ANGIOTENSIN II REGULATION OF RENAL FUNCTION IN PATIENTS W/ MILD CHF ON DIURETICS

到目前为止，氯沙坦对人类充血性心力衰竭患者肾功能的影响仍不明确。如果肾脏血管紧张素Ⅱ的激活先于循环血管紧张素Ⅱ的增加，这一过程可能在ALVD向显性CHF的转变过程中起着重要的作用。本研究的主要目的是明确血管紧张素转换酶II在轻度充血性心力衰竭患者肾血流动力学和肾小管功能调节以及钠调节激素控制中的作用。目前的工作假设是，AT1受体拮抗剂在轻度人CHF中将导致GFR的改善，肾血管阻力(RVR)的降低，同时伴随着肾小管钠重吸收的减少和钠排泄的增加。或者，如果AT1受体拮抗剂导致动脉压过度降低，则预期的肾功能改善可能被取消。本研究的具体目的是：1)测定接受利尿剂治疗的轻度充血性心力衰竭患者的肾血流动力学、肾小管功能和循环钠调节激素。2)检测利尿剂治疗轻度充血性心力衰竭患者的肾血流动力学、肾小管功能及循环钠调节激素水平。共有10名受试者将采用双盲、安慰剂对照和交叉设计进行研究。经过长达三周的固定钠饮食后，受试者将进入明尼苏达州罗切斯特市梅奥诊所的GCRC，在那里，他们将在口服50毫克氯沙坦/安慰剂前后接受肾脏清除测试，以确定氯沙坦对肾脏的影响。在每个清除期结束时采集尿样，用于测定尿量、钠、钾、多环芳烃、菊粉、ET、cGMP、ANP和BNP。在每个清除期中期采集静脉血，测定PAH、胰岛素、Na、红细胞压积、PRA、Aldo、ANP、BNP、CNP、ET、NE、cGMP、氯沙坦和Ang II。经过两个星期的洗涤期后，受试者将返回GCRC进行交叉研究。本研究将首次建立急性AT1受体抑制对慢性利尿剂治疗的轻度心力衰竭患者的肾血流动力学和肾小管效应的影响。因此，这些研究将对肾内肾素-血管紧张素系统在轻度心力衰竭中的作用提供新的理解。这项研究应该为进一步的长期研究奠定基础，验证AT1受体拮抗剂可能部分通过肾脏机制延缓ALVD向显性CHF转变的假说。一名患者在GCRC进行了研究。其余的研究是在梅奥市中心的肾脏实验室进行的。

To date, renal effects of losartan on renal function in human CHF remains undefined. If renal ANG II activation precedes increases in circulating ANG II, this process may play a fundamental step in the transition from ALVD to overt CHF. The broad objective of the current proposal is to define the role of ANG II in the regulation of renal hemodynamics and tubular function and in the control of sodium regulating hormones in humans with mild CHF. The working hypothesis of the current proposal is that AT1 receptor antagonism in mild human CHF will result in an improvement in GFR, a reduction in renal vascular resistance (RVR),in association wit a decrease in tubular sodium reabsorption and an increase in sodium excretion. Alternatively, if AT1 receptor antagonism results in an excessive reduction in arterial pressure, the predicted improvement in renal function may be abrogated. The specific aims of the current study are: 1) To determine renal hemodynamic and tubular function and circulating sodium regulating hormones in humans with mild CHF receiving diuretics. 2) To determine renal hemodynamic and tubular function and circulating sodium regulating hormones in humans with mild CHF on diuretics. A total of 10 subjects will be studied in a double blind, placebo-control and cross over design. After up to three weeks of a fixed sodium diet, subjects will be admitted to the GCRC at Mayo Clinic, Rochester, MN, where they will undergo renal clearance test before and after oral administration of 50 mg losartan/placebo to determine the renal effects of losartan. Urinary samples for determination of volume, sodium, potassiu, PAH, inulin, ET, cGMP, ANP and BNP will be obtained at the end of each clearance period. Venous blood samples for PAH, insulin, Na, hematocrit, PRA, aldo, ANP, BNP, CNP, ET, NE, cGMP, losartain and ANG II will be obtained at the middle of each clearance period. After a two week washout period, the subjects will return to the GCRC for the cross-over study. This study will etablish for the first time the renal hemodynaimc and tubular effects of acute AT1 receptor inhibition in patients with mild heart failure on chronic diuretics. Thus, these studies will provide a new understanding of the role of intra-renal renin-angiotensin system in mild heart failure. This study should lay the foundation for further long term studies testing the hypothesis that AT1 receptor antagonism may delay the transition of ALVD to overt CHF in part via renal mechanisms. One patient was studied in the GCRC. The remainder of the studies were conducted in the Renal Laboratory on the downtown Mayo campus.