Adrenomedullin enhances baroreceptor reflex response via cAMP/PKA signaling in nucleus tractus solitarii of rats
Adrenomedullin enhances baroreceptor reflex response via cAMP/PKA signaling in nucleus tractus solitarii of rats
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DOI：
10.1016/j.neuropharm.2008.06.024
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发表时间：
2008-10-01
影响因子：
4.7
通讯作者：
Yen, J. C.
中科院分区：
文献类型：
--
作者：
Ho, L. K.;Chen, K.;Yen, J. C.
肾上腺髓质素（ADM）是一种由52个氨基酸组成的多肽，当全身或直接给药于脑时，可引起不同的心血管反应。在本研究中，我们评估的假设，ADM可能通过ADM受体介导的cAMP/蛋白激酶A（PKA）依赖的机制，在孤束核（NTS），初级压力感受器传入的终端网站，调节压力感受器反射（BRR）的反应，使用Sprague-Dawley大鼠。我们的免疫印迹和免疫组化结果表明，ADM的两个组成部分的蛋白质，受体复合物，降钙素受体样受体（CRLR）和受体活性修饰蛋白（RAMP）-2，均匀分布和高度共定位在NTS。在NTS中单方面微量注射ADM（0.02-0.2 pmol）可显著增加BRR反应和敏感性，且与时间和剂量相关，而不影响动脉压和心率。ADM的BRR增强作用也与PKA β（PKA的活性形式）的上调和PKA活性的增加在时间上相关。此外，ADM（1）受体拮抗剂ADM（22-52）、腺苷酸环化酶抑制剂SQ 22536或PKA抑制剂Rp-8-bromo-cAMP均可阻断ADM诱导的BRR增强或PKA激活。这些结果表明，ADM通过激活cAMP/PKA依赖性机制，通过作用于NTS中的ADM，受体的位点特异性增强BRR。(c)2008爱思唯尔有限公司保留所有权利。
Adrenomedullin (ADM), a 52-amino acid peptide, elicits differential cardiovascular responses when it is administered systemically or directly to the brain. We evaluated in the present study the hypothesis that ADM may modulate baroreceptor reflex (BRR) response through an ADM receptor-mediated cAMP/ protein kinase A (PKA)-dependent mechanism in the nucleus tractus solitarii (NTS), the terminal site for primary baroreceptor afferents, using Sprague-Dawley rats. Our immunoblot and immunohistochemical results showed that the two component proteins of the ADM, receptor complex, calcitonin receptor-like receptor (CRLR) and receptor activity modifying protein (RAMP)-2, were uniformly distributed and highly co-localized in the NTS. Site-specific microinjection of ADM (0.02-0.2 pmol) unilaterally into the NTS significantly increased BRR response and sensitivity in a time- and dose-related manner, without affecting arterial pressure and heart rate. The BRR enhancing effect of ADM was also temporally correlated with an up-regulation of PKA beta, the active form of PKA and an increase in PKA activity. In addition, the ADM-evoked BRR enhancement or PKA activation was abolished by co-microinjection with a selective ADM(1) receptor antagonist, ADM(22-52), an adenylyl cyclase inhibitor, SQ22536, or a PKA inhibitor, Rp-8-bromo-cAMP. These results suggest that ADM enhances BRR via activation of a cAMP/PKA-dependent mechanism by acting site-specifically on ADM, receptors in NTS. (c) 2008 Elsevier Ltd. All rights reserved.