Intermedin in Paraventricular Nucleus Attenuates Sympathetic Activity and Blood Pressure via Nitric Oxide in Hypertensive Rats
Intermedin in Paraventricular Nucleus Attenuates Sympathetic Activity and Blood Pressure via Nitric Oxide in Hypertensive Rats
复制标题
室旁核中的 Intermedin 通过一氧化氮减弱高血压大鼠的交感神经活动和血压
DOI：
10.1161/hypertensionaha.113.01681
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发表时间：
2014-02-01
期刊：
影响因子：
8.3
通讯作者：
Zhu, Guo-Qing
中科院分区：
文献类型：
--
作者：
Zhou, Ye-Bo;Sun, Hai-Jian;Zhu, Guo-Qing
中介素(Intermedin，IMD)是降钙素/降钙素基因相关肽家族的一员，其受体系统由降钙素受体样受体(CRLR)和受体活性修饰蛋白(RAMP)组成。本研究探讨了室旁核(PVN)内IMD对高血压患者肾交感神经活动和平均动脉压的影响及其下游机制。采用双肾一夹(2K1C)手术诱导大鼠肾血管性高血压或假手术。4周后在麻醉状态下进行急性实验。2K1C大鼠IMD基因和蛋白表达下调。经肾上腺髓质素受体拮抗剂AM22-52或非选择性一氧化氮合酶抑制剂NG-硝基-L-精氨酸甲酯预处理后，选择性神经元型一氧化氮合酶抑制剂N-omega-丙基-L-精氨酸盐酸盐或内皮一氧化氮合酶抑制剂N(5)-(1-亚氨基乙基)-L-鸟氨酸二盐酸盐可拮抗上述作用。AM22-52增加2K1C大鼠的肾交感神经活动和平均动脉压，但对假手术大鼠无明显影响，而降钙素/降钙素基因相关肽受体拮抗剂降钙素/降钙素基因相关肽8-37对其无明显影响。2K1C组大鼠室旁核CRLR、RAMP3基因表达增加，CRLR、RAMP2、RAMP3蛋白表达增加。2K1C大鼠PVN内微量注射IMD可增加PVN内NO代谢产物(NOx)水平，AM22-52可拮抗此作用。清醒2K1C大鼠PVN慢性输注IMD降低，AM22-52升高。这些结果表明，下丘脑室旁核内的IMD抑制2K1C大鼠的交感神经活动，并通过肾上腺髓质素受体(CRLR/RAMP2或CRLR/RAMP3)及其下游的NO介导高血压。
Intermedin (IMD) is a member of calcitonin/calcitonin gene-related peptide family, which shares the receptor system consisting of calcitonin receptor-like receptor (CRLR) and receptor activity-modifying proteins (RAMPs). This study investigated the effects of IMD in paraventricular nucleus (PVN) on renal sympathetic nerve activity and mean arterial pressure and its downstream mechanism in hypertension. Rats were subjected to 2-kidney 1-clip (2K1C) surgery to induce renovascular hypertension or sham operation. Acute experiments were performed 4 weeks later under anesthesia. IMD mRNA and protein were downregulated in 2K1C rats. Bilateral PVN microinjection of IMD caused greater decreases in renal sympathetic nerve activity and mean arterial pressure in 2K1C rats than in sham-operated rats, which were prevented by pretreatment with adrenomedullin receptor antagonist AM22-52 or nonselective nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine methyl ester, and attenuated by selective neuronal NO synthase inhibitor N-omega-propyl-l-arginine hydrochloride or endothelial NO synthase inhibitor N(5)-(1-iminoethyl)-l-ornithine dihydrochloride. AM22-52 increased renal sympathetic nerve activity and mean arterial pressure in 2K1C rats but not in sham-operated rats, whereas calcitonin/calcitonin gene-related peptide receptor antagonist calcitonin/calcitonin gene-related peptide 8-37 had no significant effect. CRLR and RAMP3 mRNA, as well as CRLR, RAMP2, and RAMP3 protein expressions, in the PVN were increased in 2K1C rats. Microinjection of IMD into the PVN increased the NO metabolites (NOx) level in the PVN in 2K1C rats, which was prevented by AM22-52. Chronic PVN infusion of IMD reduced, but AM22-52 increased, blood pressure in conscious 2K1C rats. These results indicate that IMD in the PVN inhibits sympathetic activity and attenuates hypertension in 2K1C rats, which are mediated by adrenomedullin receptors (CRLR/RAMP2 or CRLR/RAMP3) and its downstream NO.