Fujisawa Genro, Okada Koji, Muto Shigeaki, Fujita Nobuya, Itabashi Naoki, Kusano Eiji, Ishibashi Shun
Division of Endocrinology and Metabolism, Department of Internal Medicine, Jichi Medical School, Minamikawachi, Tochigi, 329-0498 Japan.
Hypertension. 2003 Mar;41(3):493-8. doi: 10.1161/01.HYP.0000056769.73726.E5. Epub 2003 Feb 17.
Long-term exposure of uninephrectomized rats to desoxycorticosterone acetate (DOCA)/salt induces cardiac fibrosis and hypertrophy through mineralocorticoid receptors (MRs). However, the underlying cellular mechanisms remain unclear. To determine whether Na/H exchange isoform 1 (NHE1) is involved in the cellular mechanisms, we examined the effects of a specific NHE1 inhibitor, cariporide, and an MR antagonist, spironolactone, on DOCA/salt-induced cardiac fibrosis and hypertrophy. Uninephrectomized rats were given 20 mg of DOCA (single subcutaneous injection) plus 0.9% NaCl/0.3% KCl to drink and were killed at 8 days. Two groups of rats given DOCA/salt were treated with either spironolactone (50 mg/kg per day SC) or cariporide (30 mg/kg per day PO) for 8 days. Control rats were treated with only high salt after the operation. The DOCA/salt-induced perivascular collagen deposition was completely abolished by cariporide and spironolactone. DOCA/salt-induced interstitial collagen deposition was partially and completely suppressed by spironolactone and cariporide, respectively. The rats exposed to DOCA/salt had cardiocyte hypertrophy in the subendocardial and subepicardial regions, a finding that was completely inhibited by cariporide but not by spironolactone. In rats given DOCA/salt, NHE1 protein expression was markedly increased. This was partially and completely reversed by spironolactone and cariporide, respectively. We concluded that cardiac NHE1 contributes to DOCA/salt-induced cardiac fibrosis and hypertrophy and that the NHE1 inhibitor cariporide completely prevents the detrimental effects of DOCA/salt on the heart. We also demonstrated that DOCA/salt-induced cardiac injury through the MRs partly occurs through NHE1 activation.
单侧肾切除的大鼠长期暴露于醋酸去氧皮质酮（DOCA）/盐环境中会通过盐皮质激素受体（MRs）诱导心脏纤维化和肥大。然而，其潜在的细胞机制仍不清楚。为了确定钠/氢交换体1（NHE1）是否参与细胞机制，我们研究了特异性NHE1抑制剂卡里波罗德和MR拮抗剂螺内酯对DOCA/盐诱导的心脏纤维化和肥大的影响。对单侧肾切除的大鼠皮下单次注射20mg DOCA，并给予0.9% NaCl/0.3% KCl饮用，8天后处死。两组给予DOCA/盐的大鼠分别用螺内酯（每天50mg/kg，皮下注射）或卡里波罗德（每天30mg/kg，口服）处理8天。对照大鼠术后仅给予高盐处理。卡里波罗德和螺内酯完全消除了DOCA/盐诱导的血管周围胶原沉积。螺内酯和卡里波罗德分别部分和完全抑制了DOCA/盐诱导的间质胶原沉积。暴露于DOCA/盐的大鼠在心内膜下和心外膜下区域出现心肌细胞肥大，这一现象被卡里波罗德完全抑制，但未被螺内酯抑制。在给予DOCA/盐的大鼠中，NHE1蛋白表达明显增加。这一现象分别被螺内酯和卡里波罗德部分和完全逆转。我们得出结论，心脏NHE1促成了DOCA/盐诱导的心脏纤维化和肥大，且NHE1抑制剂卡里波罗德完全预防了DOCA/盐对心脏的有害影响。我们还证明，DOCA/盐通过MRs诱导的心脏损伤部分是通过NHE1激活发生的。
