AT1 receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats
AT1 receptor blockers increase insulin-like growth factor-I production by stimulating sensory neurons in spontaneously hypertensive rats
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DOI：
10.1016/j.trsl.2009.06.004
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发表时间：
2009-09-01
影响因子：
7.8
通讯作者：
Okajima, Kenji
中科院分区：
文献类型：
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作者：
Harada, Naoaki;Shimozawa, Nobuhiko;Okajima, Kenji
胰岛素样生长因子-I（IGH-I）是一种重要的心脏保护物质。我们以前报道过，感觉神经元刺激通过释放降钙素基因相关肽（CGRP）增加自发性高血压大鼠（SHR）IGF-I的产生。由于血管紧张素II（Ang II）通过与Ang II 1型（AT（1））受体相互作用抑制感觉神经元激活，因此AT（1）受体阻断剂（ARB）可能增加SHR中IGF-I的产生。我们在当前研究中使用ARB奥美沙坦、缬沙坦、氯沙坦和替米沙坦检查了这种可能性。SHR的血浆、肾脏和心脏CGRP和IGF-I水平均显著低于血压正常的Wistar京都大鼠（WKY）（P < 0.01），ARB给药后WKY的水平升高。这些ARB诱导的SHR增加完全逆转预处理辣椒平（CPZ），这是一个特定的香草素受体-1（VR-1）拮抗剂。ARB可降低SHR的平均动脉血压（MABP），而CPZ可逆转这种降低。硝苯地平的管理降低MABP，但没有增加CGRP或IGF-I水平在SHR。自发性高血压大鼠背根神经节（DRG）CGRP释放量和cAMP水平显著低于正常对照组（P < 0.01）。尽管ARB逆转了WKY分离的DRG中存在Ang II时CGRP释放和cAMP水平的降低，但它们增加了SHR分离的DRG中不存在Ang II时CGRP释放和cAMP水平。WKY和SHR的DRG中均未检测到Ang Ⅱ的表达，而SHR的DRG中血管紧张素转换酶mRNA的表达水平显著高于WKY（P < 0.01）。WKY和SHR背根节AT（1）受体表达无明显差异。因此，从SHR分离的DRG中CGRP释放和cAMP水平的降低可能主要是由Ang II通过自分泌机制激活AT（1）受体引起的。这些观察结果表明，ARB可能通过增加cAMP水平来敏感VR-1激活，从而增加感觉神经元的CGRP释放，从而增加SHR中IGF-I的产生。ARB的这些活性至少可以部分解释其在改善糖尿病和高血压患者胰岛素抵抗等领域的治疗作用。（翻译研究2009;154：142-152）
Insulin-like growth factor-I (IGH-I) is an important cardioprotective substance. We previously reported that sensory neuron stimulation increases IGF-I production by releasing calcitonin gene-related peptide (CGRP) in spontaneously hypertensive rats (SHRs). Because angiotensin II (Ang II) inhibits sensory neuron activation by interacting with Ang II type 1 (AT(1)) receptors, it is possible that AT(1) receptor blockers (ARBs) increase IGF-I production in SHRs. We examined this possibility in the current study, using the ARBs olmesartan, valsartan, losartan, and telmisartan. Plasma, renal, and cardiac levels of CGRP and IGF-I in SHRs were significantly lower than those in normotensive Wistar Kyoto rats (WKYs) (P < 0.01), which increased to levels found in WKYs after the administration of ARBs. These ARB-induced increases in SHRs were completely reversed by pretreatment with capsazepine (CPZ), which is a specific vanilloid receptor-1 (VR-1) antagonist. The mean arterial blood pressure (MABP) was decreased after administration of ARBs in SHRs, and those decreases were reversed by pretreatment with CPZ. The administration of nifedipine decreased MABP but did not increase CGRP or IGF-I levels in SHRs. Baseline CGRP release and cellular cyclic adenosine 3',5'-monophosphate (cAMP) levels in dorsal root ganglion neurons (DRG) isolated from SHRs were significantly lower than those in DRG isolated from WKYs (P < 0.01). Although ARBs reversed decreases in CGRP release and cAMP levels in the presence of Ang II in DRG isolated from WKYs, they increased CGRP release and cAMP levels in the absence of Ang II in DRG isolated from SHRs. Cellular levels of Ang II were not detected in DRG isolated from WKYs or SHRs, but messenger RNA (mRNA) levels for angiotensin-converting enzyme in DRG were significantly higher in SHRs than in WKYs (P < 0.01). The expression of AT(1) receptors in DRG was not different between WKYs and SHRs. Thus, it is likely that decreases in CGRP release and cAMP levels in DRG isolated from SHRs are mainly caused by AT(1) receptor activation by Ang II through an autocrine mechanism. These observations suggest that ARBs might increase CGRP release from sensory neurons by sensitizing VR-1 activation through increases in cAMP levels, which thereby increased the production of IGF-I in SHRs. These activities of ARBs might at least partly explain their therapeutic effects in areas such as improving insulin resistance in patients with diabetes and hypertension. (Translational Research 2009;154:142-152)