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作者：Horng H.Chen, Margaret M.Redfield, Linda J.Nordstrom, AlessandroCataliotti, John C.Burnett Jr.作者单位：Cardiorenal Research Laboratory, Division ofCardiovascular Diseases, Mayo Clinic, Rochester, Minnesota 55905
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5 c) a# G: F. u# ] 【摘要】
# C+ x1 C$ \6 o' P+ b Although effective in relieving symptomsof edema in congestive heart failure (CHF), diuretic-inducednatriuresis may be associated with reductions in glomerular filtrationrate (GFR) and effective renal plasma flow (ERPF), which subsequentlymay reduce the duration of natriuresis. Moreover, recent studies havereported that the preservation of GFR is an important predictor ofsurvival in human CHF. We hypothesized that the acute detrimental renalhemodynamic and tubular responses to furosemide in symptomatic humanCHF will be attenuated by AT 1 receptor blockade withlosartan. We defined the renal hemodynamic and tubular actions andaldosterone responses to furosemide (40 mg, orally) in the presence ofacute AT 1 receptor antagonism (losartan, MSD, 50 mg orally)vs. placebo in 10 subjects with CHF (New York Heart Association II-III)in a double-blind, placebo-controlled crossover study. Furosemide withplacebo increased sodium excretion and reduced ERPF and GFR( P After 4 h,sodium excretion compared with baseline was decreased ( P a greater increase in sodium excretion but withoutreductions in ERPF and GFR ( P was greater compared with the placebogroup. Importantly, plasma aldosterone tended to increase in theplacebo group, whereas it was decreased ( P These studies underscore thepathophysiological role of the AT 1 receptor in mediatingdetrimental renal and adrenal properties of diuretics in human CHF.AT 1 receptor antagonism preserves GFR and renal blood flowand enhances sodium excretion during acute diuretic therapy in additionto inhibiting aldosterone secretion. These findings support the use ofAT 1 receptor blockade for human CHF requiring acutediuretics to improve renal hemodynamic and tubular function and tosuppress aldosterone.
3 S* n0 @* r Y0 F' q' `& O+ b 【关键词】 kidney congestive heart failure aldosterone glomerularfiltration rate
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- X8 O( [" W' ^- ]5 C9 r# _' sDIURETICS REMAIN a mainstay of heart failure therapy to treat the symptomsof congestive heart failure (CHF) such as edema and dyspnea. Despitethe widespread and long history of use of diuretics in CHF, acute andchronic detrimental actions of diuretics continue to emerge ( 4, 12 ). Overdiuresis may lead to excessive preload reduction andsystemic hypotension with worsening heart failure. A well-establishedresponse to diuretic use is the activation of therenin-angiotensin-aldosterone system (RAAS), which may compromiseglomerular filtration rate (GFR) and limit the natriuretic response ofthe kidney ( 4 ).# D; s0 X$ L8 v# v, X" Y- c* _! F
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Recent studies have reported that the preservation of GFR is animportant predictor of better long-term survival in human CHF ( 3, 5 ). Although increased circulating and tissue ANG II in CHF hasbeen demonstrated, recent studies from our laboratory by Luchner et al.( 7 ) established that throughout the evolution of CHF,renal ANG II concentrations exceed concentrations in other tissues.This observation further supports the importance of ANG II as a majorfactor in mediating renal vasoconstriction and enhanced sodiumreabsorption in CHF. Importantly, angiotensin-converting enzymeinhibitor (ACEI) in CHF in the presence of diuretic therapy results inrenal vasodilatation and natriuresis with variable responses in GFR( 10 ). Although a reduction in ANG II generation has beenimplicated as the mechanism of the renal response to ACEI, thesimultaneous accumulation of the renal vasodilating and natriureticpeptide bradykinin makes interpretation of these recent reportsdifficult and controversial.
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# U! B `1 _$ H1 k# b: g7 X# YCharacterization of the importance of ANG II in the control of renalhemodynamic and tubular function in human CHF is now possible with theavailability of specific ANG II AT 1 receptor antagonists.These pharmacological agents have a high affinity for theAT 1 receptor and have no agonistic activity. Among these antagonists, losartan effectively inhibits ANG II bound to specific renal receptors ( 11 ). Administration of losartan to renalhypertensive rats results in a dose-dependent decrease in bloodpressure. Losartan may also increase renal blood flow and sodiumexcretion in normotensive and hypertensive dogs ( 14 ). Inhealthy volunteers, losartan abolishes the blood pressure response toexogenous ANG II. Furthermore, sodium status is an importantdeterminant of the therapeutic efficacy of ACEIs, an AT 1 receptor antagonist, and renin inhibitors. The correction ofvolume expansion by dietary sodium restriction, diuretic therapyconsiderably modifies the effects of ACE inhibition on blood pressure,renal hemodynamics, and proteinuria ( 9 ).
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X V& ~0 F" W% v0 pTo date, the role of AT 1 receptors in the regulation ofrenal function in human CHF receiving acute diuretic therapy remains undefined. Therefore, the objective of the present study was to definethe role of AT 1 receptors in the regulation of renalhemodynamics, tubular function, and in the control of sodium-regulatinghormones in humans with CHF receiving acute diuretic therapy. Wehypothesized that AT 1 receptor antagonism in human CHFsubjects receiving acute diuretic therapy would result in animprovement in GFR and effective renal plasma flow (ERPF) withsuppression of aldosterone (Aldo) and a greater natriuresis.5 J0 q* @% |5 B2 r+ w! M
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METHODS# f0 L; O, _1 D0 p! c) l
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Study population. Subjects recruited were limited to men and women, aged 18 yr and above,who had a resting left ventricular ejection fraction of 35% or lesswith stable symptomatic CHF [New York Heart Association (NYHA) ClassII and III] as defined by the criteria outlined by the NYHAclassification. Before initiation of the study, patients werestabilized for 1 wk on a 120-meq Na/day diet. A 24-h urine collectionwas obtained 3 days before the active study day to ensure compliancewith the diet. Subjects remained on stable doses of diuretics, digoxinand ACEI, for 2 wk before the study. Patients on long-acting ACEIs wereswitched to equivalent doses of the short-acting ACEI captopril 2 wkbefore the study, which was withheld 72 h before each study day.Therapies with other cardiovascular medications were allowed, providedstable dosing was applied for 2 wk preceding the study.Sulfa-containing medications and probenecid were withdrawn for 72 h before the study. Subjects were instructed to avoid strenuousphysical activity and to abstain from smoking, alcohol, andcaffeine-containing drinks 3 days before the first study day andthroughout the 72-h study period. All patients gave informed consent,and the study was approved by the institutional review board at our institution.5 H/ P# A; e% j$ E1 q
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Study design and protocol. A total of 10 subjects was studied in a randomized double-blind,placebo-controlled, and crossover design. All subjects received an oraldose of furosemide (40 mg) and were randomized to receive a single doseof losartan (Merck; 50 mg) or placebo. Subjects returned 2 wk later forthe crossover study.
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8 f4 b4 m5 [4 C2 x3 m2 p% m) i! JAfter ~2 wk of the controlled diet, subjects were admitted to theGeneral Clinical Research Center (GCRC) at St. Mary's Hospital, MayoClinic and Foundation, Rochester, MN, the evening before the scheduledactive study day. On the active study day, they were given their usualmedications except captopril, which was held for 72 h before thestudy day at 6 AM, and they were placed in the supine position for1 h of equilibration. Standard intravenous heparin lock was placedfor infusion and blood sampling. After a priming dose, an intravenousinfusion of inulin and para-aminohippurate (PAH) was started to providea plasma concentration of ~400 and 20 µg/ml, respectively. Subjectswere asked to empty their bladder spontaneously every 30 min throughoutthe renal clearance protocol. At the end of each period, the patientswere asked to drink an amount of water equivalent to the sum of bloodlosses and urinary volume.
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After 1 h of equilibration, a 60-min baseline period was observed.At the end of the baseline period, the subjects were given an oral doseof 40 mg of furosemide and randomized to receive a single dose oflosartan (50 mg) or placebo. Thereafter, 60-min clearance periods wererepeated for 4 h and a final clearance was done at 8 hpost-losartan/placebo administration. During each clearance period,urinary, hormonal, and hemodynamic measurements were obtained andaveraged for analysis. Blood pressure was measured at 10-min intervalsby using automatic blood pressure and heart rate continuously monitoredby electrocardiographic lead II. Urinary samples for determination ofvolume, sodium, PAH, and insulin were obtained at the end of eachclearance period. Venous blood samples for PAH, inulin, sodium, renin,and Aldo were obtained at the middle of each clearance period. Thepatients underwent a 2-wk washout period, after which they returned tothe GCRC for the crossover study.5 X5 u% o9 k1 H7 C1 ?& |/ }' F3 ~2 D
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Analytic methods. GFR was calculated from the clearance of inulin; ERPF was determinedfrom the clearance of PAH. The method of determination of ERPF with PAHis based on previous studies performed in subjects in the supineposition. Plasma and urine were analyzed for inulin by the anthronemethod, for PAH by the method of Harvey and Brothers, and for sodiumwith the Beckman ion-selective analyzer. Plasma renin activity and Aldowere measured by appropriate radioimmunoassays as previously describled( 2 ).
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: R8 o! T! |2 G: w }$ g: wStatistical analysis. Values will be expressed as means ± SE. Comparison within a groupwas assessed by repeated-measures ANOVA and post hoc Dunnett's testbefore. Comparison between losartan and placebo was assessed by two-wayANOVA test for simultaneous multiple comparisons. A statisticallysignificant difference will be considered to be present when P
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; ^# K4 d3 o1 e5 s- _Clinical characteristics. A total of 10 subjects with stable NYHA class II-III CHF was studied,eight were men and two were women with a mean age of 64 ± 5 yr.Three subjects had idiopathic dilated cardiomyopathy, and the remainingseven had ischemic cardiomyopathy. The mean ejection fractionwas 24 ± 6%, and mean plasma creatinine was 1.2 ± 0.1 mg/dl. All subjects were on stable doses of diuretics, digoxin and ACEIfor 2 wk before enrollment, and seven were receiving -blockertherapy. The mean dose of furosemide that the patients were takingbefore the study was 40 ± 8 mg daily. No patient had serum sodiumof less than 135 meq/l. All the subjects tolerated the study wellwithout any adverse events. Baseline renal and neurohumoral functionare reported in Table 1.2 S/ w ~6 v5 u0 j& J
; W- Y7 p. k. s- t1 x2 yTable 1. Baseline renal and neurohumoral characteristics
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Renal function. The responses in urinary sodium excretion (U Na V) andurinary flow from baseline after the administration of furosemide in combination with losartan or placebo are illustrated in Fig. 1. The increase of U Na V withfurosemide plus losartan was greater compared with furosemide plusplacebo ( P More importantly, at480 min after administration of furosemide plus placebo,U Na V was less compared with baseline, whereas with furosemide plus losartan this delayed sodium retention was abolished. The increase in urinary flow was greater with furosemide plus losartancompared with furosemide plus placebo ( P ANOVA)./ l4 l) g" ~' Z6 m
- ?; P) z; r" u7 o+ w7 R; Z& G2 o* }Fig. 1. Change from baseline (BL; baseline) in sodiumexcretion and urinary flow at 60, 120, 140, 180, and 480 min after theadministration of furosemide and losartan (broken line) or furosemideand placebo (solid line). * P
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. [4 ?3 c$ q* g& FThe responses in GFR, ERPF, and mean arterial blood pressure (MAP) frombaseline after administration of furosemide in combination withlosartan or placebo are illustrated in Fig. 2. Furosemide plus losartan resulted in agreater decrease in MAP compared with furosemide plus placebo( P ERPF decreasedwith furosemide plus placebo, whereas GFR and ERPF were preserved withfurosemide plus losartan ( P ANOVA).2 p7 w$ t" [. b* @- c$ k! q
7 ^. u5 b8 S5 U4 U0 L/ ^ @Fig. 2. Change from baseline ( baseline) in glomerularfiltration rate, effective renal plasma flow, and mean arterialpressure at 60, 120, 140, 180, and 480 min after the administration offurosemide and losartan (broken line) or furosemide and placebo (solidline). * P
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9 D1 M- o. g% v3 u/ d% _Neurohormonal function. The response in plasma Aldo from baseline after administration offurosemide in combination with losartan or placebo is illustrated inFig. 3. There is a trend for plasma Aldoto increase within 120 min after furosemide plus placebo but this didnot reach statistical significance. However, with furosemide pluslosartan, there is a significant suppression of plasma Aldo, and plasmaAldo remained significantly lower compared with furosemide plus placebo( P 0.05, 2-way ANOVA). Plasma renin activity(1.2 ± 0.4 to 1.3 ± 0.4 ng · ml 1 · h 1 )remained unchanged, whereas there was a trend for ANG II (30 ± 5 to 33 ± 5 pg/ml) to increase within 60 min after furosemide andplacebo. However, this did not reach statistical significance. On theother hand, with furosemide and losartan, both plasma renin (1.3 ± 0.4 and 3.0 ± 0.4 ng · ml 1 · h 1, P P after 4 h.' d. F; v. \2 n. q ]) w& q# i2 s
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Fig. 3. Change from baseline ( baseline) in plasma aldosteroneconcentration at 60, 120, 140, 180, and 480 min after theadministration of furosemide and losartan (broken line) or furosemideand placebo (solid line). * P
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/ N# I( b0 @, z" p+ C( G `" vDISCUSSION
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2 _1 S3 J# @& {This study underscores the pathophysiological role of theAT 1 receptor in mediating the detrimental renal and adrenalproperties of acute diuretic therapy in human CHF. Specifically,AT 1 receptor antagonism preserved GFR and ERPF and enhancedsodium excretion during acute diuretic therapy in addition toinhibiting Aldo secretion. Therefore, this study supports the strategyof ANG II blockade with acute diuretic therapy in human CHF to preserverenal hemodynamic and tubular function and suppress Aldo.( @8 _5 i, y; A9 o! c r N* Y z
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The kidney and adrenals play a fundamental role in the pathphysiologyof CHF, serving as a mechanism for the increase in cardiac preloadsecondary to sodium retention and by releasing renin and activating theRAAS with direct actions of ANG II and Aldo on the cardiac myocyte andfibroblast ( 13 ). Supporting a seminal role for ANG II inthe kidney is the abundance of ANG II AT 1 receptors in therenal vasculature, glomeruli, proximal and distal tubules, and inrenomedullary interstitial cells ( 6 ). The predominant receptor subtype is the AT 1 receptor, which when activatedmediates mesangial contraction, renal vasoconstriction, and increasedtubular sodium reabsorption ( 8 ). AT 1 receptorsin the adrenal glands when activated result in the release of Aldo,leading to sodium retention. Experimental studies have shown thatexogenous ANG II administration results in marked decreases in GFR,whereas antagonism of the AT 1 receptors with losartanincreases GFR ( 1 ).5 H$ \7 T$ g/ |5 E Y6 u6 g* @5 S
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The mechanisms by which AT 1 receptor antagonism enhancesGFR are several and include increasing renal blood flow andtransglomerular hydrostatic pressure with attenuation of the tubularglomerular feedback ( 13 ). In the presentplacebo-controlled, double-blind crossover investigation, thedetrimental actions of furosemide in reducing GFR and ERPF wereabolished with the AT 1 receptor antagonist losartan.Furthermore, the efficacy of natriuresis and diuresis was alsoaugmented by AT 1 blockade, which may be explained byenhancing sodium delivery in the presence of preserved GFR and bytubular actions. Underscoring a tubular effect is the presence ofreduction of Aldo observed in the presence of losartan. Previousstudies showed that a high dose of acute diuretic administration activates ANG II and Aldo. However, in the present study, there was atrend for ANG II and Aldo to increase within 60 min of the administration of furosemide and placebo. A possible explanation forthis may be due to the fact that the dose of furosemide given in thisstudy was similar to the chronic dose taken by the patients. Furthermore, the patients' baseline ANG II and Aldo levels were already elevated to begin with, which may be due to the fact that withdrawal from chronic ACE inhibition may lead to heightened neurohormonal activation and response to AT 1 receptor blockade.
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These findings may have important clinical implications and wouldsuggest that acute diuretic therapy may benefit by antagonism of ANG IIso as to potentiate the natriuretic actions of the diuretics andpreserve renal hemodynamics in addition to suppression of Aldo. One ofthe limitations of the present study is that it was done in a state ofACE inhibition withdrawal, which may affect its clinical implications.Therefore, further studies evaluating the long-term effects ofAT 1 blockade on renal function in the presence of diureticsare warranted./ c n3 S& g0 B' k m
) O1 a3 w# ~0 H. G# J* JIn summary, this study underscores the pathophysiological role of theAT 1 receptor in mediating the detrimental renal and adrenalproperties of acute diuretic therapy in human CHF. Specifically, AT 1 receptor antagonism preserved GFR and ERPF and enhancedsodium excretion during acute diuretic therapy in addition toinhibiting Aldo secretion. Therefore, this study supports the strategyof ANG II blockade with acute diuretic therapy in human CHF to preserve renal hemodynamic and tubular function and suppress Aldo.' g$ L+ x! I3 F! ?- W. s' u0 w
6 c# c; Z7 q+ ~ACKNOWLEDGEMENTS; I% O& u7 A5 B( S
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The authors gratefully acknowledge the assistance of D. M. Heublein, S. S. Sandberg, G. Harty, and L. Combs.
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发表于 2009-4-21 13:36
