹喔啉-1-酮、吲哚美辛和四乙铵降低了对照大鼠而非乙醇处理大鼠颈动脉环中IRL1620诱导的舒张。ET(A)和ET(B)受体的mRNA水平不受乙醇摄入的影响。然而，乙醇处理降低了ET(B)受体的蛋白表达。此外，免疫组化分析显示乙醇处理后内皮ET(B)受体的免疫染色减少。我们得出结论，饮酒增强了大鼠颈动脉中ET-诱导的收缩，且在本研究使用的三个处理时期中这种反应没有差异。最后，ET-1诱导的血管反应性增强可能是由于舒张性内皮ET(B)受体表达降低所致。
