Jesmin Subrina, Zaedi Sohel, Maeda Seiji, Togashi Hiroko, Yamaguchi Iwao, Goto Katsutoshi, Miyauchi Takashi
Department of Cardiovascular Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki 305-8575, Japan.
Exp Biol Med (Maywood). 2006 Jun;231(6):919-24.
Endothelin-1 (ET-1) has been implicated in hypertension, heart failure, atherosclerosis, and pulmonary hypertension. In all these conditions, plasma immunoreactive ET-1 levels are elevated, and tissue ET-1 expression is increased. Clinical trials have demonstrated potentially important benefits of ET antagonism among patients with essential hypertension, pulmonary hypertension, and heart failure. It is unknown whether ET antagonism affects the production of ET-1 in stroke-prone spontaneously hypertensive rat (SHRSP) heart at the typical hypertensive stage. The objective of this study was to investigate the effects of ET blockade on the expression levels of plasma and cardiac ET-1 in SHRSPs. SHRSPs were treated for 3 months with SB209670 (ET(A)/ET(B) dual receptor antagonist) or with saline (vehicle) commencing at the prehypertensive stage (age 6 weeks). Plasma and left ventricular ET-1 peptide levels were measured using enzyme-linked immunoabsorbent assay. Compared with age-matched control Wistar-Kyoto rats, peptide levels of ET-1 were significantly upregulated in vehicle-treated SHRSP heart; this upregulation was reversed by long-term ET antagonism. Plasma ET-1 levels were also significantly increased in vehicle-treated SHRSPs and were normalized by ET antagonism. mRNA expression of preproET-1, which is the source of ET-1 peptide production, was significantly increased in vehicle-treated SHRSP heart and was normalized by ET antagonism. Marked cardiac hypertrophy and fibrosis at the histologic level in SHRSPs were ameliorated by ET antagonism, and left ventricular hypertrophy as seen on echocardiography in SHRSPs was suppressed by ET blockade. After ET antagonism, systolic blood pressures were reduced in SHRSPs; diastolic blood pressures were unchanged. The reversal effect of the upregulated ET system in SHRSP heart by ET antagonism might be independent of blood pressure change. By suppressing the upregulated ET system, ET antagonism might be beneficial in arresting cardiac remodeling.
内皮素-1（ET-1）与高血压、心力衰竭、动脉粥样硬化和肺动脉高压有关。在所有这些病症中，血浆免疫活性ET-1水平升高，组织ET-1表达增加。临床试验表明，ET拮抗作用对原发性高血压、肺动脉高压和心力衰竭患者具有潜在的重要益处。目前尚不清楚ET拮抗作用是否会影响易中风自发性高血压大鼠（SHRSP）心脏在典型高血压阶段ET-1的产生。本研究的目的是探讨ET阻断对SHRSPs血浆和心脏ET-1表达水平的影响。从高血压前期（6周龄）开始，用SB209670（ET(A)/ET(B)双受体拮抗剂）或生理盐水（载体）对SHRSPs进行3个月的治疗。使用酶联免疫吸附测定法测量血浆和左心室ET-1肽水平。与年龄匹配的对照Wistar-Kyoto大鼠相比，载体处理的SHRSP心脏中ET-1的肽水平显著上调；这种上调通过长期ET拮抗作用得以逆转。载体处理的SHRSPs血浆ET-1水平也显著升高，并通过ET拮抗作用恢复正常。作为ET-1肽产生来源的前ET-1原的mRNA表达在载体处理的SHRSP心脏中显著增加，并通过ET拮抗作用恢复正常。ET拮抗作用改善了SHRSPs组织学水平上明显的心脏肥大和纤维化，并且ET阻断抑制了SHRSPs超声心动图上可见的左心室肥大。ET拮抗作用后，SHRSPs的收缩压降低；舒张压未改变。ET拮抗作用对SHRSP心脏中上调的ET系统的逆转作用可能与血压变化无关。通过抑制上调的ET系统，ET拮抗作用可能有助于阻止心脏重塑。
