Matsumura Y, Hashimoto N, Taira S, Kuro T, Kitano R, Ohkita M, Opgenorth T J, Takaoka M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan.
Hypertension. 1999 Feb;33(2):759-65. doi: 10.1161/01.hyp.33.2.759.
We investigated the involvement of actions mediated by endothelin-A (ETA) and endothelin-B (ETB) receptors in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertension in rats. Two weeks after the start of DOCA-salt treatment, rats were given ABT-627 (10 [mg/kg]/d), a selective ETA receptor antagonist; A-192621 (30 [mg/kg]/d), a selective ETB receptor antagonist; or their vehicle for 2 weeks. Uninephrectomized rats without DOCA-salt treatment served as controls. Treatment with DOCA and salt for 2 weeks led to a mild but significant hypertension; in vehicle-treated DOCA-salt rats, systolic blood pressure increased markedly after 3 to 4 weeks. Daily administration of ABT-627 for 2 weeks almost abolished any further increases in blood pressure, whereas A-192621 did not affect the development of DOCA-salt-induced hypertension. When the degree of vascular hypertrophy of the aorta was histochemically evaluated at 4 weeks, there were significant increases in wall thickness, wall area, and wall-to-lumen ratio in vehicle-treated DOCA-salt rats compared with uninephrectomized control rats. The development of vascular hypertrophy was markedly suppressed by ABT-627. In contrast, treatment with A-192621 significantly exaggerated these vascular changes. In vehicle-treated DOCA-salt rats, renal blood flow and creatinine clearance decreased, and urinary excretion of protein, blood urea nitrogen, fractional excretion of sodium, and urinary N-acetyl-beta-glucosaminidase activity increased. Such damage was overcome by treatment with ABT-627 but not with A-192621; indeed, the latter agent led to worsening of the renal dysfunction. Histopathologic examination of the kidney in vehicle-treated DOCA-salt rats revealed tubular dilatation and atrophy as well as thickening of small arteries. Such damage was reduced in animals given ABT-627, whereas more severe histopathologic changes were observed in A-192621-treated animals. These results strongly support the view that ETA receptor-mediated action plays an important role in the pathogenesis of DOCA-salt-induced hypertension. On the other hand, it seems likely that the ETB receptor-mediated action protects against vascular and renal injuries in this model of hypertension. A selective ETA receptor antagonist is likely to be useful for treatment of subjects with mineralocorticoid-dependent hypertension, whereas ETB-selective antagonism alone is detrimental to such cases.
我们研究了内皮素 A（ETA）和内皮素 B（ETB）受体介导的作用在醋酸去氧皮质酮（DOCA）-盐诱导的大鼠高血压发病机制中的参与情况。在 DOCA-盐治疗开始两周后，给大鼠给予 ABT-627（10[mg/kg]/天），一种选择性 ETA 受体拮抗剂；A-192621（30[mg/kg]/天），一种选择性 ETB 受体拮抗剂；或它们的溶媒，持续 2 周。未进行 DOCA-盐治疗的单侧肾切除大鼠作为对照。用 DOCA 和盐治疗 2 周导致轻度但显著的高血压；在给予溶媒的 DOCA-盐大鼠中，收缩压在 3 至 4 周后显著升高。每日给予 ABT-627 2 周几乎消除了血压的任何进一步升高，而 A-192621 不影响 DOCA-盐诱导的高血压的发展。当在 4 周时通过组织化学评估主动脉的血管肥大程度时，与单侧肾切除对照大鼠相比，给予溶媒的 DOCA-盐大鼠的壁厚、壁面积和壁腔比显著增加。ABT-627 显著抑制了血管肥大的发展。相反，用 A-192621 治疗显著加剧了这些血管变化。在给予溶媒的 DOCA-盐大鼠中，肾血流量和肌酐清除率降低，尿蛋白排泄、血尿素氮、钠分数排泄和尿 N-乙酰-β-葡萄糖苷酶活性增加。用 ABT-627 治疗可克服这种损害，但用 A-192621 则不能；事实上，后一种药物导致肾功能障碍恶化。对给予溶媒的 DOCA-盐大鼠的肾脏进行组织病理学检查发现肾小管扩张和萎缩以及小动脉增厚。给予 ABT-627 的动物这种损害减轻，而在给予 A-192621 的动物中观察到更严重的组织病理学变化。这些结果有力地支持了 ETA 受体介导的作用在 DOCA-盐诱导的高血压发病机制中起重要作用的观点。另一方面，在这种高血压模型中，ETB 受体介导的作用似乎对血管和肾脏损伤具有保护作用。选择性 ETA 受体拮抗剂可能对治疗盐皮质激素依赖性高血压患者有用，而单独的 ETB 选择性拮抗对此类病例有害。
