Low-Dose Atrial Natriuretic Factor and Furosemide in Experimental Acute Congestive Heart Failure1. (J. Am. Soc. Nephrol. 1993; 4: ) ABSTRACT

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1 Low-Dose Atril Ntriuretic Fctor nd Furosemide in xperimentl Acute ongestive Hert Filure1 Debr L. Felt, Ptrici G. vero, nd John. Burnett, Jr.2 DL. Fett, PG. vero, JO. Burnett, Jr., rdiorenl Reserch Lbortory, Deprtment of Medicine, Division of rdiovsculr Diseses, Myo linic, Pochester, MN (J. Am. Soc. Nephrol. 1993; 4: ) ABSTRAT This study ws designed to ddress three objectives in n experimentl model of cute congestive hert filure (HF) in the dog produced by rpid ventriculr pcing. The first objective ws to chrcterize crdiorenl nd humorl responses before nd dur- Ing 2 h of cute HF. The second objective ws to determine the modulting ction of iv furosemide upon these biologic responses to cute HF, testing the hypothesis tht furosemide-medited ntriuresis is ssocited with ctivtion of the renin-ngiotensinldosterone system (RAAS) compred with the control group. The third objective ws to determine the modulting ction of continuous low-dose tril ntriuretic fctor (ANF) dministrtion during cute HF upon these biologic responses, testing the hypothe- 515 tht exogenous low-dose ANF would prevent ctivtion of the RAAS nd enhnce the ntriuretic ction of furosemide. In the control group (Group 1; N= 6), plsm ANF incresed fter the onset of HF; GFR nd sodium excretion were mintined without ctivtion of this RAAS despite rteril hypotension. In Group 2 (N = 6), furosemide in cute HF incresed sodium excretion but in ssocition with decrese in GFR nd ctivtion of the RAAS. Lowdose exogenous ANF nd furosemide (Group 3; N = 6) in cute HF were ssocited with mintennce of GFR, no ctivtion of the RAAS, nd potentition of furosemide-induced ntriuresis. In summry, these studies demonstrte tht furosemide potently increses sodium excretion in cute HF, but with decrese in GFR nd ctivtion of the RAAS. Low-, Received November 19, Accepted April 27, orrespondence to Dr. J.. Burnett, Jr.. rdiorenl Reserch Lbortory. 915 Guggenheim Building, Myo linic, 2 First Street, SW, Rochester, MN i / / Journl of the Americn Society of Nephroiogy opyright 1993 by the Americn Society of Nephrology dose ANF in cute HF with furosemide mintins GFR, ttenutes ctivtion of the RAAS, nd potentites ntriuresis. Key Words: Diuretics, ntriuretic peptides, congestive hert filure A cute congestive hert filure (HF) is clinicl syndrome chrcterized by cute decreses in crdic output (O) nd rteril pressure in ssocition with increses in crdic filling pressures. Recent studies hve demonstrted functionl role for elevted endogenous tril ntriuretic fctor (ANF) in cute HF to mintin sodium excretion nd ttenute the full ctivtion of the renin-ngiotensinldosterone system (RAAS), despite the potent stimulus of rteril hypotension (1.2). Although these nd other studies support homeosttic role for endogenous ANF in HF (3), the use of dditionl potent loop diuretics is often required in the prevention nd tretment of cute pulmonry congestion. Furosemide is n efficcious loop diuretic used in the tretment of cute HF. The efficcy of furosemide is bsed upon its bility to mrkedly enhnce sodium excretion nd decrese intrvsculr volume despite the presence of decresed renl perfusion pressure. Although the bility of furosemide to increse sodium excretion in cute HF is well estblished, the full ntriuretic ction of furosemide my be limited by ctivtion of the RAAS (4,5). In ddition to the ctivtion of the RAAS by furosemide. decrese in ANF hs been reported during furosemide therpy in humns with cutely decompensted chronic HF (6). Such decrese in endogenous ANF my lso limit the full ntriuretic ction of furosemide in cute HF. This study ws designed to ddress three objectives in n experimentl model of cute HF in the dog produced by rpid ventriculr pcing. The first objective ws to chrcterize the crdiorenl nd endocrine responses before nd during 2 h of cute HF. The second objective ws to determine the modubting ction of iv furosemide upon these biologic responses to cute HF, testing the hypothesis tht the furosemide-medited ntriuresis is ssocited with ctivtion of the RAAS nd decreses in circulting ANF when compred with the control group without furosemide. The third objective ws to determine the modulting ction of continuous low-dose ANF dministrtion during cute HF upon crdiorenl nd 162 Volume 4 Number

2 -., , Fett et l endocrine function, testing the hypothesis tht exogenous low-dose ANF to mintin stedy-stte pthophysiobogic level of plsm ANF would prevent the ctivtion of the RAAS nd enhnce the ntriuretic ction of furosemide. MTHODS xperiments were performed in three groups of mongrel dogs of either sex weighing 1 7 to 25 kg. Group I (ontrol; N = 6) underwent rpid ventriculr pcing for 2 h to induce cute HF, which, s in humns, is chrcterized by incresed left ventricubr filling pressure. decresed O. nd decresed rterib pressure. Group II (furosemide; N 6) received n lv bolus of furosemide (1.7 mg/kg) 45 mm fter the onset of cute HF. Group III (furosemide plus ANF; N = 6) received furosemide s in Group II with continuous, iv, low-dose ANF (2 ng/kg. mm; Peninsul Lbortories, Belmont, A) initited t the time of furosemide dministrtion. Dogs were fsted the night before the experiment but were llowed wter d ltbttum until the time of the study. After the induction of nesthesi with pentobrbitl sodium (3 mg/kg iv), dogs were surgiclly prepred by the selective cnnultion of both femorl veins nd the left femorb rtery for infusions nd rteril pressure monitoring. The right externljugulr vein ws isolted, nd 7.5 French blloon-tipped thermodilution ctheter (Americn dwrds Lbortory, Snt An, A) ws dvnced into the pulmonry rtery. The trche ws intubted with 9.5-mm endotrchel tube, nd the niml ws mechniclly ventilted (Hrvrd Apprtus, Millis, MA). The left kidney ws exposed by retroperitonel flnk incision. The ureter ws isobted nd cnnulted for urine collection. An electromgnetic flow probe ws plced round the renl rtery nd connected to flow meter (rolin Medicl lectronics, King. N) for the continuous mesurement of RBF. The chest ws opened in the left fifth intercostl spce. An epicrdil pcing wire ws plced on the ventriculr pex nd ws subsequently connected to pulse genertor (Model 4563A; Medtronic orportion, Minnepolis, MN) for ventriculr pcing. ch dog received priming dose of inulin (Nutritionl Biochemicls, levelnd, OH) nd continuous infusion t rte of 1 ml/min through femorl vein ctheter t concentrtions to chieve stedy-stte plsm inulin level of pproximtely 5 mg/dl. One 3-mm control clernce period (Bseline) ws performed before cute HF. Ventriculr pcing. t 25 bets/mm, ws then initited to produce cute HF. After 45 mm, 15-mm clernce (HF) ws obtined. Furosemide in the presence or bsence of low-dose ANF ws then dministered, followed by finl 3-mm clernce performed 2 h fter the onset of cute HF (HF 2 h). In ddition, plsm nd 15- minute short-time urine collections were obtined throughout the protocol to permit the determintion of circulting ANF nd urinry sodium excretion. During ech clernce period. crdiovsculr. hormonl, nd renl prmeters were evluted. rdiovsculr prmeters included systemic rteril pressure. left tril pressure (LAP), O. nd systemic vsculr resistnce (SVR). For ech period. O ws determined by thermodilution in triplicte nd ws verged. xtrcted rteril plsm concentrtions of ANF were mesured by n RIA procedure previously described (7). PRA nd plsm ldosterone were mesured by RIA s previously reported (8,9). GFR ws determined by the clernce of inulin with plsm nd urine inulin concentrtions mesured by the nthrone method (1). Plsm nd urinry sodium concentrtions were quntified by the use of ion-selective electrodes (Beckmn System 2A; Beckmn Instruments, Bre, A). Dt from ech group re expressed s men ± S. Dt were nlyzed by nlysis of vrince for repeted mesurements nd by pired nd unpired t tests. omprisons within groups were nlyzed by nlysis of vrince for repeted mesurements, fobbowed by pired t test when pproprite. omprisons between groups were performed by unpired t test. Sttisticl significnce ws ccepted for P <.5. RSLTS Tble 1 reports crdiovsculr dt nd Tble 2 reports renl nd hormonl dt t Bseline, t 45 mm fter the onset of cute HF before furosemide nd/or ANF, nd t 2 h fter HF. Figures 1 nd 2 illustrte circulting ANF nd urinry sodium excretion t intervls throughout the experiment in ech group. Group I (ontrol) Acute HF decresed O nd men rteril pressure (MAP) in ssocition with incresed LAP nd SVR (Tble 1). Two hours fter HF, MAP returned to bseline in ssocition with further decrese in O nd n increse in SVR. LAP remined elevted nd unchnged. With the onset of cute HF. GFR ws unchnged in ssocition with decrese in RBF nd n increse in renl vsculr resistnce (RVR) (Tble 2). rinry sodium excretion nd the frctionl excretion of sodium were mintined t bseline. At 2 h fter cute HF, these renl prmeters were mintined, with the exception of modest but significnt increse in urine flow. Plsm ANF incresed with the onset of cute HF nd decresed therefter, lthough remining t con- Journl of the Americn Society of Nephrology 163

3 Low-Dose ANF nd Furosemide in HF TABL 1. rdiovsculr hemodynmic function Group I, ontrol Gro up II, Furosemide Group III, ANF + Furosemide Bseline HF HF 2 h Bseline HF HF 2 h Bseline HF HF 2 h MAP(mmlOO±2 9±4#{176} 13±6b 111±7 91±8#{176} 12±8b 12±7 1±3#{176} 11±4#{176} Hg) O (1/ 4. ± ±.2#{176} 1.6 ±.2b 3.9 ±.3 2. ±.2#{176} 1.7 ±.2b 3.8 ± ±.3#{176} 1.5 ±.1b mm) LAP(mm 6.1 ± ± 3.#{176}16.1 ± 3.2#{176}5.6 ± ± 2.1#{176} 17.7 ± 2.1#{176}4.9 ± ± 1.7#{176} 12.5 ±.8#{176} Hg) SVR (R) 25 ± 2 39 ± 4#{176} 61 ± 7.b 29 ± 2 44 ± 2#{176} 63 ± 6b 4 ± 4 4 ± 4#{176} 75 ± bob p<.5 HV versus bseline. b p<.5 HF 2 h versus HF. centrtions bove bseline (Tble 2; Figure 1 ). PRA ws unchnged with the onset of cute HF nd decresed t 2 h compred with the cute HF period. Plsm ldosterone remined unchnged throughout cute HF. Group II (Furosemide) rdic nd systemic hemodynmic responses to cute HF were similr in the furosemide group s compred with the control group (Tble 1). MAP nd O decresed, wheres LAP nd SVR incresed. At 2 h fter HF, MAP incresed to bseline in ssocition with progressive decrese in O nd n increse in SVR. Renl responses to cute HF t 45 mm were similr to those observed in Group I (Tble 2). In response to furosemide, however, GFR decresed 2 h fter HF. rinry sodium excretion nd the frction excretion of sodium incresed with pek effect 3 mm fter furosemide (Figure 2) nd remined elevted 2 h fter HF. Plsm ANF incresed with the onset of cute HF (Tble 2; Figure 1 ) nd decresed therefter, lthough remining bove bseline. PRA did not chnge with the onset of cute HF but ws incresed t 2 h. Aldosterone ws unchnged with the onset of HF but incresed 2 h fter HF. Group III (Furosemide nd Low-Dose ANF) With the onset of cute HF (Tble 1), MAP nd O decresed in ssocition with n increse in LAP nd SVR. At 2 h fter HF in the presence of both furosemide nd continuous low-dose ANF, MAP remined decresed in ssocition with further decrese in O nd n increse in SVR. LAP remined elevted. With the onset of HF. renl responses were simibr to those of the other groups with mintined GFR, decresed RBF. nd incresed RVR (Tble 2). In contrst to Group II with furosemide, low-dose ANF ws ssocited with mintennce of GFR. RBF decresed nd RVR incresed 2 h fter HF. As illustrted in Figure 2, the pek increse in sodium excretion ws gretest in Group III. Plsm ANF incresed with the onset of cute HF nd remined elevted with the continuous bow-dose ANF infusion (Tble 2; Figure 1). With the onset of HF, PRA remined unchnged nd ws mintined t bseline concentrtions for the durtion of the protocol. Plsm bdosterone ws lso unchnged with the onset of HF nd t 2 h. DISSSION This study demonstrtes tht experimentl cute HF is chrcterized by decrese in O nd rteril pressure with n increse in LAP nd plsm ANF. Despite the decrese in renl perfusion pressure, GFR nd sodium excretion were mintined without ctivtion of the RAAS. In cute HF, iv furosemide incresed sodium excretion, but in ssocition with decrese in GFR nd ctivtion of the RAAS. The continuous dministrtion of bow-dose ANF, which mintined stedy-stte concentrtions of elevted circulting ANF, mintined GFR nd prevented the ctivtion of the RAAS, despite sustined rteril hypotension nd ugmented furosemide-medited ntriuresis. This study confirms recent investigtions of Lee nd collegues tht demonstrted tht endogenous ANF serves n importnt functionl robe in cute HF (3). In bow-anf model of cute HF produced by thorcic inferior ven cvl constriction, those investigtors observed RAAS ctivtion nd mrked sodium retention tht were not observed in high- ANF model of cute HF, despite comprble decreses in O nd rteril pressure. When exogenous ANF ws infused in dogs with the bow-anf model produced by cute cvb constriction to mimic circubting concentrtions chieved in high-anf hert filure produced by rpid ventriculr pcing, sodium 164 Volume 4. Number

4 4-. -, Fett et l S S ) c*1 - ) i 2, N -H #{176} - -H H -H 118 H H 41 -H ( ) -,,,j I ) o u_ _(v) N ) _ + I z,( (D ) (D ) 8 c,1 ) 8 i V) r it) g, o -,, - N D - it) NV) 1 OON - It) 8 It) ODc,,iV) OIt) V) (V) - It) -H-H-H-H-H-H-H-H-H V) 8 It) - i N uuu t V-r N H D D - - OON V)N cc o#{176} It) N ) N N O N.,, ) 41I NN It) ),,..OOV)N 8r. V) (V) Q cl d ) -H H Q 8 It) 8 OON u V) I),, V V,, Furosemide Time, Figure 1. Plsm ANF before nd during experimentl cute HF in nesthetized dogs in Group I (controls; open squres), Group II (furosemide; 1.7 mg/kg, iv bolus; closed tringles), nd Group Ill (furosemide nd exogenous ANF; 2 ng/kg.mmn, iv; closed circles). 6 5 #{176}#{176}. w 3 > 2 1 mm ) -) L -i 8 I- -) (D N -.) - S ) 8 1-q It) - Q - N D N. Q 8 OONO N ) N :io VIt) It) 8 - It) - ) N. 8 ) - f ) - OONO -.i#{243}n ) -I-I , it) ) N 41 ) - #%.%,, -.., -!I c z,, V 2: > z... u,.. u, u, Oh oo - ) ) qq oq vv <,, o u Time, Figure 2. rinry sodium excretion (NV) before nd during experimentl cute HF in nesthetized dogs in Group I (control; open squres), Group II (furosemide; 1.7 mg/kg, iv bolus; closed tringles), nd Group Ill (furosemide s in Group I with exogenous ANF; 2 ng/kg/mmn. iv; closed circles). retention nd RAAS ctivtion did not occur. This study is consistent with such role for ANF in cute HF. In the presence of furosemide, increses in PRA nd plsm ldosterone were observed. Such ctivtion of the RAAS is consistent with the elegnt humn studies of Ikrm et l., which documented mild ctivtion of the RAAS in response to cute furosemide in ptients with chronic HF (5). Those uthors stted tht such ctivtion in HF ws less thn tht observed in norml humns or nimls nd specubted tht tril distention vi crdiorenl neurogenic reflexes my ttenute furosemide-medited mm Journl of the Americn Society of Nephrology b65

5 Low-Dose ANF nd Furosemide in HF chnges in the RAAS. This study confirms nd extends this specultion nd suggests tht such n ttenuting ction upon the RAAS in cute HF my be secondry to increses in endogenous ANF ctivted by tril stretch. The observtion tht the lowdose dministrtion of ANF, resulting in higher pthophysiobogic concentrtions of circulting ANF, reversed furosemide-medited chnges in the RAAS supports this specultion. Moreover, such biologic ction my explin in prt the report of Bennett nd coworkers tht cute HF in humns with myocrdil infrction my be ssocited with trnsient diuresis, despite ventriculr dysfunction ( 1 1). This study lso importntly extends previous reports nd describes the temporl ltertions in endogenous ANF with cute HF. Despite continued cute HF nd elevtion of LAP, the pek elevtion of endogenous circulting ANF ws not mintined. In this study, plsm ANF decresed by pproximtely 4% t 2 h fter the onset of cute HF. The mechnism of this decrese is uncler but my be secondry to the depletion of stored tril ANF. Indeed, Perrell et l. reported tht cute HF for 3 hours is unssocited with detectble increses in tril ANF mrna. suggesting tht incresed ANF synthesis my not be ugmented in cute HF, resulting in reltive deficiency stte during the initil hours fter the onset of ventriculr dysfunction (12). One might conclude tht more severe hert filure could hve incresed circulting ANF to higher levels, which my hve ttenuted furosemide-induced renl nd endocrine responses. Studies by Redfield et l., however, hve suggested mximl ceiling for plsm ANF in cute HF tht limits circulting ANF to levels observed in this study (13). nder such circumstnces, reltive deficiency could occur, ugmenting the reductions in GFR nd the increses in the RAAS in ssocition with furosemide in cute HF. Such n occurrence would underscore the rtionle for low-dose iv ANF s djunct therpy to furosemide in cute left ventriculr filure. Intrvenous furosemide resulted in n immedite ntriuretic response despite reduced renl perfusion pressure. Although the ntriuretic ction of furosemide hs been well chrcterized, investigtions conflict with regrd to furosemide-medited renl hemodynmic responses. Such conflict my be rebted to whether investigtions were performed under norml physiologic conditions or in pthophysiobogic sttes ssocited with reduced renl perfusion pressure. Our findings re consistent with the reports of Dikshit et l., which described the renl hemodynmic effects of furosemide in the humns fter cute myocrdil infrction ( 1 4). In these previous reports. furosemide resulted in n initil increse in GFR 15 mm fter diuretic dministrtion. However, 2 h fter furosemide therpy, in ssocition with reduced rteril pressure nd elevted crdic filling pressures, GFR ws below bseline. The physiologic mechnism(s) tht medite the decrese in GFR in this nd previous studies in response to furosemide my be mubtifctorib. Becuse RBF decresed in ll three groups but GFR decresed only in the furosemide group, direct or indirect ction of furosemide upon the ultrfiltrtion coefficient, K, could be speculted. Becuse the decrese in PRA observed in Group I without furosemide did not occur in the furosemide group, role for incresed ctivity of the intrrenb renin-ngiotensin system could medite the reduction in GFR (1 5), lthough ngiotensmn my lterntively serve to mintm GFR vi efferent rteriolr constriction (16). Further, lthough not mesured in this investigtion. furosemide my hve ctivted the sympthetic nervous system, s reported in humn studies by Frncis et t., resulting in decreses in the filtrtion process ( 1 7). Indeed, increses in plsm norepinephrine, together with decreses in O. could importntly contribute to reductions in GFR. The low-dose dministrtion of ANF to mintin stedy-stte pthophysiobogic concentrtions fter furosemide resulted in mintennce of GFR. The mechnism of this preservtion is consistent with the known bility of ANF to increse GFR (18-2). This ction is medited by decrese in fferent rteriolr resistnce, n increse in efferent rteriobr resistnce, n increse in K, nd n inhibition of tububogbomerulr feedbck (1 8-24). The ction of ANF in this study is lso remrkble becuse it occurred despite sustined renl hypoperfusion. Furosemide-medited ntriuresis ws incresed by ANF, despite persistently lower renl perfusion pressure. The mechnism of this enhnced ntriuresis my lso be mubtifctoril. The mintennce of GFR with low-dose ANF my hve resulted in greter delivery of sodium to the loop of Henle, resulting in greter increse in sodium excretion. Although not determined in this study, low-dose ANF could hve resulted in decreses in both the proximl nd distl rebsorption of sodium, which re tubulr sites of ANF ction, thus ugmenting the decrese in the loop of Henle rebsorption secondry to furosemide (1,25). Further, the bck of ctivtion of the RAAS observed with low-dose ANF my hve prevented n ntintriuretic ction of ngiotensmn II upon the proximl tubule nd n ntintriuretic ction of ldosterone on the distl tubule (26). In summry, this study provides continuing insight into the role of endogenous ANF in cute HF in which increses in this crdic hormone my serve functionl role to mintin sodium excretion nd prevent ctivtion of the RAAS, despite rteril hypotension. These studies lso demonstrte tht furosemide-mnduced ntriuresis is ssocited with de- 166 Volume 4 Number

6 Fett et l creses in GFR with ctivtion of the RAAS. Such responses could limit the full ntriuretic ction of furosemide in cute HF. Lst, these investigtions lso demonstrte tht bow-dose continuous ANF infusion potentites furosemide-induced ntriuresis nd tht this modulting ction my occur by the preservtion of GFR nd the prevention of the ctivtion of the RAAS. AKNOWLDGMNTS The reserch ws supported by grnts HL36634 nd HLO7 1 1 from the NIH nd grnts from the Myo Foundtion. P.O. vero ws supported by the NIH Multidisciplinry Trining Grnt in Hypertension HL7269. RFRNS 1. Burnett J Jr. Grnger JP, Opgenorth TJ: ffects of synthetic tril ntriuretic fctor on renl function nd renin relese. Am J Physiol 1 984;247:F863-F Mck T, Mrion DN, mrgo MJ, et l. : ffects of uriculin (trib ntriuretic fctor) on blood pressure, renl function, nd the reninbdosterone system in dogs. Am J Med 1984;77: Lee M, Miller W, dwrds BS, Burnett J Jr: Role of endogenous tril ntriuretic fctor in cute congestive hert filure. J lin Invest 1989;84: Scher G, ovit AB, rgh JH, ody RJ: Assocition of hypontremi with incresed renin ctivity in chronic congestive hert filure: Impct of diuretic therpy. Am J rdiol 1983; 51: Ikrm H, hn W, spiner A, Nicholls MG: Hemodynmic nd hormone responses to cute nd chronic furosemide therpy in congestive hert filure. lin Sci 1 98;59: Anderson JV, Woodruff PWR, Bloom SR: The effect of tretment of congestive hert filure on plsm tril ntriuretic peptide concentrtion: A longitudinl study. Br Hert J 1 988;59: Burnett J Jr, Ko P, Hu D, t l.: Atril ntriuretic peptide elevtion in congestive hert filure in the humn. Science 1 986;23 1: Hber, Loerner D, Pge T, Kiemen K, Pm-node A: Appliction of rdioimmunossy for ngiotensin I to the physiologic mesurement of plsm renin ctivity in norml humn subjects. J lin ndocrinob Metb 1969;29: nderwood RD, Arhus L, Heublein DM, Burnett J Jr: ndothelin in thorcic inferior ven cvl constriction model of hert filure. Am J Physiol 1 992;263:H95 1 -H Fuhr JJ, Kczmrczyk KJ, Kruttgen D: ine einfuche cobor-metrische Methode zur Inubinbestimung for Nieren-clernce-undersuchungen bei Stoffwechselgesunden und Dibetikern. Kiln Wochenschr 1 955;33: Bennett D, Brooks NH, Keddie J, Lis Y, Wilson A: Incresed renl function in ptients with cute left ventriculr filure: A possible homeosttic mechnism. lin Sci Mob Med 1977:52: Perrell MA, Schwb TR, O Murchu B, et l.: rdic tril ntriuretic fctor during evolution of congestive hert filure. Am J Physiol 1992; 262:H 1248-H Redfield MM, dwrds BS, McGoon MD, Heublein DM, Arhus L, Burnett J Jr: Filure of tril ntriuretic fctor to increse with volume expnsion in cute nd chronic congestive hert filure in the dog. ircultion 1989:8: Dikshit K, Vyden JK, Forrester JS, htterjee K, Prksh R, Swn HJ: Renl nd extrrenl hemodynmic effects of furosemide in congestive hert filure fter cute myocrdil infrction. N ngl J Med 1973;288:187-l Showlter J, Zimmermn RS, Schwb TR, dwrds BS, Opgenorth TJ, Burnett J Jr: Renl response to tril ntriuretic fctor is modulted by intrrenl ngiotensmn II. Am J Physiol 1988; 254:R453-R Ichikw I, Hrris R: Angiotensmn ctions in the kidney: Renewed insight into the old hormone. Kidney Int ;4:S Frncis GS, Siegel RM, Goldsmith SR, Olivri MT, Levine TB, ohn JN: Acute vsoconstrictor response to intrvenous furosemide in ptients with chronic congestive hert filure: Activtion of the neurohumorl xis. Ann Intern Med 1985; 13: Nkmoto M, Shpiro JI, Shnley PF, hn, Schrier RW: In vitro nd in vivo protective effect of triopeptmn III on ischemic cute renl filure. J lin Invest 1987;8: Mrgulies KB, Hildebrnd FL, Heublein DM, Burnett J Jr: Rdiocontrst increses plsm nd urinry endothelin. J Am Soc Nephrol 1991; 2: Sndok K, Lermn A, Stingo AJ, Perrell MA, Gloviczki P. Burnett J Jr: ndothelin in model of cute ischemic renl dysfunction: Modulting ction of tril ntriuretic fctor. J Am Soc Nephrob 1992;3: Ichikw I, Dunn BR, Troy J, Brenner BM: Influence of tril ntriuretic peptide on glomerulr microcircultion in vivo. lin Res 1985; 33:487A. 22. Ohishi K, Hishid A, Hond N: Direct vsodiltory ction of tril ntriuretic fctor on cnine glomerulr fferent rterioles. Am J Physiol 1988;255:F4 1 5-F dezeeuw D, Jnssen WMT, dejong P: Atril ntriuretic fctor: Its (ptho)physiologicl significnce in humns. Kidney Int 1992:41: Loftus JP, Redfield MM, Burnett J Jr: Atril ntriuretic fctor inhibits hypertonic sline-medited decreses in renl hemodynmics. Kidney Int 199;38: Itbshi A, hn, Shpiro JI, heung, Schrier RW: omprison of the ntriuretic response to triopeptmn III nd loop diuretic in the isolted perfused rt kidney. lin Sci 1987:73: Hrris PJ, Skinner S: Intr-renl interctions between ngiotensmn II nd tril ntriuretic fctor. Kidneylnt 199;38:S87-S91. Journl of the Americn Society of Nephrology 167