BG9719 (CVT-124), an A1 Adenosine Receptor Antagonist,Protects Against the Decline in Renal Function Observed

With Diuretic TherapyStephen S. Gottlieb, MD; D. Craig Brater, MD; Ignatius Thomas, MD; Edward Havranek, MD;

Robert Bourge, MD; Steven Goldman, MD; Farere Dyer, MD; Miguel Gomez, MD;Donald Bennett; Barry Ticho, MD, PhD; Evan Beckman, MD; William T. Abraham, MD

Background—Adenosine may adversely affect renal function via its effects on renal arterioles and tubuloglomerularfeedback, but effects of adenosine blockade in humans receiving furosemide and ACE inhibitors is unknown.

Methods and Results—This was a randomized, double-blind, ascending-dose, crossover study evaluating 3 doses ofBG9719 in 63 patients with congestive heart failure. Patients received placebo or 1 of 3 doses of BG9719 on 1 day andthe same medication plus furosemide on a separate day. Renal function and electrolyte and water excretion wereassessed. BG9719 alone caused an increase in urine output and sodium excretion (P�0.05). Although administration offurosemide alone caused a large diuresis, addition of BG9719 to furosemide increased diuresis, which was significantat the 0.75-�g/mL concentration. BG9719 alone improved glomerular filtration rate (GFR) at the 2 lower doses.Furosemide alone caused a decline in GFR. When BG9719 was added to furosemide, however, creatinine clearanceremained at baseline at the 2 lower doses.

Conclusions—In patients with congestive heart failure on standard therapy, including ACE inhibitors, BG9719 increasedboth urine output and GFR. In these same patients, furosemide increased urine output at the expense of decreased GFR.When BG9719 was given in addition to furosemide, urine volume additionally increased and there was no deteriorationin GFR. A1 adenosine antagonism might preserve renal function while simultaneously promoting natriuresis duringtreatment for heart failure. (Circulation. 2002;105:1348-1353.)

Key Words: adenosine antagonist � renal function � congestive heart failure � diuretics

Renal function is exceedingly important in patients withchronic congestive heart failure. Although it has long

been known that good fluid balance is essential for symptom-atic control of heart failure, recent studies have demonstratedthat worsening renal function is associated with poorerclinical outcome among hospitalized patients with heartfailure.1 Indeed, renal function is one of the most importantdeterminants of survival in patients with heart failure.2

Furthermore, renal impairment is an important cause ofsuboptimal prescription of medications known to be benefi-cial, such as diuretics and ACE inhibitors.

Renal function can be modulated by extracellular levelsof adenosine acting on specific cell-surface receptors.Adenosine binding to receptors on the afferent arteriolecauses local constriction, thereby reducing renal bloodflow. Stimulation of A1 adenosine receptors also increasessodium reabsorption in the proximal and distal tubules. An

acute increase in the delivery of sodium in the distal tubulecauses an increase in adenosine concentrations, whichreduces glomerular filtration rate (GFR) via tubuloglomer-ular feedback at the macula densa and afferent arterioles.Antagonism of A1 adenosine receptors therefore maintainsrenal function by vasodilation of the afferent arteriole anddisruption of the tubuloglomerular feedback loop whilecausing natriuresis.

BG9719 is a selective A1 adenosine receptor antagonistwith the potential to improve renal function in patients withheart failure. In animal studies, BG9719 has caused a potas-sium neutral diuresis while maintaining renal function.3 Priorhuman studies have also suggested that it promotes diuresiswhile maintaining glomerular function.4 However, there havebeen no previous evaluations in humans of the effects of A1

antagonism in combination with standard heart failure ther-apy that includes furosemide and ACE inhibitors.

Received November 29, 2001; revision received January 2, 2002; accepted January 4, 2002.From the University of Maryland School of Medicine and the D.V.A. Medical Center (S.S.G.), Baltimore, Md; Indiana School of Medicine (D.C.B.),

Indianapolis, Ind; Medical Research Institute (I.T.), Slidell, La; Denver Health Medical Center (E.H.), Denver, Colo; University of Alabama (R.B.),Birmingham, Ala; Tucson VAMC, SAVAHCS, University of Arizona (S.G.), Tucson, Ariz; New Orleans Clinical Trials Management (F.D., M.G.),Covington, La; Biogen Inc (D.B., B.T., E.B.), Cambridge, Mass; and University of Cincinnati College of Medicine (W.T.A.), Cincinnati, Ohio. DrAbraham is now at University of Kentucky College of Medicine, Lexington, Ky.

Correspondence to Stephen S. Gottlieb, MD, Division of Cardiology, University of Maryland School of Medicine, 22 South Greene St, Baltimore, MD21201. E-mail sgottlie@medicine.umaryland.edu

© 2002 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/hc1102.105264

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The purpose of the present study was to compare theeffects of BG9719 alone, furosemide alone, and BG9719 incombination with furosemide in patients with congestiveheart failure. We evaluated renal function, urine volume, andurinary electrolyte excretion.

MethodsThis was a randomized, double-blind, crossover study evaluating 3doses of BG9719 and placebo (Figure 1). The study compared therenal actions of BG9719 (or placebo) alone and in combination with80 mg of intravenous furosemide in 63 edematous patients withsymptomatic heart failure. The study enrolled patients at 8 clinicalsites over 14 months. Inclusion criteria included New York HeartAssociation class II through IV heart failure with an ejection fraction�40% and the presence of edema despite a daily furosemide dose ofat least 80 mg. All patients were taking ACE inhibitors. Two patientswere receiving spironolactone. Baseline GFR, as measured bycreatinine clearance, was at least 30 mL/min per 1.73 m2 or serumcreatinine was �1.9 mg/dL. The study protocol was approved by allparticipating institutional review boards, and all patients gave writteninformed consent for participation in this study.

Patients were enrolled into 1 of 3 dosing cohorts of ascendingdoses of BG9719. Within each cohort, patients were randomized toreceive either active investigational drug (BG9719) or placebo(Figure 1). After an equilibration period, baseline urine was collectedfor urine volume, electrolyte determinations, and creatinine clear-ance. On the following day, subjects received investigational drug(BG9719 or placebo) and either a bolus of intravenous furosemide orplacebo. On the second dosing day after another equilibration period,the patient received the same dose of investigational drug but withplacebo if furosemide had previously been given or with furosemideif placebo had previously been given. Thus, the effect of addingfurosemide to BG9719 could be compared within the same patients,but the effect of different doses of BG9719 was compared acrossdifferent patient groups. Seventy-nine patients were enrolled in thestudy. Of these, 8 patients were withdrawn from the study beforestudy drug dosing because of unstable weight (n�3), adverse events(n�2), voluntary withdrawal (n�2), or laboratory abnormality(n�1). Eight other patients were not evaluated because of weightthat did not meet the prespecified criteria (n�5), incomplete datacollection (n�2), or incorrect dosing (n�1).

All patients were confined to an inpatient study unit for theduration of the study. The equilibration diet was a tightly controlled30 mEq sodium, 60 mEq potassium, 1.0 to 1.5 g/kg protein diet.Patients continued to take ACE inhibitors, but no diuretics, duringthe equilibration period of 3 to 5 days. Nevertheless, their weight hadto be stable to be dosed. The 2 study dates were separated by 2 to 5

days, during which time sodium could be replaced (if necessary)with intravenous saline to maintain constant total body fluid volumeand stable body weight. The saline was given to make the patient assimilar as possible on the 2 dosing days, and thus we believe wasunlikely to influence the results.

The doses of BG9719 used were designed to yield serum concen-trations of 0.1, 0.75, or 2.5 �g/mL. A loading dose was givenfollowed by a 7-hour infusion. The doses given resulted in averageserum concentrations during the infusion of 0.101, 0.787, and 3.19�g/mL, respectively. Dose escalation occurred after 15 patientssafely completed treatment at the previous concentration.

Renal FunctionUrine was collected to determine urine volume, electrolyte excretion,and creatinine clearance on the day before the first dosing day and onboth dosing days. Patients were instructed to urinate after thefollowing time intervals with respect to dosing: 0 to 1, 1 to 2, 2 to 4,4 to 6, and 6 to 8 hours; a Foley catheter was used in 3 patients. Thedata presented are cumulative for the first 8 hours after drugadministration. Because of creatinine washout, creatinine clearancewas measured during the 7 hours of the infusion. Creatinineclearance was determined from serum creatinine and urinary creat-inine excretion and adjusted for body surface area. Serum creatininewas measured at each urine collection.

StatisticsAnalysis of dose effects was based on mixed-effect ANOVA andANCOVA. Two-sided tests were used with statistical significance atP�0.05. Multiple covariates were considered, including baselinerenal function, severity of heart failure, and demographicinformation.

Response variables were calculated as change from baselinemeasurements during the same time interval on the predosing day.

Results

Patient PopulationThe patients in this study reflect a typical heart failure studypopulation (Table 1). The patients were elderly, predomi-nantly male, and racially mixed. Patients receiving placebowere slightly younger, although this was not statisticallysignificant. 33% of patients were classified as NYHA class IIand 65% as class III. One patient was class IV. Mean ejectionfraction was 28�7%. Forty-three percent of the patients haddiabetes mellitus, and 57% had ischemic heart disease.

Mean baseline urine volume (before any intervention) was758 mL for 8 hours. Sodium excretion was 20.3 mEq for thistime. Creatinine clearance for 1 to 8 hours was 87.5�43mL/min per 1.73 m2. Although the mean baseline creatinineclearance was higher in patients who received placebo, thiswas not statistically significant.

Urine Output and Sodium ExcretionThe urine output during the infusion of BG9719 (or placebo),with or without furosemide bolus, is shown in Figure 2.BG9719 caused a statistically significant dose-dependentincrease in urine output and sodium excretion, with noadditional effect of the 2.5 �g/mL concentration comparedwith the 0.75 �g/mL concentration. Both the trend and the 2higher doses were significant (P�0.05). Furosemide alonecaused a large diuresis. The addition of BG9719 caused anadditional increase, which was significant at the 0.75 �g/mLconcentration.

Figure 1. The study design is depicted. After equilibration andbaseline measurements, all patients received BG9719 (in 3ascending doses) or placebo. The same dose was given bothwith and without furosemide on different days in random order.

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Creatinine ClearanceBG9719, when given without furosemide, tended to improveGFR at the 2 lower doses, with a P value of 0.055 at the0.75-�g/mL concentration (Figure 3). Furosemide alonecaused a significant decline in GFR. When BG9719 wasadded to furosemide, however, creatinine clearance remainedat baseline at the 2 lower doses. BG9719 at 2.5 �g/mL did notprevent the decline in creatinine clearance associated withfurosemide.

The relationship between change in urine volume andchange in creatinine clearance is shown in Figure 4 forpatients receiving the 0.75-�g/mL concentration. BG9719increased both urine output and GFR compared with placebo.Furosemide increased urine output at the expense of de-creased GFR. When BG9719 was given in addition tofurosemide, urine volume additionally increased, and therewas no deterioration in GFR seen.

Adjustment for covariates such as age, gender, race,weight, underlying disease, creatinine clearance, and renaloutput did not significantly affect the results.

Electrolyte ExcretionPotassium and sodium excretion is shown in Table 2. Alone,BG9719 did not significantly increase potassium excretiondespite increasing sodium excretion. In combination withfurosemide, sodium excretion increased, as did potassiumexcretion. Magnesium and uric acid excretion are also shownin Table 2.

Blood Pressure and Heart RateThe baseline blood pressure and heart rate and the change inthese parameters from pretreatment are shown in Table 3.After 3.5 hours, heart rate (as determined by electrocardiog-raphy) did not change significantly in any group. When

Figure 3. Percent change from the baseline day of creatinineclearance for 8 hours after BG9719 bolus and subsequent infu-sion with and without 80 mg furosemide. BG9719 led toincreased creatinine clearance at the 2 lower doses when givenalone. In combination with furosemide, creatinine clearance wasmaintained at the 2 lower doses compared with furosemidealone and the 2.5-�g/mL concentration. *P�0.055 comparedwith baseline, **P�0.05 compared with baseline.

TABLE 1. Baseline Characteristics by Randomization Group

Placebo(n�16)

BG9719,0.1 �g/mL

(n�15)

BG9719,0.75 �g/mL

(n�15)

BG9719,2.5 �g/mL

(n�17)

Age 61�10 64�14 65�12 64�15

Sex, % male 81 87 93 71

Race, %

White or hispanic 44 80 47 71

Black 56 20 53 29

NYHA class, %

II 19 27 47 41

III 81 73 47 59

IV 0 0 7 0

Ejection fraction, % 28�6 29�9 30�7 25�8

Etiology of heart failure, %

Ischemic 63 67 53 59

Adjusted creatinine clearance,�g/mL (1–8 h)

108�51 75�40 83�34 83�40

Urine volume, mL (0–8 h) 798�455 702�435 775�544 720�491

Figure 2. The urine volume for 8 hours after BG9719 bolus andsubsequent infusion, with and without 80 mg furosemide. Pla-cebo and 3 doses are depicted. BG9719 increased urine vol-ume both alone and in combination with furosemide. *P�0.05compared with placebo.

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furosemide was not given, systolic blood pressure wasminimally changed in the placebo and BG9791 0.1 and 0.75groups; it was slightly increased in the BG9719 2.5 group.The group treated with furosemide alone had a small reduc-tion in blood pressure at 4 hours; there was no additionalreduction when furosemide was combined with BG9719 atany of the 3 dose levels. Overall, there were no significantdifferences in the degree of change in systolic blood pressureamong the treatment groups.

DiscussionThis is the first study to evaluate the combination of an A1

adenosine receptor antagonist and furosemide in humans. Inthis study, BG9719 increased urine output and sodiumexcretion when given without a diuretic in patients with heartfailure receiving ACE inhibitors, confirming the diureticeffect of adenosine A1 receptor antagonism. It also increasedurine output when given in addition to furosemide. Althoughfurosemide alone caused a decline in creatinine clearance,when furosemide was given in addition to the 2 lower dosesof BG9719, creatinine clearance was maintained in thepresence of an effective diuresis. These results suggest thatBG9719 might prevent deterioration in renal function whileincreasing urine output during standard heart failure therapy.Moreover, A1 receptor antagonism may protect against the

commonly observed decline in glomerular filtration associ-ated with the use of loop diuretics.

Possible Mechanism of ActionAdenosine acts on 2 different receptor subtypes in the kidney(the A1 and A2 receptors).5 A2 receptor stimulation increasesmedullary blood flow and would be expected to improverenal function. However, the A1 receptor seems to predomi-nate in the kidney. Adenosine (via stimulation of the A1

receptor) may directly decrease glomerular filtration bydilatation of postglomerular vessels6 or vasoconstriction be-fore the glomerulus.7 The A1 receptor seems to be themediator of tubuloglomerular feedback, the macula densamechanism by which increased sodium concentration in theproximal tubule leads to decreased glomerular filtration.8 A1

receptor blockade could therefore inhibit tubuloglomerularfeedback and dilate afferent arterioles, leading to improvedglomerular filtration.

Selective A1 receptor blockade has also demonstrated aphysiological role for adenosine in the control of tubularfunction.9 A1 adenosine receptor blockade seems to directlyimpact the proximal and distal tubules, increasing Na�

excretion.10 At the distal tubule, this could lead to apotassium-neutral natriuresis, as was demonstrated in thisstudy. It is thus not surprising that xanthines, which alsoantagonize adenosine, cause diuresis.11 The highly specific A1

receptor antagonist BG9719 also has been shown to increasenatriuresis and diuresis.12 Effects on tubuloglomerular feed-back and the proximal and distal tubules could thereforeexplain the diuretic and natriuretic observations of the presentstudy.

It is unlikely that differences in hemodynamics couldexplain the differences in renal function that were observedbetween the treatment groups, because no significant changeswere noted in heart rate or blood pressure between the groups(Table 3). Prior studies in patients with heart failure treatedwith BG9719 demonstrated only minor changes in heart rateand blood pressure (unpublished results). Healthy subjectsalso demonstrated no significant changes in pulse or blood

TABLE 2. Electrolyte Excretion With BG9719, With and Without Furosemide

PlaceboBG9719,

0.1 �g/mLBG9719,

0.75 �g/mLBG9719,

2.5 �g/mL

Na� excretion, mEq/L

Without furosemide 9�18 17�24 43�20* 44�39*

In addition to furosemide 187�84 188�82 270�93* 202�102

K� excretion, mEq/L

Without furosemide 9�12 11�14 14�13 13�13

In addition to furosemide 29�14 34�17 45�19* 34�27

Mg excretion, mEq/L

Without furosemide 0.1�1.9 1.5�1.6* 2.2�1.3* 0.8�1.7

In addition to furosemide 3.5�2.9 4.7�2.4 4.9�2.4 3.8�2.4

Uric acid excretion

Without furosemide �0.3�0.6 0.0�0.6 0.4�0.5* 0.3�0.4*

In addition to furosemide �0.5�0.6 �0.3�0.4 0.1�0.5* �0.4�0.4

*P�0.05 vs placebo.

Figure 4. The relationship between change in urine volume andchange in creatinine clearance for patients receiving the 0.75-�g/mL concentration. BG9719 increased urine output whengiven with or without furosemide. The decrease in GFR withfurosemide alone was not seen when BG9719 was given.

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pressure when treated with BG9719. Animal studies withselective A1 adenosine antagonists did not show an effect onheart rate or blood pressure in dogs.10 Additional support forthe lack of hemodynamic effect comes from animal studies inwhich arterial blood pressure and heart rates were indistin-guishable between A1 adenosine receptor–deficient mice andnormal controls.13

Prior Studies in Heart FailurePlasma adenosine levels are elevated in patients with heartfailure, implying that adenosine antagonism might havephysiological or pathologic importance in these patients.14 Aprior study of the effects of BG9719 in patients with heartfailure suggested potential beneficial effects of A1 receptorblockade.4 BG9719 caused a mild diuresis without decreasingglomerular filtration. In contrast, furosemide produced amarked decrease in glomerular filtration. While interpretationof this previous study was limited by differences in the extentof diuresis between the treatment groups, it did raise hope thatBG9719 might preserve renal function in the setting ofdiuresis.

Most studies evaluating the renal effects of furosemidehave demonstrated decreased glomerular function.15–18 Theseeffects may be mediated by adenosine release in the kidney.The marked furosemide-induced decrease in creatinine clear-ance in the present study is consistent with the clinicalobservation that diuresis may be limited by worsening renalfunction. Considering the known adverse prognostic impor-tance of an increased serum creatinine in the hospital,1 anintervention that might permit diuresis while maintainingrenal function could conceivably have a favorable impact onpatients hospitalized for heart failure.

Concentration of 2.5 �gCreatinine clearance was not maintained when BG9719 at aconcentration of 2.5 �g/mL was given in addition to furo-semide. It is unclear why no benefit was seen at thisconcentration when GFR improved with the 2 lower doses. It

is possible that the contrasting results are secondary toadditional pharmacological activity of the high dose or tocross-reactivity of BG9719 to another receptor system. Inter-estingly, when BG9719 was given alone, creatinine clearancedid not increase as much with the higher dose as it did withthe lower doses. This additionally supports the idea ofvarying effects at different doses.

LimitationsThis study is a preliminary evaluation of BG9719, havingevaluated a limited number of patients. Thus, it is possiblethat the dose-related findings of the present study wereattributable to the relatively small size of the study. It is alsopossible that the baseline differences (although not statisti-cally different) impacted comparisons of placebo and thedifferent doses of BG9719. There may have been differencesin patient characteristics leading to divergent results. Indeed,the placebo group tended to have better baseline renalfunction. However, this baseline difference would not explainthe high-dose observations, because baseline creatinine clear-ance was similar in all 3 groups that received active drug.Baseline differences also cannot explain the intragroup ef-fects noted when the actions of BG9719 in addition tofurosemide were compared with the furosemide-only dosing.

Because this study was performed in stable patients, at thistime one must be cautious in extrapolating the findings tounstable patients. Nevertheless, patients in this study did haveevidence of fluid overload (edema, dyspnea), even if they didnot have an acute change in their clinical status. Althoughpatients in this study were more stable than patients withdecompensated heart failure, there is no reason to believe thatthe renal physiology should differ greatly between these 2groups.

ConclusionCombining the A1 adenosine receptor antagonist BG9719 (at0.1 and 0.75 �g/mL) with standard diuretic therapy mayincrease renal output while protecting renal function. The

TABLE 3. Hemodynamics With BG9719, With and Without Furosemide

PlaceboBG9719,

0.1 �g/mLBG9719,

0.75 �g/mLBG9719,

2.5 �g/mL

Heart rate, bpm

Without furosemide

Predosing 75.3�8.8 77.1�14.5 72.0�13.0 71.4�10.7

� After 3.5 hrs 0.5�5.4 0.1�8.3 �1.2�7.7 �0.2�7.3

In addition to furosemide

Predosing 78.7�12.8 80.0�14.5 76.7�17.1 70.7�9.1

� After 3.5 hrs 4.7�19.2 2.4�10.6 �1.3�15.4 3.1�11.5

Systolic pressure (mm Hg)

Without furosemide

Predosing 125.6�23.0 121.5�19.8 124.8�18.0 119.2�18.7

� After 4 hrs 1.4�21.1 �0.5�10.5 �0.9�14.7 7.6�14.8

In addition to furosemide

Predosing 131.7�18.6 119.7�18.2 130.4�23.0 123.0�19.6

� After 4 hrs �7.4�15.2 �3.0�11.8 �7.8�20.0 �4.4�18.8

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present study suggests that treatment with an A1 adenosinereceptor antagonist may be useful in the therapy of congestiveheart failure. Additional investigation of this mechanismmight lead to novel approaches to the treatment of patientswith renal dysfunction associated with diuresis and heartfailure.

AcknowledgmentsThis study was supported by a grant from Biogen Inc, Cambridge,Mass.

References1. Krumholz HM, Chen YT, Vaccarino V, et al. Correlates and impact on

outcomes of worsening renal function in patients 65 years of age withheart failure. Am J Cardiol. 2000;85:1110–1113.

2. Hillege HL, Girbes ARJ, de Kam PJ, et al. Renal function, neurohormonalactivation, and survival in patients with chronic heart failure. Circulation.2000;102:203–210.

3. Gellai M, Schreiner GF, Ruffolo RR Jr, et al. CVT-124, a novel adenosineA1 receptor antagonist with unique diuretic activity. J Pharmacol ExpTher. 1998;286:1191–1196.

4. Gottlieb SS, Skettino SL, Wolff A, et al. Effects of BG9719 (CVT-124),an A1–adenosine receptor antagonist, and furosemide on glomerular fil-tration rate and natriuresis in patients with congestive heart failure. J AmColl Cardiol. 2000;35:56–59.

5. Balakrishnan VS, Coles GA, Williams JD. Effects of intravenous aden-osine on renal function in healthy human subjects. Am J Physiol. 1996;40:F374–F381.

6. Edlund A, Ohlsen H, Sollevi A. Renal effects of local infusion of aden-osine in man. Clin Sci. 1994;87:143–149.

7. Marraccini P, Fedele S, Marzilli M, et al. Adenosine-induced renalvasoconstriction in man. Cardiovasc Res. 1996;32:949–953.

8. Schnermann J. Juxtaglomerular cell complex in the regulation of renalsalt excretion. Am J Physiol Reg Integr Comp Physiol. 1998;274:R263–R279.

9. Kuan CJ, Herzer WA, Jackson EK. Cardiovascular and renal effects ofblocking A1 adenosine receptors. J Cardiovasc Pharmacol. 1993;21:822–828.

10. Yamagata T, Kobayashi T, Kusaka H, et al. Diuretic effect of KW 3902,a novel adenosine A1-receptor antagonist, in anesthetized dogs. BiolPharm Bull. 1994;17:1599–1603.

11. Collis MG, Baxter GS, Keddie JR. The adenosine receptor antagonist,8-phenyltheophylline, causes diuresis and saliuresis in the rat. J PharmPharmacol. 1986;11:850–852.

12. Wilcox CS, Welch WJ, Schreiner GF, et al. Natriuretic and diureticactions of a highly selective adenosine A1 receptor antagonist. J Am SocNephrol. 1999;10:714–720.

13. Sun D, Samuelson LC, Yang T, et al. Mediation of tubuloglomerularfeedback by adenosine: evidence from mice lacking adenosine 1receptors. Proc Natl Acad Sci U S A. 2001;98:9983–9988.

14. Funaya H, Kitakaze M, Node K, et al. Plasma adenosine levels increasein patients with chronic heart failure. Circulation. 1997;95:1363–1365.

15. Tenstad O, Williamson HE. Effect of furosemide on local and zonalglomerular filtration rate in the rat kidney. Acta Physiol Scand. 1995;155:99–107.

16. Lunau HE, Bak M, Peterson JS, et al. Renal adaptations to continuousadministration of furosemide and bendroflumethiazide in rats. PharmacolToxicol. 1994;74:216–222.

17. Smith FG, Abraham J. Renal and renin responses to furosemide inconscious lambs during postnatal maturation. Can J Physiol Pharmacol.1995;73:107–112.

18. Skott P, Hommel E, Bruun NE, et al. The acute effect of acetazolamideon glomerular filtration rate and proximal tubular reabsorption of sodiumand water in normal man. Scand J Clin Lab Invest. 1989;49:583–587.

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and William T. AbrahamSteven Goldman, Farere Dyer, Miguel Gomez, Donald Bennett, Barry Ticho, Evan Beckman

Stephen S. Gottlieb, D. Craig Brater, Ignatius Thomas, Edward Havranek, Robert Bourge,Renal Function Observed With Diuretic Therapy

Adenosine Receptor Antagonist, Protects Against the Decline in1BG9719 (CVT-124), an A

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2002 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/hc1102.105264

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In the article, “BG9719 (CVT-124), an A1 Adenosine Receptor Antagonist, Protects Against theDecline in Renal Function Observed With Diuretic Therapy,” by Gottlieb et al, which appearedin the March 19, 2002, issue of the journal (Circulation. 2002;105:1348–1353), the units in Table2 were incorrect. The corrected table appears below.

In the article, “Angiotensin II Type 2 Receptor Overexpression Preserves Left VentricularFunction After Myocardial Infarction,” by Yang et al, which appeared in the July 2, 2002, issueof the journal (Circulation. 2002;106:106–111), an author was omitted from the byline. Thecorrected author list appears below.

Zequan Yang, MD, PhD; Christina M. Bove, MD; Brent A. French, PhD;Frederick H. Epstein, PhD; Stuart S. Berr, PhD; Joseph M. DiMaria, BA;

Jennifer J. Gibson, MS; Hiroaki Matsubara, MD, PhD; Robert M. Carey, MD;Christopher M. Kramer, MD

TABLE 2. Electrolyte Excretion With BG9719, With and Without Furosemide asCompared With Baseline Day

PlaceboBG9719, 0.1

�g/mLBG9719, 0.75

�g/mLBG9719, 2.5

�g/mL

Na� excretion, mEq/8 h

Without furosemide 9�18 17�24 43�20* 44�39*

In addition to furosemide 187�84 188�82 270�93* 202�102

K� excretion, mEq/8 h

Without furosemide 9�12 11�14 14�13 13�13

In addition to furosemide 29�14 34�17 45�19* 34�27

Mg excretion, mEq/8 h

Without furosemide 0.1�1.9 1.5�1.6* 2.2�1.3* 0.8�1.7

In addition to furosemide 3.5�2.9 4.7�2.4 4.9�2.4 3.8�2.4

Uric acid excretion, mEq/8 h

Without furosemide �0.3�0.6 0.0�0.6 0.4�0.5* 0.3�0.4*

In addition to furosemide �0.5�0.6 �0.3�0.4 0.1�0.5* �0.4�0.4

*P�0.05 vs placebo.

(Circulation. 2002;206:1743.)© 2002 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000035793.32708.D2

1743

Corrections