Matsumura Y, Kuro T, Kobayashi Y, Konishi F, Takaoka M, Wessale J L, Opgenorth T J, Gariepy C E, Yanagisawa M
Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Nasahara, Takatsuki, Osaka, Japan.
Circulation. 2000 Nov 28;102(22):2765-73. doi: 10.1161/01.cir.102.22.2765.
Endothelin (ET)-1 plays an important role in the pathogenesis of deoxycorticosterone acetate (DOCA)-salt-induced hypertension. We evaluated the pathological role of ET(B) receptors in DOCA-salt-induced hypertension, cardiovascular hypertrophy, and renal damage by using the spotting-lethal (sl) rat, which carries a naturally occurring deletion in the ET(B) receptor gene.
Homozygous (sl/sl) rats exhibit abnormal development of neural crest-derived epidermal melanocytes and the enteric nervous system, and they do not live beyond 1 month because of intestinal aganglionosis and intestinal obstruction. The dopamine ss-hydroxylase (DssH) promoter was used to direct ET(B) transgene expression in sl/sl rats to support normal enteric nervous system development. DssH-ET(B) sl/sl rats live into adulthood and are healthy, expressing ET(B) receptors in adrenal glands and other adrenergic neurons. When homozygous (sl/sl) and wild-type (+/+) rats, all of which were transgenic, were treated with DOCA-salt, homozygous rats exhibited earlier and higher increases in systolic blood pressure than did wild-type rats. Chronic treatment with ABT-627, an ET(A) receptor antagonist, completely suppressed DOCA-salt-induced hypertension in both groups. Renal dysfunction and histological damage were more severe in homozygous than in wild-type rats. Marked vascular hypertrophy was observed in homozygous rats than in wild-type rats. Renal and vascular injuries were significantly improved by ABT-627. In DOCA-salt-treated homozygous rats, there were notable increases in renal, urinary, and aortic ET-1, all of which were normalized by ABT-627.
ET(B)-mediated actions are protective in the pathogenesis of DOCA-salt-induced hypertension. Enhanced ET-1 production and ET(A)-mediated actions are responsible for the increased susceptibility to DOCA-salt hypertension and tissue injuries in ET(B) receptor-deficient rats.
内皮素（ET）-1在醋酸脱氧皮质酮（DOCA）-盐诱导的高血压发病机制中起重要作用。我们通过使用斑点致死（sl）大鼠评估ET（B）受体在DOCA-盐诱导的高血压、心血管肥大和肾损伤中的病理作用，该大鼠的ET（B）受体基因存在天然缺失。
纯合子（sl/sl）大鼠表现出神经嵴衍生的表皮黑素细胞和肠神经系统发育异常，由于肠道神经节缺失和肠梗阻，它们存活不超过1个月。多巴胺β-羟化酶（DβH）启动子用于指导sl/sl大鼠中ET（B）转基因表达，以支持正常的肠神经系统发育。DβH-ET（B）sl/sl大鼠存活至成年且健康，在肾上腺和其他肾上腺素能神经元中表达ET（B）受体。当纯合子（sl/sl）和野生型（+/+）大鼠（均为转基因大鼠）接受DOCA-盐处理时，纯合子大鼠收缩压升高比野生型大鼠更早且更高。用ET（A）受体拮抗剂ABT-627进行慢性治疗可完全抑制两组DOCA-盐诱导的高血压。纯合子大鼠的肾功能障碍和组织学损伤比野生型大鼠更严重。与野生型大鼠相比，纯合子大鼠观察到明显的血管肥大。ABT-627可显著改善肾和血管损伤。在DOCA-盐处理的纯合子大鼠中，肾、尿和主动脉ET-1显著增加，所有这些均通过ABT-627恢复正常。
ET（B）介导的作用在DOCA-盐诱导的高血压发病机制中具有保护作用。ET-1产生增加和ET（A）介导的作用导致ET（B）受体缺陷大鼠对DOCA-盐高血压和组织损伤的易感性增加。
