Endothelin receptor antagonism does not prevent the development of in vivo glyceryl trinitrate tolerance in the rat

作     者：Ratz, JD Fraser, AB Rees-Milton, KJ Adams, MA Bennett, BM 

作者机构：Queens Univ Fac Hlth Sci Dept Pharmacol & Toxicol Kingston ON K7L 3N6 Canada 

出 版 物：《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》 (药理学与实验治疗学杂志)

年 卷 期：2000年第295卷第2期

页      面：578-585页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

主　　题：主动脉 胸/药物作用 主动脉 胸/代谢 主动脉 胸/生理学 结合 竞争性 生物转化 血压/药物作用 环GMP/代谢 药物耐受性/生理学 内皮缩血管肽1/拮抗剂和抑制剂 内皮缩血管肽1/代谢 内皮缩血管肽1/生理学 肌收缩/药物作用 肌松弛/药物作用 硝酸甘油/药代动力学 硝酸甘油/药理学 吡嗪类/药理学 大鼠 Sprague-Dawley 受体 内皮素A 受体 内皮缩血管肽/拮抗剂和抑制剂 受体 内皮缩血管肽/代谢 磺胺类/药理学 血管舒张药/药代动力学 血管舒张药/药理学 动物 男(雄)性 大鼠 

摘      要：There is evidence that increased endothelial production of endothelin-1 (ET-1) may contribute to glyceryl trinitrate (GTN) tolerance. We used the competitive ETA receptor antagonist ZD2574 to determine whether chronic ETA receptor blockade affected the biochemical and functional responses to GTN during the development of GTN tolerance in vivo. Tolerance induced using transdermal GTN patches resulted in a 5.3 +/- 1.2-fold increase in the EC50 value for GTN relaxation in isolated aorta from GTN-tolerant rats. Coadministration of ZD2574 (100 mg kg(-1) t.i.d. for 3 days) during tolerance induction had no effect on GTN-induced relaxation. This dose of ZD2574 markedly blunted the pressor response to ET-1, indicating effective blockade of ETA receptors, and also abolished the initial transient depressor response to ET-1, indicating that blockade of endothelial ETB receptors also occurred using this dosage regimen for ZD2574. Consistent with the relaxation data, coadministration of ZD2574 had no effect on the decrease in GTN-induced cGMP accumulation or on the decrease in GTN biotransformation that occurred in aortae from GTN-tolerant animals. Radioimmunoassay data indicated that the GTN tolerance induction protocol caused a 2.3 +/- 0.4-fold and a 2.2 +/- 0.5-fold increase in total tissue ET-1 levels in tolerant aorta and vena cava, respectively. These data suggest that chronic inhibition of ET receptors by ZD2574 was not sufficient to prevent or diminish the tolerance-inducing effects of GTN, and that the increase in ET-1 levels observed in tolerant tissues may occur as a consequence of the vascular changes that occur during chronic GTN exposure.