Wright John W, Tamura-Myers Elizabeth, Wilson Wendy L, Roques Bernard P, Llorens-Cortes Catherine, Speth Robert C, Harding Joseph W
Department of Psychology, Washington State University, Pullman, Washington 99164-4820, USA.
Am J Physiol Regul Integr Comp Physiol. 2003 Mar;284(3):R725-33. doi: 10.1152/ajpregu.00326.2002. Epub 2002 Nov 14.
The present investigation measured the relative pressor potencies of intracerebroventricularly infused ANG II, ANG III, and the metabolically resistant analogs d-Asp(1)ANG II and d-Arg(1)ANG III in alert freely moving rats. The stability of these analogs was further facilitated by pretreatment with the specific aminopeptidase A inhibitor EC33 or the aminopeptidase N inhibitor PC18. The results indicate that the maximum elevations in mean arterial pressure (MAP) were very similar for each of these compounds across the dose range 1, 10, and 100 pmol/min during a 5-min infusion period. However, d-Asp(1)ANG II revealed significantly extended durations of pressor effects before return to base level MAP. Pretreatment intracerebroventricular infusion with EC33 blocked the pressor activity induced by the subsequent infusion of d-Asp(1)ANG II, whereas EC33 had no effect on the pressor response to subsequent infusion of d-Arg(1)ANG III. In contrast, pretreatment infusion with PC18 extended the duration of the d-Asp(1)ANG II pressor effect by about two to three times and the duration of d-Arg(1)ANG III's effect by approximately 10 to 15 times. Pretreatment with the specific AT(1) receptor antagonist losartan blocked the pressor responses induced by the subsequent infusion of both analogs indicating that they act via the AT(1) receptor subtype. These results suggest that the brain AT(1) receptor may be designed to preferentially respond to ANG III, and ANG III's importance as a centrally active ligand has been underestimated.
本研究测量了在清醒自由活动的大鼠中，脑室内注射血管紧张素II（ANG II）、血管紧张素III（ANG III）以及代谢抗性类似物d - 天冬氨酸（1）血管紧张素II（d - Asp(1)ANG II）和d - 精氨酸（1）血管紧张素III（d - Arg(1)ANG III）的相对升压效力。通过用特异性氨肽酶A抑制剂EC33或氨肽酶N抑制剂PC18进行预处理，进一步提高了这些类似物的稳定性。结果表明，在5分钟输注期内，在1、10和100 pmol/分钟的剂量范围内，这些化合物各自引起的平均动脉压（MAP）最大升高非常相似。然而，d - Asp(1)ANG II在恢复到基础MAP水平之前，显示出明显延长的升压作用持续时间。脑室内预先注射EC33可阻断随后注射d - Asp(1)ANG II诱导的升压活性，而EC33对随后注射d - Arg(1)ANG III的升压反应没有影响。相反，预先注射PC18使d - Asp(1)ANG II的升压作用持续时间延长约两到三倍，使d - Arg(1)ANG III的作用持续时间延长约10到15倍。用特异性AT(1)受体拮抗剂氯沙坦进行预处理可阻断随后注射这两种类似物诱导的升压反应，表明它们通过AT(1)受体亚型起作用。这些结果表明，脑内AT(1)受体可能被设计为优先对ANG III作出反应，并且ANG III作为中枢活性配体的重要性被低估了。
