血管紧张素转换酶抑制剂和血管紧张素Ⅱ1型受体拮抗剂对大鼠慢性一氧化氮合成抑制所致心脏重塑的亚细胞差异作用

Differential subcellular actions of ACE inhibitors and AT(1) receptor antagonists on cardiac remodeling induced by chronic inhibition of NO synthesis in rats.

作者信息

Sanada S, Kitakaze M, Node K, Takashima S, Ogai A, Asanuma H, Sakata Y, Asakura M, Ogita H, Liao Y, Fukushima T, Yamada J, Minamino T, Kuzuya T, Hori M

机构信息

Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine, Suita, Japan.

出版信息

Hypertension. 2001 Sep;38(3):404-11. doi: 10.1161/01.hyp.38.3.404.

DOI:10.1161/01.hyp.38.3.404

PMID:11566913

Abstract

Chronic inhibition of NO synthesis induces cardiac hypertrophy independent of systemic blood pressure (SBP) by increasing protein synthesis in vivo. We examined whether ACE inhibitors (ACEIs) enalapril and temocapril and angiotensin II type-I receptor antagonists (angiotensin receptor blockers [ARBs]) losartan and CS-866 can block cardiac hypertrophy and whether changes in activation of 70-kDa S6 kinase (p70S6K) or extracellular signal-regulated protein kinase (ERK) are involved. The following 13 groups were studied: untreated Wistar-Kyoto rats and rats treated with NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME), D-NAME (the inactive isomer of L-NAME), L-NAME plus hydralazine, L-NAME plus enalapril (3 mg. kg(-1). d(-1)) or temocapril (1 or 10 mg. kg(-1). d(-1)), L-NAME plus losartan (10 mg. kg(-1). d(-1)) or CS-866 (1 or 10 mg. kg(-1). d(-1)), L-NAME plus temocapril-CS866 in combination (1 or 10 mg. kg(-1). d(-1)), and L-NAME plus rapamycin (0.5 mg. kg(-1). d(-1)). After 8 weeks of each experiment, ratios of coronary wall to lumen (wall/lumen) and left ventricular weight to body weight (LVW/BW) were quantified. L-NAME increased SBP, wall/lumen, and LVW/BW compared with that of control. ACEIs, ARBs, and hydralazine equally canceled the increase in SBP induced by L-NAME. However, ACEIs and ARBs equally (but not hydralazine) attenuated increase in wall/lumen and LVW/BW induced by L-NAME. The L-NAME group showed both p70S6K and ERK activation in myocardium (2.2-fold and 1.8-fold versus control, respectively). ACEIs inactivated p70S6K and ARBs inactivated ERK in myocardium, but hydralazine did not change activation of either kinase. Thus, ACEIs and ARBs modulate different intracellular signaling pathways, inhibiting p70S6K or ERK, respectively, to elicit equal reduction of cardiac hypertrophy induced by chronic inhibition of NO synthesis in vivo.

摘要

长期抑制一氧化氮合成可通过增加体内蛋白质合成诱导心脏肥大，且与全身血压（SBP）无关。我们研究了血管紧张素转换酶抑制剂（ACEIs）依那普利和替莫卡普利以及血管紧张素II 1型受体拮抗剂（血管紧张素受体阻滞剂[ARBs]）氯沙坦和CS-866是否能阻止心脏肥大，以及70 kDa S6激酶（p70S6K）或细胞外信号调节蛋白激酶（ERK）的激活变化是否与之有关。研究了以下13组：未处理的Wistar-Kyoto大鼠以及用一氧化氮合酶抑制剂Nω-硝基-L-精氨酸甲酯（L-NAME）、D-NAME（L-NAME的无活性异构体）、L-NAME加肼屈嗪、L-NAME加依那普利（3 mg·kg⁻¹·d⁻¹）或替莫卡普利（1或10 mg·kg⁻¹·d⁻¹）、L-NAME加氯沙坦（10 mg·kg⁻¹·d⁻¹）或CS-866（1或10 mg·kg⁻¹·d⁻¹）、L-NAME加替莫卡普利 - CS866联合用药（1或10 mg·kg⁻¹·d⁻¹）以及L-NAME加雷帕霉素（0.5 mg·kg⁻¹·d⁻¹）处理的大鼠。每项实验8周后，对冠状动脉壁与管腔比值（壁/腔）以及左心室重量与体重比值（LVW/BW）进行定量分析。与对照组相比，L-NAME增加了SBP、壁/腔和LVW/BW。ACEIs、ARBs和肼屈嗪同样消除了L-NAME诱导的SBP升高。然而，ACEIs和ARBs同样（但肼屈嗪不行）减弱了L-NAME诱导的壁/腔和LVW/BW升高。L-NAME组心肌中p70S6K和ERK均被激活（分别是对照组的2.2倍和1.8倍）。ACEIs使心肌中的p70S6K失活，ARBs使心肌中的ERK失活，但肼屈嗪未改变这两种激酶的激活状态。因此，ACEIs和ARBs调节不同的细胞内信号通路，分别抑制p70S6K或ERK，从而同等程度地减轻体内长期抑制一氧化氮合成所诱导的心脏肥大。