Harada Naoaki, Shimozawa Nobuhiko, Okajima Kenji
Department of Translational Medical Science Research, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Transl Res. 2009 Sep;154(3):142-52. doi: 10.1016/j.trsl.2009.06.004. Epub 2009 Jul 7.
Insulin-like growth factor-I (IGF-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.
胰岛素样生长因子-I（IGF-I）是一种重要的心脏保护物质。我们之前报道过，在自发性高血压大鼠（SHRs）中，感觉神经元刺激通过释放降钙素基因相关肽（CGRP）来增加IGF-I的产生。由于血管紧张素II（Ang II）通过与1型血管紧张素II（AT(1)）受体相互作用来抑制感觉神经元的激活，因此AT(1)受体阻滞剂（ARBs）有可能增加SHRs中IGF-I的产生。在本研究中，我们使用奥美沙坦、缬沙坦、氯沙坦和替米沙坦这几种ARBs来检验这种可能性。SHRs的血浆、肾脏和心脏中CGRP和IGF-I的水平显著低于正常血压的Wistar Kyoto大鼠（WKYs）（P < 0.01），在给予ARBs后，这些水平升高至WKYs中的水平。这些ARBs在SHRs中引起的升高被辣椒素（CPZ）预处理完全逆转，CPZ是一种特异性的香草酸受体-1（VR-1）拮抗剂。给予ARBs后，SHRs的平均动脉血压（MABP）降低，而这些降低被CPZ预处理逆转。硝苯地平的给药降低了MABP，但没有增加SHRs中CGRP或IGF-I的水平。从SHRs分离的背根神经节神经元（DRG）中的基线CGRP释放和细胞环磷酸腺苷（cAMP）水平显著低于从WKYs分离的DRG中的水平（P < 0.01）。尽管ARBs在从WKYs分离的DRG中存在Ang II的情况下逆转了CGRP释放和cAMP水平的降低，但它们在从SHRs分离的DRG中不存在Ang II的情况下增加了CGRP释放和cAMP水平。在从WKYs或SHRs分离的DRG中未检测到细胞内的Ang II水平，但SHRs中DRG的血管紧张素转换酶信使核糖核酸（mRNA）水平显著高于WKYs（P < 0.01）。WKYs和SHRs之间DRG中AT(1)受体的表达没有差异。因此，从SHRs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，ARBs可能通过增加cAMP水平来使VR-1激活敏感化，从而增加感觉神经元中CGRP的释放，进而增加SHRs中IGF-I的产生。ARBs的这些作用可能至少部分解释了它们在改善糖尿病和高血压患者胰岛素抵抗等方面的治疗效果。
