Wang Xin, Nishikimi Toshio, Akimoto Kazumi, Tadokoro Kazuyoshi, Mori Yosuke, Minamino Naoto
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan.
J Hypertens. 2003 Jun;21(6):1171-81. doi: 10.1097/00004872-200306000-00018.
We investigated the pathophysiological role of the cardiac adrenomedullin (AM) system, including the ligand, receptor and amidating activity in the hypertrophied heart in severe hypertension.
We studied the following four groups: control Wistar-Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), 8 weeks captopril-treated SHR-SP, and 8 weeks trichlormethiazide-treated SHR-SP. AM precursor is converted to inactive glycine-extended AM (AM-Gly) and subsequently AM-Gly is converted to active mature AM (AM-m) by enzymatic amidation. We measured AM-m, AM-total (AM-T; AM-T = AM-m + AM-Gly), and atrial natriuretic peptide (ANP) in the plasma and left ventricle (LV) by immunoradiometric assay. We also measured gene expression of AM and ANP was and gene expression and protein levels of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor-activity modifying protein (RAMP) 2 and RAMP3.
At 7 weeks old, SHR-SP had higher blood pressure and ANP mRNA levels and lower plasma AM-T compared with WKY, however, there were no differences in other indices between the two groups. At 17 weeks old, SHR-SP had increased blood pressure, LV weight, plasma and LV ANP levels and mRNA levels of ANP compared with WKY. AM-m and AM-T levels in plasma (AM-m: + 31%; AM-T: + 56%) and the LV (AM-m: + 84%; AM-T: + 31%) were significantly higher in SHR-SP than in WKY. The LV tissue AM-m/AM-T ratio was significantly higher in SHR-SP (93.2%) than in WKY. The mRNA levels of AM, CRLR, and RAMP2 in the LV were significantly higher in SHR-SP than in WKY. Captopril and trichlormethiazide similarly decreased blood pressure and LV hypertrophy with the reduction of the LV AM-m and AM-T levels and mRNA abundance of AM and its receptor component.
These results suggest that cardiac AM system is upregulated in the hypertrophied heart in this hypertension model. Considering that AM acts as an anti-remodeling autocrine and/or paracrine factor, upregulation of the AM system may modulate the pathophysiology in LV hypertrophy.
我们研究了心脏肾上腺髓质素（AM）系统在严重高血压所致肥厚心脏中的病理生理作用，包括配体、受体及酰胺化活性。
我们研究了以下四组：对照Wistar-Kyoto大鼠（WKY）、自发性高血压易中风大鼠（SHR-SP）、卡托普利治疗8周的SHR-SP以及三氯噻嗪治疗8周的SHR-SP。AM前体先转化为无活性的甘氨酸延伸型AM（AM-Gly），随后AM-Gly通过酶促酰胺化转化为活性成熟型AM（AM-m）。我们通过免疫放射分析测定血浆和左心室（LV）中的AM-m、总AM（AM-T；AM-T = AM-m + AM-Gly）及心钠素（ANP）。我们还测定了AM和ANP的基因表达以及AM受体系统组分如降钙素受体样受体（CRLR）、受体活性修饰蛋白（RAMP）2和RAMP3的基因表达及蛋白水平。
7周龄时，与WKY相比，SHR-SP血压更高、ANP mRNA水平更高且血浆AM-T更低，然而，两组间其他指标无差异。17周龄时，与WKY相比，SHR-SP血压升高、左心室重量增加、血浆和左心室ANP水平及ANP mRNA水平升高。SHR-SP血浆（AM-m：升高31%；AM-T：升高56%）和左心室（AM-m：升高84%；AM-T：升高31%）中的AM-m和AM-T水平显著高于WKY。SHR-SP左心室组织AM-m/AM-T比值（93.2%）显著高于WKY。SHR-SP左心室中AM、CRLR和RAMP2的mRNA水平显著高于WKY。卡托普利和三氯噻嗪同样降低了血压和左心室肥厚，同时降低了左心室AM-m和AM-T水平以及AM及其受体组分的mRNA丰度。
这些结果表明在该高血压模型中，肥厚心脏中的心脏AM系统上调。鉴于AM作为一种抗重塑自分泌和/或旁分泌因子，AM系统上调可能调节左心室肥厚中的病理生理过程。
