Effects of V2-receptor antagonist tolvaptan and the loop diuretic furosemide in rats with heart failure.
Effects of V2-receptor antagonist tolvaptan and the loop diuretic furosemide in rats with heart failure.
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DOI：
10.1016/j.bcp.2007.11.011
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发表时间：
2008-03
影响因子：
5.8
通讯作者：
P. Veeraveedu;Kenichi Watanabe;Meilei Ma;S. Palaniyandi;K. Yamaguchi;M. Kodama;Y. Aizawa
中科院分区：
文献类型：
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作者：
P. Veeraveedu;Kenichi Watanabe;Meilei Ma;S. Palaniyandi;K. Yamaguchi;M. Kodama;Y. Aizawa
利尿剂经常用于治疗慢性心力衰竭（CHF）患者的液体潴留。不幸的是，它们会导致肾功能下降、电解质消耗和神经激素激活。精氨酸抗利尿激素（AVP）通过v2受体（V2R）促进肾脏水重吸收，其水平在CHF中升高。本研究旨在研究非肽AVP V2R拮抗剂托伐普坦和环状利尿剂速尿在实验性自身免疫性心肌炎后CHF大鼠模型中的利尿作用。用猪心肌蛋白免疫诱导Lewis大鼠CHF，免疫后28 d，口服托伐普坦和速尿28 d。CHF的特征是左心室重构和收缩和舒张功能受损。托伐普坦的利尿作用与速尿相当。与托伐普坦不同，呋塞米显著增加尿钠和钾的排泄。托伐普坦显著提高无电解质水清除率（E-CH2O）或贫血至阳性值，并增加尿AVP排泄。与托伐他坦相比，速尿只提高电解质清除率（E-Cosm），而不提高E-CH2O。利尿剂谱的差异反映了血浆钠和激素水平的变化。托伐普坦剂量依赖性地升高血浆钠浓度，而速尿倾向于降低血浆钠浓度。速尿显著提高血浆肾素活性和醛固酮浓度。另一方面，托伐普坦对这些参数没有影响。我们的研究结果表明，托伐普坦通过从体内清除多余的水分而不激活RAAS或引起血清电解质失衡，对治疗CHF中的水肿状况具有潜在的医学益处。
Diuretics are frequently required to treat fluid retention in patients with chronic heart failure (CHF). Unfortunately, they can lead to a decline in renal function, electrolyte depletion, and neurohormonal activation. Arginine vasopressin (AVP) promotes renal water reabsorption via the V2receptor (V2R) and its levels are increased in CHF. This study was conducted to characterize the diuretic effect of tolvaptan, a non-peptide AVP V2R antagonist, and furosemide, a loop diuretic in a rat model of CHF after experimental autoimmune myocarditis. CHF was elicited in Lewis rats by immunization with porcine cardiac myosin, and 28 days after immunization rats were treated for 28 days with oral tolvaptan, and furosemide. CHF was characterized by left ventricular remodeling and impaired systolic and diastolic function. Tolvaptan produces a diuresis comparable to furosemide. Unlike tolvaptan, furosemide significantly increased urinary sodium and potassium excretion. Tolvaptan markedly elevated electrolyte-free water clearance (E-CH2O) or aquaresis to a positive value and increased urinary AVP excretion. In contrast to tolvaptan, furosemide elevated only electrolyte clearance (E-Cosm) but not E-CH2O. The differences in diuretic profile reflected the changes in plasma sodium and hormone levels. Tolvaptan dose dependently elevated plasma sodium concentration, but furosemide tended to decrease it. Furosemide significantly elevated plasma renin activity and aldosterone concentration. On the other hand, tolvaptan did not affect these parameters. Our results suggest that, tolvaptan have a potential medical benefit for the treatment of edematous conditions in CHF by removing excess water from the body without activating the RAAS or causing serum electrolyte imbalances.