THERAPY AND PREVENTIONCONGESTIVE HEART FAILURE

Systemic and regional hemodynamic elfects ofcaptopril and milrinone administered alone andconcomitantly in patients with heart failureTHIERRY H. LEJEMTEL, M.D., CAROL S. MASKIN, M.D., DONNA MANCINI, M.D.,LAWRENCE SINOWAY, M.D., HARRY FELD, M.D., AND BRIAN CHADWICK, R.N.

ABSTRACT The effects of milrinone and captopril on ventricular performance, renal blood flow,and femoral vein oxygen content were compared in 11 patients with severe chronic heart failure. Theincrease in stroke volume index was greater with milrinone than with captopril (28 -+ 7 vs 24 + 7ml/m2; p < .05), while pulmonary capillary wedge pressures fell similarly (19 -+ 10 vs 21 7 mmHg). Mean systemic arterial pressure decreased significantly from 84 + 10 to 73 + 11 mm Hg (p <.05) with captopril but did not with milrinone. Neither drug changed heart rate significantly. Althoughmilrinone produced a greater improvement in ventricular performance than captopril, renal blood flowincreased similarly with both drugs from 289 78 to 417 + 1 1 ml/min (p < .05) and from 278 ± 77to 441 + 115 ml/min (p < .05), respectively. Femoral vein oxygen content was increased by milrinonefrom 7.9 2.6 to 9.8 + 3.0 ml/100 ml (p < .05) and was not changed by captopril. In seven additionalpatients, intravenous milrinone, administered at the peak effect of captopril, further augmented strokevolume index from 24 + 6 to 32 + 6 mI/M2 (p < .05) and tended to reduce pulmonary capillary wedgepressure further from 20 ± 8 to 18 ± 9 mm Hg (p = NS). The addition of intravenous milrinone tocaptopril did not reduce mean systemic arterial pressure (71 + 8 vs 71 + 8 mm Hg) or significantlyincrease heart rate (89 ± 17 vs 92 ± 18 beats/min) when compared with captopril alone. Althoughrenal blood flow was not further increased by the addition of intravenous milrinone to captopril.femoral vein oxygen content increased from 6.8 ± 1.9 to 9.9 + 1.8 ml/100 ml (p < .05). Thussimultaneous administration of captopril and milrinone has synergistic effect on cardiac performanceand complementary effects on the peripheral circulation.Circulation 72, No. 2, 364-369, 1985.

RECENTLY, angiotensin-converting enzyme inhibi-tion with captopril has been shown not only to improveshort-term left ventricular performance but also to en-hance long-term exercise tolerance in patients withchronic congestive heart failure during long-term ther-apy. 11 Accordingly, therapy with captopril has gainedwide acceptance for the treatment of congestive heartfailure not controlled by digitalis glycosides and diuret-ics. However, in addition to the fact that some patientsfail to benefit or have side effects from long-term cap-topril therapy that limit its efficacy, some patients withadvanced heart failure also become increasingly symp-tomatic despite this therapy and thus may benefit fromfurther inotropic support.' Milrinone, a newly synthe-sized, selective phosphodiesterase inhibitor that exerts

From the Department of Medicine, Division of Cardiology, TheAlbert Einstein College of Medicine, Bronx, NY.

Address for correspondence: Thierry H. LeJemtel, M.D., Depart-ment of Medicine, Albert Einstein College of Medicine, 1300 MorrisPark Ave., Forchheimer Bldg., G-42, Bronx, NY 10461.

Received March 19. 1985; revision accepted May 16, 1985.

both positive inotropic and vasodilatory properties,can produce sustained improvement in cardiac per-formance in patients with refractory heart failure..9 Incontrast to its precursor amrinone, milrinone, whenadministered over the long term, has not been compli-cated by side effects and thus may be more promisingfor the treatment of patients with congestive heart fail-ure. This study was undertaken to compare the short-term effects of captopril and milrinone on cardiac per-formance and regional hemodynamics and to assessthe hemodynamic safety and possible synergistic bene-fits of combined administration of captopril and mil-rinone in patients with severe heart failure.

Materials and methodsPatients. Sixteen men and two women with severe chronic

congestive heart failure were studied (mean age 60 years, range32 to 79). Ten had ischemic heart disease as documented on thebasis of past myocardial infarctions or coronary arteriograms.Eight had cardiomyopathy of unknown origin. No patients hadhypertension, recent myocardial infarction, or primary valvular

CIRCULATION364

by guest on May 24, 2018

http://circ.ahajournals.org/D

ownloaded from

THERAPY AND PREVENTION-CONGESTIVE HEART FAILURE

disease. All patients were restricted in activity by fatigue and/ordyspnea, and not by angina, despite therapy with digitalis,diuretics, and long-acting nitrates. Mean digoxin level was 0.9ng/ml (range 0.3 to 1.9). All patients were in functional class IIIor IV of the New York Heart Association for at least 3 months.All were in sinus rhythm except one patient, who was in atrialfibrillation. Their maximal oxygen uptake averaged 9.9ml/kg/min (range 6.1 to 15.4). Left ventricular ejection fractionmeasured under resting conditions by gated nuclear scanningwas below 20% in all patients.The patients were admitted to the, coronary care unit at least

24 hr before the hemodynamic evaluation. Long-acting nitrateswere discontinued and a 2 g sodium diet was prescribed. Thepatients continued to receive their usual daily doses of digitalisglycosides and diuretics during the study. The nature, potentialbenefits, and possible risks of the study were explained to allpatients, who then gave written informed consent. The studyprotocol was approved in advance by the Committee on ClinicalInvestigations of the Albert Einstein College of Medicine.Hemodynamic measurements. After 24 hr of bedrest, pa-

tients underwent right heart catheterization performed withflow-directed, balloon-tipped, thermodilution catheters (Ed-wards Laboratories). Mean pulmonary arterial, pulmonarywedge, and right atrial pressures were recorded on a photo-graphic recorder (Electronics for Medicine). Cardiac output wasdetermined by the thermodilution technique with 5% dextrose inwater and obtained in triplicate with less than 10% variation.Systemic arterial pressure was measured via an indwelling ar-tery catheter. Mean systemic arterial pressure was obtained byelectronic integration. Derived hemodynamic variables, includ-ing cardiac index, stroke volume index, and systemic vascularresistance, were calculated from standard formulas. An electro-cardiographic lead was monitored throughout the study.Renal blood flow. Renal blood flow was determined as the

left renal venous blood flow by the continuous thermodilutiontechnique and a No. 7F dual thermistor catheter (Webster Labo-ratories). 1W13 The injection orifice is located 15 mm proximal tothe distal end and on the concavity of the bend to preventvascular wall contact with the opening obliquely oriented at 30to 40 degrees against the blood stream to increase turbulenceand to ensure optimal indicator/blood admixture. The external"dilution" thermistor is located 10 mm proximal to the injectionorifice and the second "indicator" thermistor is within the cath-eter just proximal to the orifice. The catheter was introducedinto the femoral vein via the Seldinger technique and advancedinto the left renal vein under fluoroscopy. Optimal positioningwithin the renal vein was confirmed by injection of megluminediatrizoate (Renografin) through the catheter, and determinationof oxygen saturation of renal vein blood was done with sampleswithdrawn from the catheter. At the end of the study, the posi-tion of the catheter was reconfirmed by fluoroscopy. For eachdetermination of blood flow, 5% dextrose at room temperaturewas infused through the catheter with a Harvard Pump (Model921) at a constant rate of 50 ml/min until the resistance deflec-tions of both termistors were stable. A standard three-channelthermodilution Wheatstone Bridge (Webster Laboratories) wasused to convert the resistance changes into calibrated voltages,which were recorded on photographic paper. Blood flow wasthen calculated with the formula derived by Ganz et al., 12 with amodification to correct for thermotransport within the Webstercatheter at blood flow rate ranging from 300 to 1500 ml/min. 14Each measurement of left renal vein blood flow was made atleast five times, and three determinations within 10% wereaveraged.Femoral vein oxygen content. Retrograde catheterization of

the femoral vein was also performed with an 18 gauge angio-graphic catheter introduced percutaneously and advanced 10 cm

distally into the femoral vein. The catheter was used to with-draw blood samples while the patient was resting in a supineposition. All samples were evaluated in triplicate for oxygencontent (ml/100 ml) with a Lex 02-Con-TL oxygen analyzer(Lexington Instruments).Drug administration. In the first 1 1 patients, evaluated in

the postprandial state, 7.5 mug of milrinone and 12.5 mg ofcaptopril were administered orally in variable order. Six pa-tients received milrinone and then captopril, and five receivedcaptopril and then milrinone. Milrinone or captopril was firstadministered after two similar sets of control measurementswere obtained 30 min apart. Systemic hemodynamic measure-ments were repeated at 30 min intervals for 2 hr and hourlythereafter until values returned to baseline levels. Renal bloodflow and femoral vein oxygen content were measured at 30, 60,and 90 min. One of these measurements corresponded to peakincrease in cardiac index in all patients. Two hours after returnof the hemodynamic parameters to baseline levels, captopril ormilrinone was administered and measurements were repeated aspreviously described. Renal and femoral vein catheters wereremoved immediately after completion of the study.

During the first day of the study, the remaining seven patientsreceived an intravenous bolus of 25 g£g/kg milrinone. Threepatients who failed to demonstrate an increase in cardiac indexof at least 20% received a second bolus of 50 gg/kg milrinoneadministered 3 hr after the initial one. On the second day of thestudy, captopril was administered after renal and femoral veincatheters had been inserted. Systemic hemodynamic measure-ments, renal blood flow, and femoral vein oxygen content weremeasured at 30, 60, and 90 min, with the last measurementcorresponding to the peak increase in cardiac index in all pa-tients. Milrinone was then administered intravenously at a doseidentical to that given the day before. Ten minutes later, allmeasurements were repeated and femoral and renal vein cath-eters were removed.

Statistical analysis. The results are expressed as mean ± SDand were considered significant at p < .05. Comparison of thehemodynamic and metabolic effects of milrinone and captoprilwere made with a two-factor repeated measures analysis ofvariance. Comparisons of hemodynamic and metabolic param-eters under the three treatment conditions (milrinone, captopril,and captopril plus milrinone) were performed with analysis ofcovariance.

ResultsMilrinone, which was administered orally to 11 pa-

tients at a dose of 7.5 mg, produced a greater improve-ment in cardiac performance than did 12.5 mg of cap-topril, as documented by a greater stroke volume index(28 + 7 vs 24 ± 7 ml/m2; p < .05) and similardecrements in pulmonary capillary wedge pressures(19 + 10 vs 21 ± 7 mm Hg; p = NS) (figure 1). Meansystemic arterial pressure was significantly reduced bycaptopril from 84 + 10 to 73 + 11 mm Hg (p < .05)but was only modestly decreased by milrinone from 84+ 10 to 80 O10 mm Hg (p = NS). Heart rate tendedto decrease after captopril from 94 + 15 to 91 + 17beats/min (p = NS) and was not changed by milrinone(93 ± 15 vs 94 ± 15 beats/min). Systemic vascularresistance significantly decreased with both captopriland milrinone from 1981 + 416 to 1406 + 251 dyne-

Vol. 72, No. 2, August 1985 365

by guest on May 24, 2018

http://circ.ahajournals.org/D

ownloaded from

LEJEMTEL et al.

>.CLlJ

LAJ_ _:

I-

LI)

35

30

[KSl - -O MILRINONE

-O CAPTOPRIL

**

*

251_

20k_

15 20 25 30 35 40PULMONARY CAPILLARY WEDGE PRESSURE

(mmHg)FIGURE 1. Stroke volume index and pulmonary capillary wedge pres-sure in 11 patients during the control period (closed circles) and atmaximum response (open circles). Values are mean + SD at an oraldose of 7.5 mg of milrinone and 12.5 mg of captopril. *p < .05.

sec-cm` (p < .05) and from 1929 + 367 to 1269 ±199 dyne-sec-cm-5 (p < .05), respectively.

Captopril, which at peak effect did not augmentcardiac index as much as milrinone at peak effect (2.0+ 0.4 vs 2.5 + 0.4 liters/min/m2; p < .05), increasedrenal blood flow from 278 + 77 to 441 ± 115 ml/min(p < .05) (figure 2). Milrinone increased renal bloodflow from 289 + 78 to 417 ± 111 ml/min (p < .05).The increase in renal blood flow after milrinone tended

S . CAPTOPRIL0--0 MILRINONE

3.0-

-J

clk

,_

--0

LaJi

C-,

.-,

C.>

2.5sH

T

F I

1.5'

to be lower than that produced by captopril, although itdid not reach statistical significance.Of note was the observation that resting femoral

oxygen content was unchanged by captopril (8.0 ±2.8 vs 8.1 ± 2.4 ml/100 ml) but was increased bymilrinone (7.9 ± 2.6 to 9.8 ± 3.0 ml/100 ml; p <.05).An intravenous bolus of milrinone administered to

seven patients at a mean dose of 36 gg/kg (range 25 to50) increased stroke volume index from 20 ± 4 to 27+ 4 in/M2 (p < .05) and decreased pulmonary capil-lary wedge pressure from 26 ± 7 to 20 ± 6 mm Hg(p < .05) (figure 3). Systemic vascular resistance de-creased significantly from 1874 ± 389 to 1332 ± 129dyne-sec-cm-5 (p < .05). The changes in systemicarterial pressure from 83 + 12 to 84 ± 13 mm Hg andin heart rate from 89 ± 15 to 94 ± 18 beats/min werenot statistically significant. In the same seven patients,captopril at an oral dose of 12.5 mg increased strokevolume index from 19 ± 5 to 24 ± 6mm Hg (p < .05)and decreased pulmonary capillary wedge pressurefrom 29 ± 9 to 20 ± 8 mm Hg (p < .05). Systemicarterial pressure and vascular resistance decreased sig-nificantly from 82 ± 9 to 71 ± 8 mm Hg (p < .05) andfrom 1926 ± 418 to 1392 ± 362 dyne-sec-cm-1 (p <.05), respectively. An identical intravenous bolus ofmilrinone administered at the peak hemodynamic ef-fect of captopril increased stroke volume index furtherfrom 24 ± 6 to 32 ± 6 ml/m2 (p < .05) and tended todecrease pulmonary capillary wedge pressure further

_._

E 400-J

°300-J

L&-C>C>30

tUvv

L

I

I1

CONTROLI

PEAK CONTROL PEAKFIGURE 2. Maximal changes in cardiac index and renal blood flow after an oral dose of 7.5 mg of milrinone and 12.5 mg ofcaptopril in 1 1 patients. Values are mean + SD. *p < .05.

CIRCULATION366

15L_

s()nr1

11111-L)l

.l

by guest on May 24, 2018

http://circ.ahajournals.org/D

ownloaded from

THERAPY AND PREVENTION-CONGESTIVE HEART FAILURE

35'

uJ

-J

zzoLo

1-7-

T

30F-

x

-i251-

201-

15L

*---0 MILRINONE WN0- CAPTOPRIL

l l l l l10 15 20 25 30PULMONARY CAPILLARY WEDGE PRESSURE

(mmHg)FIGURE 3. Maximal changes in stroke volume index and pulmonarycapillary wedge pressure during control period (closed circles) and atmaximum response (open circles) to 12.5 mg of captopril and to anintravenous bolus of 36 ag/kg milrinone administered alone and at peakhemodynamic effect of captopril in seven patients. Values are mean +SD. *p < .05.

from 20 ± 8 to 18 ± 9 mm Hg (p = NS). Systemicvascular resistance also decreased further after con-comitant intravenous administration of milrinone from1392 ± 362 to 1071 ± 283 dyne-sec-cm-5 (p < .05)when compared with captopril alone. Systemic arterial

pressure and heart rate did not change (71 ± 8 vs 71 ±8 mm Hg and 89 ± 17 vs 92 ± 18 beats/min). Whencompared with intravenous milrinone alone, the con-comitant administration of captopril and intravenousmilrinone also resulted in a greater stroke volume in-dex (32 ± 6 vs 27 ± 4 ml/m2; p < .05), while pulmo-nary capillary wedge pressure tended to be lower (18± 9 vs 20 ± 6 mm Hg; p = NS).Resting femoral vein oxygen content and renal

blood flow were measured before oral administrationof captopril, at peak effect of captopril, and after intra-venous administration of milrinone (figure 4). Femoralvein oxygen content was unchanged by captopril (7.1± 1.5 vs 6.8 ± 1.9 ml/100 ml), but was increased bymilrinone (9.3 ± 1.8 ml/100 ml; p < .05). Renalblood flow, which was increased by captopril (278 +

63 to 403 ± 110 ml/min; p < .05), was not furtherenhanced by concomitant administration of milrinone(437 ± 123 vs 403 ± 110 ml/min; p = NS).

DiscussionIn this study, milrinone produced a greater improve-

ment in cardiac performance than captopril for a simi-lar increase in renal blood flow. Resting limb bloodflow was increased by milrinone but not by captopril.In addition, concomitant administration of captopriland milrinone was safe and resulted in synergistic ef-fects on cardiac performance and complementary ef-fects on the peripheral circulation.

*-~@*RBF0--0 FVO2

450r

400H2

-_ 2

C>o__om E

L.C>Zi E

3501-

3001-

250

F

*

I*

1

A

CONTROLA

CAPTOPRIL

10LUJ

9 co-m o

8 CX _= °~

7 -cCYm

6&

A

CAPTOPRIL+ MILRINONE

FIGURE 4. Renal blood flow (RBF) and femoral vein oxygen content (FVO2) during control, at maximal response to 7.5 mg ofcaptopril, and after concomitant intravenous administration of milrinone at a mean dose of 36 1.g/kg in seven patients. Values aremean ± SD. *p < .05.

Vol. 72, No. 2, August 1985 367

by guest on May 24, 2018

http://circ.ahajournals.org/D

ownloaded from

LEJEMTEL et al.

After administration of 12.5 mg of captopril, ourpatients demonstrated an improvement in cardiac per-formance similar to that reported previously.>4 In viewof the flat dose-response curve to captopril, adminis-tration of higher doses would not have improved ven-tricular performance further, although the duration ofaction may have been prolonged. 15 With oral mil-rinone, 7.5 mg now represents the starting dose and, aswas demonstrated by Kubo et al.,"6 a dose of 10 or 12.5mg probably would have produced greater improve-ment in cardiac performance. Despite the relativelylow dose used in this study, milrinone increased strokevolume index substantially more than angiotensin-con-verting enzyme inhibition with short-term administra-tion of captopril, while left ventricular filling pressureswere reduced to a similar extent by both pharmaco-logic interventions.

Milrinone improves cardiac performance by en-hancing myocardial contractility and directly loweringcardiac afterload. I 1 ` The positive inotropic action ofmilrinone seems to be mediated by selective inhibitionof a fraction III of cardiac phosphodiesterase that isspecific for cyclic AMP.'` The vasodilating propertiesof milrinone most probably result from phosphodies-terase inhibition in the smooth muscle. In contrast,captopril improves cardiac performance only by low-ering arterial impedance through inhibition of the pro-duction of angiotensin II and perhaps by additionalmechanisms. 19 The substantial fall in systemic arterialpressure that was observed only with captopril sup-ports the potent arteriolar vasodilator effects of thelatter drug.The hemodynamic safety of short-term intravenous

administration of milrinone at the peak hemodynamiceffect of captopril was documented by the absence offurther reduction in systemic arterial pressure and bythe lack of excessive fall in left ventricular filling pres-sure when compared with captopril alone. The syner-gistic hemodynamic effect was demonstrated by therise in stroke volume index, which was greater thanthat derived with either drug administered alone. Wedid not determine whether a similar synergistic effectof captopril and milrinone would have been observedat a higher dose of milrinone. This study has signifi-cant implications for the use of inotropic agents vsvasodilators for the treatment of patients with chroniccongestive heart failure. Theoretically, enhancingmyocardial contractility may have adverse effects onthe rate of progression of the underlying disease20 andmay have the potential for increasing malignant ven-tricular arrhythmias.2' Thus one might prefer to reducearterial impedance with specific vasodilators such as

368

captopril before mobilizing the entire contractile re-serve available with higher doses of milrinone.`7 Inaddition, the complementary effects of captopril andmilrinone on the peripheral circulation further supportcombining the two agents.

Captopril did not alter resting femoral oxygen con-tent. In patients lying supine, in whom lower limboxygen consumption was presumably constant, an in-crease in femoral oxygen content would have occurredif captopril had increased blood flow to the limbs. Ourfindings corroborate with those of Faxon et al.,22 whofound that captopril did not alter calf vascular resis-tance over the short term. In contrast, milrinone in-creased femoral vein oxygen content and thus presum-ably lowered limb vascular resistance flow at rest.Whether milrinone can cause short-term increasedlimb blood flow during maximal exercise is as yet notknown. However, an increase in resting blood flowmay have contributed to the delay in anaerobic metab-olism induced by short-term administration of amri-none (the precursor of milrinone) during submaximalexercise." Such short-term improvement in submaxi-mal exercise may explain the immediate clinical bene-fit noted during therapy with milrinone.`

Both captopril and milrinone increased renal bloodflow in our patients. However, the increase tended tobe greater with captopril. Thus the ratio of the increasein renal blood flow and cardiac index was substantiallyhigher for captopril as compared with milrinone (2.7vs 0.9). In experimental preparations, short-term inhi-bition of the converting enzyme consistently increasesrenal blood flow.'9' 24 25 In patients with chronic con-gestive heart failure, the results are more controver-sial. Creager et al.26 showed that captopril increasedrenal blood flow by 60%, which is identical to ourfindings. In contrast, Powers et al.27 failed to demon-strate an increase, and Mujais et al.28 even noted adecrease in renal blood flow at initiation of captopriltherapy. As pointed out by Blythe,29 an excessive fallin systemic arterial pressure may, in certain instances,be responsible for a fall in renal blood flow. However,a difference in the methods used to determine renalblood flow may also help explain the discrepancy inresults. Although the continuous thermodilution tech-nique, as used in this study, allows instantaneous de-termination, clearance methods are not instantaneousand require a steady hemodynamic state for 60 to 160min, which may not be present after administration ofcaptopril. The increase in renal blood flow producedby milrinone is consistent with our prior data withamrinone30 but is at variance with the lack of changesin renal blood flow measured after 1 month of therapy

CIRCULATION

by guest on May 24, 2018

http://circ.ahajournals.org/D

ownloaded from

THERAPY AND PREVENTION-CONGESTIVE HEART FAILURE

with milrinone. * The lack of additional improvementin renal blood flow despite the further improvement incardiac performance produced by intravenous admin-istration of milrinone at the peak hemodynamic effectof captopril cannot be readily explained. The renalvasculature, which was already dilated by angiotensin-converting enzyme inhibition, may have been less sen-sitive to the vasodilating effect of milrinone. Conse-quently, the increase in cardiac output produced bymilrinone may have been shunted to vascular bedswhere conductance could be improved, i.e., skeletalmuscle. Such complementary redistribution of the in-creased cardiac output may be an important therapeuticbenefit of combining therapy with captopril and mil-rnnone.

References1. Davis R, Ribner HS, Keung E, Sonnenblick EH, LeJemtel TH:

Treatment of chronic congestive heart failure with captopril, anoral inhibitor of angiotensin-converting enzyme. N Engl J Med301: 117, 1979

2. Dzau VJ, Colucci WS, Williams GH, Curfman G, Meggs L, Hol-lenberg NK: Sustained effectiveness of converting enzyme inhibi-tion in patients with severe congestive heart failure. N EngI J Med302: 1373, 1980

3. Levine BT, Franciosa JA, Cohn JA: Acute and long-term responseto an oral converting enzyme inhibitor, captopril, in congestiveheart failure. Circulation 62: 35, 1980

4. Ader R, Chatterjee K, Ports T, Brundage B, Hiramatsu B, ParmleyW: Immediate and sustained hemodynamic and clinical improve-ment in chronic heart failure by an oral angiotensin-convertingenzyme inhibitor. Circulation 61: 931, 1980

5. Applefeld MM, Newman KA, Grove SR, Sutton FJ, Roffman DS,Reid WP, Linzberg SE: Intermittent, continuous outpatient dobuta-mine infusion in the management of congestive heart failure. Am JCardiol 51: 455, 1983

6. Maskin CS, Sinoway L, Chadwick B, Sonnenblick EH, LeJemtelTH: Sustained hemodynamic and clinical effects of a new cardio-tonic agent WIN 47203 in patients with severe congestive heartfailure. Circulation 67: 1065, 1983

7. Baim DS, McDovell AV, Cherniles J, Monrad ES, Parker JA,Edelson J, Braunwald E, Grossman W: Evaluation of a new bipyri-dine inotropic agent- milrinone- in patients with severe conges-tive heart failure. N Engl J Med 309: 748, 1983

8. Sinoway L, Maskin CS, Chadwick B, Forman R, Sonnenblick EH,LeJemtel TH: Long-term therapy with a new cardiotonic agentWIN 47203: drug dependent improvement in cardiac performanceand progression of the underlying disease. J Am Coll Cardiol 2:327, 1983

9. Jaski BE, Fifer MA, Wright RF, Braunwald E, Colucci WS: Posi-tive inotropic and vasodilator actions of milrinone in patients withsevere congestive heart failure: dose response relationship andcomparison with nitroprusside. J Clin Invest 75: 623, 1985

10. Hornych A, Brod J, Sclechta V: The measurement of the renalvenous outflow in man by the local thermodilution method. Neph-ron 8: 17, 1971

*Cody RG: Personal communication.

11. Warembourg H, Ketellers JY, Lekieffre J, Bertrand M, Houdas Y,Carre A: La mesure du debit sanguin renal par la methode dethermodilution. Arch Mal du Coeur 65: 218, 1972

12. Ganz W, Tamura K, Marcus HS, Donoso R, Yoshida S, SwanHJC: Measurement of coronary sinus blood flow by continuousthermodilution in man. Circulation 54: 181, 1971

13. Sato Y, Matsuzawa H: Comparative study of effects of adrenaline,dobutamine and dopamine on systemic hemodynamics and renalblood in patients following open heart surgery. Jpn Circ J 46: 1059,1982

14. Haggmark S, Biber B, Sjodin JG, Winso 0, Gustarsson B, Reiz S:The continuous thermodilution method for measuring high bloodflows. Scand J Clin Lab Invest 42: 315, 1982

15. Brunner HR, Gavras H, Walber B, Kersharr GR, Turini GA, Va-kovich RA, McKinstry DN, Gavras I: Oral angiotensin-convertingenzyme inhibitor in long-term treatment of hypertensive patients.Ann Inten Med 90: 19, 1979

16. Kubo SH, Cody RG, Chatterjee K, Simonton C, Ruttman H, Leon-ard D: Acute dose range study of milrinone in congestive heartfailure. Am J Cardiol 155: 726, 1985

17. Borow KM, Come P, Newmann A, Baim DS, Braunwald E,Grossman W: Milrinone (WIN 47203): differentiation of its ino-tropic and vasodilator effects in humans. J Am Coll Cardiol 3: 472,1984 (abstr)

18. Bristol JA, Sircar I, Moos WH, Evans DB, Weishaar RE: Cardio-tonic agents 1 ,4,5-dihydro-6-{4-1H-imidazol-l-yl) phenyl}-3 (2H)-pyridazones: novel positive inotropic agents for the treatment ofcongestive heart failure. J Med Biochem 27: 1099, 1984

19. Hollenberg NK: Renal response to angiotensin-converting enzymeinhibition. Am J Cardiol 49: 1425, 1982

20. Katz AM: Biochemical "defect" in the hypertrophied and failingheart: deleterious or compensatory. Circulation 47: 1076, 1973

21. Dobmeyer DJ, Stine RA, Leier CV, Greenberg R, Schaal SF: Thearrhythmogenic effects of caffeine in human beings. N Engl J Med308: 814, 1983

22. Faxon DP, Halperin JL, Creager MA, Gavras H, Schick EC, RyanTJ: Angiotensin inhibition in severe heart failure: acute central andlimb hemodynamic effects of captopril with observation on sus-tained oral therapy. Am Heart J 101: 548, 1981

23. Siskind SJ, Sonnenblick EH, Forman R, Scheuer J, LeJemtel TH:Acute substantial benefit of inotropic therapy with amrinone onexercise hemodynamics and metabolism in severe congestive heartfailure. Circulation 64: 966, 1981

24. Gavras H, Liang C, Brunner HR: Redistribution of regional bloodflow after inhibition of the angiotensin-converting enzyme. CircRes 43(suppl I): 1-59, 1978

25. Heyndrickx GR, Baettcher DH, Vatner SF: Effects of angiotensin,vasopressin and methoxamine on cardiac function and blood flowdistribution in conscious dogs. Am J Physiol 231: 1579, 1976

26. Creager MA, Halperin JL, Bernard DB, Faxon DP, MelidossianCD, Gavras H, Ryan TJ: Acute regional circulatory and renalhemodynamic effects of converting enzyme inhibition in patientswith congestive heart failure. Circulation 64: 483, 1981

27. Powers ER, Bannerman KS, Stone J, Reison DS, Escala EL, Ka-lisher A, Weiss MB, Sciacca RR, Cannon PJ: The effect of capto-pril on renal, coronary and systemic hemodynamics in patients withsevere congestive heart failure. Am Heart J 104: 1203, 1982

28. Mujais SK, Fouad FM, Textor SC, Tarazi RC, Bravo EL, Hart N,Gifford RW: Transient renal dysfunction during initial inhibition ofconverting enzyme in congestive heart failure. Br Heart J 52: 63,1984

29. Blythe WB: Captopril and renal autoregulation. N Engl J Med 308:390, 1983

30. LeJemtel TH, Keung E, Ribner HS, Davis R, Wexler J, BlaufoxDM, Sonnenblick EH: Sustained beneficial effects of oral amri-none on cardiac and renal function in patients with severe conges-tive heart failure. Am J Cardiol 45: 123, 1980

Vol. 72, No. 2, August 1985 369

by guest on May 24, 2018

http://circ.ahajournals.org/D

ownloaded from

T H LeJemtel, C S Maskin, D Mancini, L Sinoway, H Feld and B Chadwickalone and concomitantly in patients with heart failure.

Systemic and regional hemodynamic effects of captopril and milrinone administered

Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 1985 American Heart Association, Inc. All rights reserved.

is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/01.CIR.72.2.364

1985;72:364-369Circulation. 

http://circ.ahajournals.org/content/72/2/364the World Wide Web at:

The online version of this article, along with updated information and services, is located on

  http://circ.ahajournals.org//subscriptions/

is online at: Circulation Information about subscribing to Subscriptions: 

http://www.lww.com/reprints Information about reprints can be found online at: Reprints:

  document. Permissions and Rights Question and Answer information about this process is available in the

located, click Request Permissions in the middle column of the Web page under Services. FurtherEditorial Office. Once the online version of the published article for which permission is being requested is

can be obtained via RightsLink, a service of the Copyright Clearance Center, not theCirculationpublished in Requests for permissions to reproduce figures, tables, or portions of articles originallyPermissions:

by guest on May 24, 2018

http://circ.ahajournals.org/D

ownloaded from