The renal response to low dose dopamine

JOURNAL

OF SURGICAL

RESEARCH

45, 574-588

CURRENT

(1988)

RESEARCH

REVIEW

The Renal Response to Low Dose Dopamine LEWIS

B.

SCHWARTZ,

M.D.,

AND BRUCE

L. GEWERTZ,

The University of Chicago, Department of Surgery, Chicago, Illinois Submitted for publication

INTRODUCTION

Dopamine (DA) is an endogenous catecholamine which is the precursor of norepinephrine and epinephrine. The synthesis of DA was first reported, independently, by Mannich and Jacobsohn [ 1] and Barger and Ewins [2] in 1910. DA was initially considered to be just another pressor amine which was less potent than its metabolites [3]. One of the first reports of DA’s unique properties came from Gurd in 1937 who administered DA to guinea pigs and rabbits and found that blood pressure was decreased[4]. This was in direct contrast to the known pressor effects of norepinephrine and epinephrine. Later investigators discovered that DA exerted a biphasic effect on blood pressure in dogs (i.e., the pressor effect was preceded by a transient depressor effect) and that the pressor effect was potentiated by the concomitant use of an MAO inhibitor [5, 61. Similar results were obtained in hypertensive human volunteers in 1960 [7]. This was apparently the first time that DA was administered to human subjects [8]. Since that time, the use of DA in humans has been an area of intense interest especially regarding the treatment of shock, heart failure, and renal failure. The purpose of this review is to describe the renal effects of DA infusion in normal subjects and in certain diseasestates. A brief overview of DA pharmacology is provided as well as guidelines for the clinical use of DA. $1 SO

Copyri&t 8 1988 by Academic FTW. Inc. Au rights of reproduction in any form moved.

60637

June 11, 1987

Dopamine Receptor Pharmacology

History of Dopamine

0022-4804/88

M.D.

The pharmacological actions of low dose DA are a result of stimulation of specific DA receptors at the target organs. There are now thought to be two populations of DA receptors traditionally designated as DA, and DA2. DA1 receptors are located on the effector organ (i.e., they are postsynaptic). The locations of DA1 receptors include vascular smooth muscle cells of renal, mesenteric, coronary, cerebral [9, lo], gastric [ 111, and hepatic arterial beds where they subserve vasodilatation. Additional peripheral sites that have been postulated in man and other mammals include the esophagus, stomach, small intestine, pancreas, submandibular gland [ 12, 131, heart, spleen [ 131, carotid body [ 141,glomerulus [ 151,juxtaglomerular cell, renal tubule, adrenal cortex [ 161, and vas deferens [ 17, 181. DAz receptors are located at the presynaptic terminals of sympathetic postganglionic nerves. Stimulation of DA2 receptors inhibits the release of norepinephrine thus attenuating sympathetic discharge [13, 16, 19, 201. The DA2 receptor, then, performs a similar function to the presynaptic o+adrenergic receptor (the a2 receptor). There is also evidence to support the presence of DA receptors within the sympathetic ganglia that inhibit ganglionic transmission although these receptors are not fully characterized and hence cannot be classified [21, 221. Because of the growing list of neurotropic and end organ locations of DA receptors,

574

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575

some investigators have searched for peripheral “dopaminergic nerves.” Dinerstein et al. in 1979, used histofluorescence techniques to conclude that DA is the predominant catecholamine contained within the neuronal element at the glomerular vascular pole [ 151. Additional evidence for DA-containing nerves is summarized in recent reviews [23-251.

In addition to activation of DA receptors, DA in higher doses also activates @-and (Yadrenergic receptors [ 19, 261. 0 and QIreceptors are activated at dosesin the range of 5.0 and 10.0 &kg/min, respectively [27]. Postsynaptic & receptors mediate cardiac contractility and heart rate, while stimulation of flZ receptors causes vasodilatation in coronary, skeletal, pulmonary, and visceral arterial beds. Like DA receptors, there are both pre (cQ)- and postsynaptic ((Y, and a~) (Yadenoreceptors. Both postsynaptic (~1and cyz receptors subserve vasoconstriction in coronary, skin, mucosal, skeletal, pulmonary, visceral, and renal arterial beds as well as systemic venoconstriction. Presynaptic (~2receptors, like DA2 receptors, act to inhibit norepinephrine release from sympathetic nerve endings. The multiplicity of receptors that are potentially activated and the wide interpatient variability of response has led to confusion regarding DA’s dose-dependency. D’Orio et al. compiled dose-response curves based on hemodynamic changes in patients treated with varying doses of DA [27]. Stimulation of DA receptors was quantified by measuring renal vascular resistance (RVR), glomerular filtration rate (GFR), and renal blood flow (RBF). The effect on p receptors was evaluated by stroke volume, cardiac output (CO), and left ventricular work index, and the effect on cxreceptors was evaluated by systemic blood pressure (BP) and systemic vascular resistance. The results are shown in Fig. 1. As shown, DA acts exclusively on DA receptors at a dose of ~1.0 pg/kg/min and p receptor stimulation occurs with as little as 3.0 &kg/ min. Actually, increases in CO have been shown with even smaller doses than 3.0

DOSE (pg/kqfminl FIG. 1. Dopamine dose-related effectsin man.At low doses(53.0 pglkglmin), pharmacological effectsare limited to those resulting from stimulation of DA receptors. With increasing doses, stimulation of fl and wadenoreceptors is observed. Reproduced, by permission of the publisher, from Ref. [27].

cLglkg/min [28-331. Therefore, the maximal dose at which DA affects only DA receptors is still in question. Some have used the term “subpressor” to indicate a dose of DA which does not increase BP, i.e., the dose at which DA and 8 stimulation predominate. Generally, this corresponds to 15 pg/kg/min although increases in BP have occasionally been seen with lower doses [34, 351. In this review, the term “low dose” DA is used when the desired effect of drug infusion was to stimulate either DA or 0 receptors (or both) and not to raise BP. The term “subpressor dose” is used only when it was the expressedintent to titrate the dose to find the maximum for which BP was not increased. EFFECTS ON THE NORMAL HUMAN SUBJECT

Renal Blood Flow and Renovascular Resistance Perhaps the most widely known pharmacological effect of low dose DA is that of selective renal vasodilatation and increased RBF. This phenomenon was first demonstrated in humans in 1964 when normal volunteers given subpressor doses of intravenous DA developed a 57% increase in RBF

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JOURNAL OF SURGICAL RESEARCH: VOL. 45, NO. 6, DECEMBER 1988

[ 351. Subsequent studies have shown similar results; doses in the range of 0.5-5.0 &kg/ min have resulted in RBF increases of 25-100% [25, 27, 35-401. Increased RBF under dopaminergic stimulation has also been demonstrated in many disease states including congestive heart failure [32, 4 1, 421, hypertension [29, 36, 43-451, chronic renal disease [40, 46-481, cirrhosis [49], and following surgery [39, 501. The effect of DA on RBF lasts only as long as the drug is infused [44, 48, 491. Furthermore, there is evidence that “tolerance” develops during long infusion periods. Orme et al. treated hypertensive patients with low dose DA for periods of 36- 105 hr. DA significantly increased paraaminohippurate clearance during the first 4 hr but repeat measurements after 45-50 hr of continuous therapy were not significantly different than baseline [44]. DA increases RBF through selective dilatation of the renal arterial bed, i.e., through a decrease in renovascular resistance. Decreasesin RVR were demonstrated in normal subjects by D’Orio et al. who found that RVR was lowered from 8874 dyn crne5 to 5114,4907, and 5475 dyn cm-’ using doses of 1, 3, and 5 pg/kg/min, respectively [27]. Similar results have been obtained in patients with congestive heart failure [32] and in postoperative cardiac surgery [50]. Renovasodilatation has also been directly observed angiographically [37]. DA-induced changes in RVR are mediated through specific dopaminergic receptors within the renal vasculature [ 16, 19, 26, 51-541. DA, receptors have been measured by radioligand binding in the rabbit renal artery [55, 561. As of yet, the distribution of DA receptors among the different segments of the renovascular tree and at other locations within the kidney has not been fully elucidated. Data derived from the use of the split hydronephrotic rat model indicate that DA dilates arcuate and interlobular arteries and afferent arterioles [57, 581. The efferent arterioles also respond, but to a lesserextent. In normal humans subjects, Abrams et al.

administered DA in doses of 3 pg/kg/min and observed angiographically that all orders of renal arterial vessels(i.e., renal, segmental, interlobar, arcuate, and interlobular) were affected [59]. Intrarenal Blood Flow Distribution It has long been recognized that different portions of the kidney are perfused at different rates [60,61]. Hollenberg et al. examined the regional renal vascular responseto DA in potential kidney donors by angiography and xenon washout [37]. The more rapid disappearance of radioisotope from the DAtreated kidney was attributed to the enhanced washout of the “rapid component” corresponding to increased cortical blood flow [62]. It is interesting to note that studies in rats yielded results different from those performed in humans. Using Hz-washout curves, Chapman et al. showed that medullary flow increased more that cortical flow using subpressor dosesof DA [63]. At higher doses, in the phenoxybenzamine-treated rat (i.e., a-blocked), cortical flow increased more than medullary flow. The effect of DA within different regions of the cortex was studied by Hardaker and Wechsler who used radioactive microspheres to measure regional cortical blood flow in anesthetized dogs [64]. They found that during intravenous or renal intraarterial DA infusion, blood flow to the inner cortex increasedby 92%, while outer cortical flow increased by only 38%. Similar results have been seen using “IQ washout techniques [65]. At the present time, no data involving distribution of cortical flow in humans is available. The possible links between intracortical blood flow distribution, glomerular filtration, and renal sodium and water handling will be addressedin a later section. Glomerular Filtration and Filtration Fraction Glomerular filtration rate, as measured by inulin clearance, increases significantly in

SCHWARTZ AND GEWERTZ: RENAL RESPONSE TO DOPAMINE

normal subjects treated with low dose DA [27, 35, 36, 401. McDonald et al. demonstrated an average increase of 9.4% in the first series of normal controls using subpressor doses of 2.6-7.1 pg/kg/min [35]. Subsequent studies have confirmed this finding; dosesof 1.5-2 ccg/kg/min caused GFR to increase by ll-48% [27, 36, 38, 401. Significant increases in filtration have been shown to occur in many disease states including congestive heart failure [28, 32, 42, 661, hypertension [28, 36, 38, 441, oliguria [30, 671, and chronic renal disease[46,48,68], and in premature neonates [47,69]. Not all patients will show a GFR increase, however. ter Wee et al. studied 137 patients with varying degrees of renal insufficiency [40]. Patients with a baseline GFR of less that 70 ml/min/ 1.73 m2 did not increase glomerular filtration when given 1.5-2.0 pg/kg/min DA. Similar data has been complied for pediatric patients [47]. According to these investigators, the “renal reserve filtration capacity” is exhausted in this patient population. There is also evidence supporting the development of tolerance to the DA effect on filtration. In a previously mentioned study by Orme et al., values for GFR, while initially significantly elevated, returned to baseline after 45-50 hr of DA therapy [44]. There is disagreement on this point. Other investigators treating postoperative oliguric patients with 1.54 and/or 3.08 pg/kg/min DA demonstrated that urine output, creatinine clearance, osmolar clearance, and free water clearance were all significantly higher than baseline after an average of 28 hr and even after discontinuation of DA therapy [30]. Others have reported variable directional responsesin GFR after discontinuation of DA [48]. The initial level of renal function appears to be the prime factor which determines whether DA will have a lasting therapeutic effect. Diuresis, Natriuresis, and Kaliuresis There is considerable disagreement concerning the effect of low dose DA on urine

577

output. In the original studies on normal humans, urine output decreasedfrom 11.44 to 9.86 ml/min, a difference which was not statistically significant [35]. The authors provided each subject with 15-20 ml water/ kg body weight at the outset of the procedure as is customary during clearance tests to maintain urine output and improve precision [70]. Other investigators have found that urine output does increase significantly. D’Orio et al. observed an increase from 2.5 to 4.6 ml/min in 10 normal controls infused with 1.5 pg/kg/min DA [27]. Significant increaseshave also been documented in other control populations [36, 38, 711, congestive heart failure [28, 42, 661, hypertension [29, 441, oliguria [30, 67, 731, chronic renal disease[40,48], postoperatively [30, 731,and in premature neonates [47,69,74]. Others have shown a tendency toward diuresis although the data did not reach statistical significance (4 1,75,76]. The problems in obtaining accurate data regarding changes in urine output are many and include (a) difficulty in precise urine collection even with bladder catheterization, (b) high interpatient variability, (c) large intrapatient fluctuations, and (d) inability to precisely quantify the state of hydration. Despite these limitations, it can be concluded that low dose DA increases urine output in some oliguric subjects and in subjects with good renal function that are adequately hydrated. DA-induced diuresis may be mediated through cu-adrenergicreceptors since the diuresis is abolished by a-antagonists but not by DA antagonists in rats [77]. One of the most consistent effects of intravenous low dose DA is marked enhancement of sodium excretion. In McDonald’s series, subpressor doses of DA increased the excretion of sodium from 17 1 to 575 peq/min [ 351.In normal subjects, significant natriuresis has been seen in doses as low as 1.5 pg/kg/min [27]. Natriuresis has been observed in virtually every diseasestate studied including congestive heart failure [28,35,4 1, 42, 761, hypertension [29, 36, 38, 44, 451, postsurgery [78], oliguria [73], chronic renal disease[40,47,48,75], and prematurity [69,

578

JOURNAL

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RESEARCH:

74, 791. DA-induced natriuresis is usually profound, it is not uncommon to observe increasesof over 300% [35, 38,41,42, 721. The effect of DA on potassium excretion is less marked. Studies of normal controls report slight increases which are not statistically significant [ 35, 801.In contrast, kaliuresis has been documented in patients with congestive heart failure [42,76]. The reasons for this discrepancy are not understood. The mechanism of DA-induced diuresis and natriuresis has been the subject of much experimentation and debate. The question remains as to whether the natriuretic effect is secondary to changes in RBF and GFR or to a direct effect upon the renal tubules favoring decreased resorption and water and solute loss. The work of Imbs et al. suggeststhat the natriuretic effect of DA is entirely a consequence of the renal hemodynamic changes [81-831. They studied the effects of low dose DA on water-loaded and water-deprived animals. In the water-deprived animal, DA increased RBF and GFR but did not alter FF or produce natriuresis. In the water-loaded animal, RBF again increased but the GFR was unchanged, FF decreased,and natriuresis ensued. Their interpretations included the following: (1) in the dehydrated animals, FF decreased thus lowering postglomerular oncotic pressure and inhibiting sodium and water reabsorption in the proximal tubule, and (2) in the water-loaded animals, GFR was stimulated by efferent arteriolar constriction mediated by angiotensin II release but, since FF was unchanged, natriuresis did not occur. Although it would seem that an increase in GFR alone should increase the filtered sodium load and cause natriuresis, it has been shown that the increased load is reabsorbed in the distal tubule [84]. The hypothesis presented by Imbs et al. [81-831, therefore, supposes that natriuresis cannot occur in the absenceof a decreasedFF. Data from human subjects does not help to test this theory since FF invariably decreasesin humans [27,29,35,36,40-42,481. Dissociation of the renal hemodynamic effects and

VOL. 45, NO. 6, DECEMBER

1988

natriuresis has been observed, however, in rats [85], cats [86], and dogs [87, 881. Some have speculated that DA’s natriuretic effect may be a consequence of the changes in the distribution of blood flow within the renal vasculature. As previously mentioned, low dose DA causes an increase in cortical perfusion with either a less-striking or absent effect on medullary perfusion [37]. Although the changes in cortical flow are absolutely greater than changesin medullary flow, some have conjectured that the relative increase in medullary flow decreases medullary tonicity causing a reduction in sodium reabsorption and subsequent natriuresis [89, 901. The more profound increases in flow to the inner cortex relative to the outer cortex have also been previously alluded to. Functional heterogeneity of nephrons within different anatomical and functional cortical regions clearly exists [9 l-941; the GFR of juxtaglomerular (inner cortical) nephrons is more than twice that of superficial nephrons. One could postulate that the increase in inner cortical flow relative to outer cortical flow would tend to increase GFR and tubular flow velocity causing diuresis and natriuresis [62]. Indeed, it is difficult to design an experiment to test this hypothesis since indirect measurement of intrarenal blood flow in humans is crude at best and often inaccurate [95]. A particularly provocative study was that of Hilberman et al. in which DA and dobutamine were alternately administered to twelve post-operative cardiac patients in titrated doses such that CO, RBF, RVR, were identical for the two agents [78]. Urine flow and sodium excretion were significantly elevated during DA infusion when compared to dobutamine infusion. The authors concluded that the results could best be explained by a direct action of DA upon the renal tubule. To fully establish that exogenous DA has a direct effect on the renal tubule, natriuresis must be demonstrated in the absence of alterations in RBF, GFR, and intrarenal blood flow distribution. Contributions by vaso-

SCHWARTZ

AND

GEWERTZ:

RENAL

pressin, aldosterone, and atria1 natriuretic factor must be excluded. Finally, specific dopaminergic receptors within the renal tubule should be demonstrated. As mentioned above, natriuresis in the absenceof hemodynamic change is well documented; hormonal influences are more difficult to examine. Investigating the effect of DA infusion on vasopressin has been complicated by the fact that the side effectsof exogenous DA include nausea and vomiting and these are potent stimuli of vasopressin release [96]. Despite this limitation, experiments in asymptomatic (i.e. non-nauseated) rats [96], conscious dogs [97], and man [47] have failed to establish a relationship between exogenous DA and vasopressin release. It should be noted, however, that L-dopa, the precursor of DA that crossesthe blood-brain barrier, does suppress resting levels of vasopressin by exerting a central effect [98]. The intravenous infusion of DA has never been shown to significantly affect plasma aldosterone levels in dogs [97] or man [38, 47, 80, 99, 1001. However, Norbiato et al. in 1977, demonstrated that metoclopramide (a DA antagonist) increased plasma aldosterone levels [ 1011. This lead to speculation that aldosterone was under tonic dopaminergic suppression [ 102, 1031. Atria1 natriuretic factor (ANF) is the generic name for a family of newly discovered peptides that are present in saline extract of cardiac atria [ 104, 1051.The actions of ANF include natriuresis, diuresis, RBF redistribution, increased GFR, hemoconcentration, vasorelaxation, increased insulin release,and inhibition of renin release [ 105- 1lo]. Since ANF is a powerful natriuretic and hypotensive hormone, a link with DA was naturally sought. Although no data exists for adult populations, low dose DA infusion fails to affect ANF levels in premature neonates [79] or pediatric patients with chronic renal failure [47]. The converse may be true, however. There is data to suggest that the effects of ANF may be mediated though the dopaminergic system since DA antagonists appear to block the effect of intravenously adminis-

RESPONSE

579

TO DOPAMINE

tered ANF in rats [ 11 l-l 151. The precise mechanism of ANF as well as its role in chronic sodium and water homeostasis remains unclear. If one postulates that DA acts at specific sites within the renal tubule, binding studies should reveal the locations of dopaminergic receptors. Using radioligand binding and adenylate cyclase studies, Felder et al. were able to demonstrate at least two binding sites within homogenates of rat renal tubules [ 1161. Similar studies have been performed on the renal tubule of the rabbit [ 1171.The authors note, however, that the possibility of arterial contamination during tissue preparation cannot be entirely excluded. In addition to receptor binding, the physiology of isolated renal tubules has also been studied. In vitro microperfusion of isolated rabbit proximal renal tubule with DA resulted in a significant decreasein fluid reabsorption that was abolished with the addition of DA antagonists [ 1181. This provided additional evidence that DA exerts its natriuretic effect directly on pars recta segments. Other microperfusionists, however, provide equally conclusive data suggesting that DA actually stimulates active sodium resorption in proximal tubule cells and that the natriuresis is either controlled by the distal segment or hemodynamically mediated [ 119, 1201. In summary, there is considerable evidence to suggest that exogenous DA has a direct effect on the renal tubule which may afford diuresis and natriuresis although the possibility that these changes are a consequence of alterations in intrarenal blood flow distribution cannot be discounted. Furthermore, the role of endogenous DA on sodium and water regulation remains controversial [121, 1221. DOPAMINE

AND

RENAL

DISEASE

Acute Renal Failure The abilities of low dose DA to increase whole kidney perfusion, cortical perfusion, GFR, and urine output have led to its use in the treatment and/or prevention of acute

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JOURNAL OF SURGICAL RESEARCH: VOL. 45, NO. 6. DECEMBER 1988

renal failure (ARF, acute tubular necrosis, vasomotor nephropathy). The first report of the efficacy of DA in the treatment of ARF came from Talley et al. in 1970 [ 1231.They described five patients in ARF who underwent therapy with unspecified diuretics and 4.0 pg/kg/min DA. Urine flows of 1 ml/min were achieved but the clinical outcomes were not described. Since that time, many reports have appeared in the literature studying DA alone or in combination with diuretics (Table 1) [30, 72, 124-1291. Each study reports a significant diuresis following DA infusion with or without furosemide. One particularly illustrative study was that of Davis et al. who studied 15 adult cardiac surgery patients with oliguria (two consecutive hourly periods of urine output ~0.5 ml/kg/hr) and left ventricular dysfunction [30]. Subjects were treated with DA in doses of 1.54 pg/kg/min which was doubled if no diuresis ensued. Urine output increased from 22 to 54 ml/hr and creatinine clearance increased from 70 to 115 ml/min. Similar significant increases were shown in urine sodium, osmolar clearance, and free water clearance. Most of the parameters remained elevated even after discontinuation of the drug. Fourteen of the fifteen patients lived and none of the survivors required chronic dialysis. The authors attributed the beneficial results to improvements in intrarenal hemodynamics and cortical blood flow. However, it must be noted that (1) increases in cardiac index could contribute to improved renal function, (2) increases in GFR are probably overestimated since improving renal function favors creatinine secretion, and (3) the study was uncontrolled. Some clinicians have advocated the combined use of DA and furosemide in the treatment of ARF [67, 123, 125-1301. It is thought that DA vasodilation can improve the delivery of furosemide to its site of action (the loop of Henle), increasing urine flow and chloride concentration at the macula densa and down-regulating the renin-angiotensin axis [ 127, 1291. One study enrolled

patients with persistent oliguria despite 24 hr of mannitol and high-dose furosemide therapy [ 1281.Of the 24 patients studied, 19 responded to a combination of DA, 3.0 &kg/ min, and furosemide, lo- 15 mg/kg hr; urine output increased from 11 to 85 ml/hr. It was further noted that all responders received the therapy within 17 hr of the onset of oliguria, while the delay in therapy for the nonresponders was 32 hr. This illustrates the importance of prompt intervention for acute renal failure. The apparent successin the treatment of oliguric renal failure has lead to investigation into the use of a DA as a prophylactic renalsparing agent. It has been suggestedfor aortic surgery and liver transplantation, two common surgical procedures that carry a substantial risk of renal failure. The effects of infrarenal aortic cross-clamping on the function of the kidneys has been studied for many years. Although studies have yielded conflicting results, substantial decrements in RBF and glomerular function have been demonstrated in dogs [ 13 1, 1321 and humans [ 133, 1341.In an attempt to prevent the deleterious effects of cross-clamping, Salem et al. treated 18 patients undergoing aortic surgery with 2.0 pg/kg/min DA and found that both urine output and creatinine clearance were significantly elevated [ 351. Contradictory results were reported by Paul et al., however, who found that the combination of 3 pg/kg/min DA and 200 mg/kg/hr mannitoi delayed the renal depression of cross-clamping but did not prevent it [ 1341. They concluded that no clinically relevant benefit was derived from these prophylactic agents. Renal failure is also a devastating complication of orthotopic liver transplantation. Polson et al. retrospectively compared 19 transplant patients (21 operations) who received prophylactic 2.0 pg/kg/min DA to 15 patients who did not [ 1361.They found that renal impairment (defined as urine output ~0.5 ml/kg/hr) occurred in 10 routine operations but in only 2 of the DA-augmented operations. They recommended that all pa-

0.5-3.0

Severe oliguria

~1 ml/kg/hr

5

126

1980

Graziani

3.0

~20 ml/hr X 2 hrb

Note. -, not reported. u Failed furosemide therapy (possible persistent furosemide on board). bFailed mannitol/furosemide therapy. ’ Failed DA therapy ( 1.54 pg/kg/min). d Oliguria with left ventricular dysfunction.

128

24

1984

Graziani

lo- 15 mg/kg/hr

200 mg q 8 hr

100-200 mg q 6-8 hr

1.0

lo-15 ml/hr”

1

1.o-3.0

<20 ml/hrd

6

129

1984

125

1983

Lindner

Docci

none

3.08

9

30

1982

Davis

11

10-15


22

22

none

1.54

~30 ml/hr c

15

30

1982

12

Davis

21

3-5c 10-15

16

1.5-2.5

52

67

127

1981

1982

Parker

Graziani

1.o-3.0

19

1-5

10

-

0 a

Baseline

Furosemide dose h/k/dw)

~30 ml/hrb

1.0

~20 ml/hr X 3 hrs”

11

4.0

72

1980

Henderson

~30 ml/hra

Level of oligmia

5

1970

Talley

Reference Subjects

123

Year

Investigator

Dopamine dose WWmin)

85

105

106

50

54

100

30

105

104

>60

DA

Urine volume (ml/hr)

RESULTSOF DOPAM~NEINFUSIONSIN TREATMENT OF OLIGURM

TABLE 1

-

-

-

63

70

-

-

-

-

-

Baseline

-

f3.8

-

-

-

DA

-

-

-

108

115

GFR (ml/min)

45

-

-

5

15

31

-

38

45

_

Baseline

88

-

18 -

29

82

-

15

78

_

DA

Urine Na (mEq/l)

79

100

50

-

93

62

-

60

63

-

Survival @I

z

8 P r

8

E a” k? K

$

z

f? & B 8

%

z % i4

x

582

JOURNAL OF SURGICAL RESEARCH: VOL. 45, NO. 6, DECEMBER 1988

tients undergoing orthotopic liver transplantation be covered prophylactically with low dose DA.

Chronic Renal Disease The most common causesof chronic renal failure (CRF) are glomerulonephritis, tubulointerstitial disease, diabetic nephropathy, and nephrosclerosis. BecauseDA can only be administered by an intravenous route, longterm therapy of CRF is not practical. However, some investigators have studied the effect of DA on CRF to further examine the mechanism of DA-induced improvements in renal function. The largest experience involving DA and CRF comes from ter Wee et al. who gave DA in doses of 1.5-2.0 pg/kg/min to 28 normal volunteers, 14 healthy individuals following uninephrectomy, and 123 patients with varying degrees of renal insufficiency from chronic disease of mostly unspecified or unknown etiology [40, 751. Overall, DA caused significant increases in GFR, RBF, urine output, and sodium excretion, while FF was significantly decreased. When patients were stratified according to baseline GFR, it was found that DA caused persistent increases in GFR only in patients with initial GFR >70 ml/min/1.73 m2. Similarly, elevations in RBF were only consistently observed in patients with initial GFR ~50 ml/min/ 1.73 m2. Urine output and sodium excretion were unfortunately not stratified according to baseline renal function. The dependence of DA-induced filtration improvement on the baseline renal state has been confirmed by other groups in pediatric [47] and postoperative patients [39]. ter Wee attributes the lack of response in patients with depressedrenal function to the exhaustion of the “reserve filtration capacity” in certain renal diseases.He postulates that during chronic disease, blood flow has already been partially shifted to the inner cortex in an adaptive response to the loss of nephrons. This would account for the dependence of DA-induced RBF improvement

on baseline GFR as well as the dependence of filtration itself. A comparable dependence on preexisting renal function has been observed with protein loading, a manipulation which has also been shown to improve renal function [ 137, 1381.

Renal Transplantation DA’s ability to raise blood pressure while selectively dilating the renal vasculature has lead to speculation that it may lessen the time and/or severity of “warm ischemia.” Anticipating a beneficial effect in “unstable” kidney donors, DA was administered to 15 cadaveric donors (systolic blood pressure of 55, urine output of 6 ml/hr) as part of a protocol which included methylprednisone, furosemide, chlorpromazine, phenoxybenzamine, and heparin [ 1391. Both blood pressure and urine output increased. Of the 30 kidneys that were subsequently transplanted, 17 functioned immediately, 10 showed delayed function, and 3 never functioned. The authors concluded that DA was useful in that 27 functioning kidneys were obtained from donors who had experienced long periods of hypotension and oliguria. Similar evidence that donor pretreatment with DA improved transplant function has been derived from animal models [ 1401. However, no controlled clinical trials have been undertaken. It has also been suggestedthat DA may be beneficial in the renal graft recipient. In dogs, low dose DA treatment of the recipient improved the function of kidneys harvested from hypotensive donors [ 14I]. The effect of low dose DA on human cadaveric renal transplants has been prospectively studied by two separate groups. Grundmann et al. administered 2.0 pg/kg/min DA to 25 of 50 graft recipients for 4 days and found that the DA-treated group had a higher urine output, but that creatinine clearance and dialysis requirements were identical [ 1421. Furthermore, DA caused frequent tachycardia and was associated with several acute (first week) graft rejections. Similar negative results were obtained by DeLosAngeles et al. in 1985; low

SCHWARTZ AND GEWERTZ: RENAL RESPONSE TO DOPAMINE

dose DA and furosemide did not decrease the incidence of post-transplant renal failure and only aggravated fluid, electrolyte, and cardiac rhythm disturbances [ 1431. CONCLUSIONS

The effects of low dose DA on the normal human kidney include increased glomerular filtration rate, renal blood flow, urine output, and sodium excretion and a decreasein renovascular resistance and filtration fraction. The specific locations of dopaminergic receptors with the renal vasculature and parenchyma are still largely unknown. It has been suggestedthat DA may be useful in the treatment of renal ischemia. Encouraging results have been obtained in patient with postoperative oliguria using low dose DA alone or in combination with furosemide. We believe that sufficient data has been amassedto recommend the use of DA in dosesof 0.5-2.0 pg/kg/min for postoperative oliguria provided that the patient’s fluid status is adequately evaluated. Careful monitoring of the patient’s state of hydration, urine output, and serum and urine electrolytes should be undertaken. Perhaps the group of patients that would benefit most are those with both marginal urine output and depressedventricular function taking advantage of DA’s positive inotropic effects. The data regarding the use of prophylactic low dose DA is incomplete. Recommendations for the use of DA for the prevention of renal failure await further clinical trials. REFERENCES 1. Mannich, C., and Jacobsohn, W. Uber oxyphenylalkylamine und diophenylalkylamine. Ber. D&z. Chem. Ges. 43: 189, 1910. 2. Barger, G., and Ewins, A. J. Some phenolic derivatives of b-phenylalanine. J. Chem. Sot. 41: 18, 1910. 3. DiPalma, J. R. Dopamine: new uses for an old drug. AFP 11: 149, 1975. 4. Gurd, M. R. The physiological action of dihydroxyphenylethylamine and sympatol. Q. J. Pharm. Pharmacol. 10: 188, 1937. 5. Goldberg, L. I., and Sjoerdsma, A. Effects of sev-

583

era1monoamine oxidase inhibitors on the cardiovascular actions of naturally occurring amines in the dog. J. Pharmucol. Exp. Ther. 127: 2 12, 1959. 6. Goldberg, L. I. The pharmacological basis of the clinical use of dopamine. Proc. R. Sot. Med. 7O(Suppl. 2): 7, 1977. 7. Horwitz, D., Goldberg, L. I., and Sjoerdsma, A. Increased blood pressure responses to dopamine and norepinephrine produced by monoamine oxidase inhibitors in man. J. Lab. Clin. Med. 56: 747, 1960. 8. Goldberg, L. I. Introductory lecture, the dopamine vascular receptor: Agonists and antagonists. In J. Imbs and J. Schwartz (Ed%),Peripheral Dopamine Receptors. Oxford: Pergamon, 1978. Pp. 1-12. 9. McCulloch, J., and Harper, A. M. Cerebral circulation: Effect of stimulation and blockade of dopamine receptors. Amer. J. Physiol. 55: H222, 1977. 10. Toda, N. Dopamine vasodilates human cerebral artery. Experentia 39: 1131, 1983. 11. Reinsberg, J., and Kullman, H. Characterization of vascular dopamine receptors in the gastric circulation of the rabbit. J. Cardiovasc. Pharmacol. 8: 1067, 1986. 12. Goldberg, L. I., Volkman, P. H., and Kohli, J. D. A comparison of the vascular dopamine receptor with other dopamine receptors. Annu. Rev. Pharmacol. Toxicol. 18: 57, 1978.

13. Willems, J. L., Buylaert, W. A., Lefebvre, R. A., and Bogaert, M. G. Neuronal dopamine receptors on autonomic ganglia and sympathetic nerves and dopamine receptors in the gastrointestinal system. Pharmacol. Rev. 37: 165, 1985. 14. Fidone, S. J., Gonzalez, C., and Yoshizaki, K. Putative neurotransmitters in the carotid body: The case for dopamine. Fed. Proc. 39: 2636, 1980. 15. Dinerstein, R. J., Vannice, J., Henderson, R. C., Roth, L. J., Goldberg, L. I., and Hoffman, P. C. Histofluorescence techniques provide evidence for dopamine-containing neuronal elements in the canine kidney. Science 205: 497, 1979. 16. Lokhandwala, M. F., and Barrett, R. J. Cardiovascular dopamine receptors: Physiological, pharmacological and therapeutic implications. J. Auton Pharmacol. 3: 189, 1982. 17. Relja, M., Lackovic, Z., and Neff, L. H. Evidence for the presence of dopaminergic receptors in vas deferens. Life Sci. 31: 2571, 1982. 18. Tayo, F. M., Occurrence of exitatory dopamine receptors in the rat and guinea pig vas deferens. Clin. Exp. Pharmacol. Physiol. 6: 275, 1979.

19. Goldberg, L. I. Cardiovascular and renal actions of dopamine: A review. Pharmacol. Rev. 24: 1, 1972. 20. Stoof, J. C., and Kebabian, J. W. Two dopamine receptors: Biochemistry, physiology, and pharmacology. Life Sci. 35: 228 1, 1984.

21. Alkadhi, K. A., Sabouni, M. H., and Lokhandwala, M. F. Characterization of dopamine recep-

584

JOURNAL OF SURGICAL RESEARCH: VOL. 45, NO. 6, DECEMBER 1988

tors in mammalian sympathetic ganglion. Fed. Proc. 43: 1094, 1984. 22. McIssac, R. J. Ganglionic blocking properties of epinephrine and other related amines. Znt. J. Neuropharmacol. I: 5 17, 1966. 23. Dinerstein, R. J., Jones, R. T., and Goldberg, L. I. Evidence for dopamine-containing renal nerves. Fed. Proc. 42: 3005, 24. Lackovic, Z., and Neff, N. H. Evidence for the existence of peripheral dopaminergic neurons. Brain Rex 193: 289, 1980. 25. Lackovic, Z., and Relja, M. Evidence for a widely distributed peripheral dopaminergic system. Fed. Proc. 42: 3000, 1983. 26. Goldberg, L. I. Dopamine: Receptors and clinical applications, C&z. Physiol. Eiochem. 3: 120, 1985. 27. DOrio, V., El Allaf, D., Juchmes, J., and Marcelle, R. The use of low doses of dopamine in intensive care medicine. Arch. Int. Physiol. Biochim. 92: Sll, 1984. 28. Beregovich, J., Bianchi, C., Rubler, S., Lomnitz, E., Cagin, N., and Levitt, B. Dose-related hemodynamic and renal effects of dopamine in congestive heart failure. Amer. Heart J. 87: 550, 1974. 29. Breckenridge, A., Orme, M., and Dollery, C. T. The effect of dopamine on renal blood flow in man. Eur. J. Clin. Pharmacol. 3: 131, 1971. 30. Davis, R. F., Demitrios, G. L., Kirklin, J. K., Buckley, M. J., and Lowenstein, E. Acute oliguria after cardiopulmonary bypass: Renal functional improvement with low-dose dopamine infusion. Crit. Care Med. 10: 852, 1982. 31. Holloway, E. L., Stinson, E. B., Derby, G. C., and Harrison, D. C. Action of drugs in patients early after cardiac surgery. I. Comparison of isoproterenol and dopamine. Amer. J. Cardiol. 35: 656, 1975. 32. Maskin, C. S., Ocken, S., Chadwick, B., and LeJemtel, T. H. Comparative systemic and renal effects of dopamine and angiotensin-converting enzyme inhibition with enalaprilat in patients with heart failure. Circulation 72: 846, 1985. 33. Miller, D. C., Stinson, E. B., Oyer, P. E., Derby, G. C., Reitz, B. A., and Shumway, N. E. Postoperative enhancement of left ventricular performance by combined inotropic-vasodilator therapy with preload control. Surgery 88: 108, 1980. 34. Leier, C. V., Heban, P. T., Huss, P., Bush, C. A., and Lewis, R. P. Comparative systemic and regional hemodynamic effects of dopamine and do butamine in patients with cardiomyopathic heart failure. Circulation 58: 466, 1978. 35. McDonald, R. H., Jr., Goldberg, L. I., McNay, J. L., and Tuttle, E. P., Jr. Effect of dopamine in man: Augmentation of sodium excretion, glomerular filtration rate, and renal plasma flow. J. Clin. Invesf. 43: 1116, 1964. 36. Andrejak, M., and Hary, L. Enhanced dopamine

renal responsivenessin patients with hypertension. Clin. Pharmacol. Ther. 40: 610, 1986. 37. Hollenberg, N. K., Adams, D. F., Mendell, P., Abrams, H. L., and Merrill, J. P. Renal vascular responsesto dopamine: Hemodynamic and angiographic observations in man. Clin. Sci. Mol. Med. 45: 733, 1973. 38. Kikuchi, K., Miyama, A., Nakao, T., Takigami, Y., Kondo, A., Mito, T., Ura, N., Tsuzuki, M., and Iimura, 0. Hemodynamic and natriuretic responses to intravenous infusion of dopamine in patients with essential hypertension. Japan. Circ. J. 46: 486, 1982. 39. Schwartz, L. B., Bissell, M., Murphy, M., and Gewertz, B. L. Renal effects of dopamine in surgical patients. Submitted for publication. 40. ter Wee, P. M., Smit, A. J., Rosman, J. B., Sluiter, W. J., and Donker, A. J. M. Effect of intravenous infusion of low dosedopamine on renal function in normal individuals and in patients with renal disease.Amer. J. Nephrol. 6: 42, 1986. 41. Abrahamsen, A. M., Storstein, L., Westlie, L., and Storstein, 0. Effects of dopamine on hemodynamics and renal function. Acta Med. &and. 195: 365, 1974. 42. Rosenblum, R., Tai, A. R., and Lawson, D. Dopamine in man: Cardiorenal hemodynamics in normotensive patients with heart disease.J. Pharmacol. Exp. Ther. 183: 256, 1972. 43. Hollenberg, N. K., Adams, D. F., Soloman, H., Chenitz, W. R., Burger, B. M., Abrams, H. L., and Merrill, J. P. Renal vascular tone in essential and secondary hypertension. Medicine 54129, 1975. 44. Orme, M. L., Breckenridge, A., and Dollery, C. T. The effects of long term administration of dopamine on renal function in hypertensive patients. Eur. J. Clin. Pharmacol. 6: 150, 1973. 45. Velasco, M., Tjandramaga, T. B., and McNay, J. L. Differential dose-related effects of dopamine on systemic and renal hemodynamics in hypertensive patients. Clin. Res. 22: 308A, 1974. 46. ter Wee, P. M., van Ballegooie, E., Rosman, J. B., Meijer, S., and Donker, A. J. M. The effect of low dose dopamine on renal hemodynamics in patients with type I diabetes does not differ from normal individuals. Diabetologia 29: 78, 1986. 47. Tulassay, T., Rascher, W., and Schlrer, K. Effect of low dose dopamine on kidney function and vasoactive hormones in pediatric patients with advanced renal failure. Clin. Nephrol. 28: 22, 1987. 48. Vlachoyannis, J., Wismuller, G., and Schoepe, W. Effects of dopamine on kidney function and of the adenylate cyclase phosphodiesterase system in man. Eur. J. Clin. Invest. 6: I3 I, 1976. 49. Bamardo, D. E., Baldus, W. P., and Maher, F. T. Effects of dopamine on renal function in patients with cirrhosis. Gastroenterology 58: 524, 1970. 50. Sato, Y., Matsuzawa, H., and Eguchi, S. Compara-

SCHWARTZ AND GEWERTZ: RENAL RESPONSE TO DOPAMINE tive study of effects of adrenalin, dobutamine and dopamine of systemic hemodynamics and renal blood flow in patients following open heart surgery. Japan. Circ. J. 46: 1059, 1982. 51. Lee, M. R. Dopamine and the kidney. Clin. Sci. 62: 439, 1982. 52. Lee, M. R. Dopamine and the kidney. In C. A. Lobe (Ed.), Advances in Renal Physiology, New York: A. R. Liss, 1986. Pp. 2 18-246. 53. Schmidt, M., and Imbs, J. L. Pharmacological characterization of renal vascular dopamine recep tors. J. Cardiovasc. Pharmacol. 2: 595, 1980. 54. Ueda, S., Yano, S., and Sakanashi, M. In vitro evidence for dopaminergic receptors in human renal artery. J. Cardiovasc. Pharmacol. 4: 76, 1982. 55. Alessandrini, C., Cavallotti, C., De Rossi, M., Fruschelli, C., Gerli, R., Mione, M. C., Sacchi, G., and Amenta, F. Localization of dopamine receptors in the rabbit renal artery: A histoautoradiologic study. Pharmacology 29: 17, 1984. 56. Brodde, 0. E. Demonstration of vascular dopamine receptors in membranes from rabbit renal artery using [3H]spiroperidol binding. Experentia 37: 1099, 1980. 57. Steinhausen, M., Snoei, H., Parekh, H., Baker, R., and Johnson, P. C. Hydronephrosis: A new method to visualize vas afferens, efferens, and the glomerular network. Kidney Int. 23: 794, 1983. 58. Steinhausen, M., Weis, S., Fleming, J., Dussel, R., and Parekh, N. Responsesof in vivo renal microvesselsto dopamine. Kidney Int. 30: 36 1, 1986. 59. Abrams, H. L., Obrez, I., Hollenberg, N. K., and Adams, D. F. Pharmacoangiography of the renal vascular bed. Curr. Probl. Radiol. 1: 1, 197I. 60. Barger, A. C., and Herd, J. A. The renal circulation. N. Engl. J. Med. 284: 482, 1971. 6 1. Barger, A. C., and Herd, J. A. Renal vascular anatomy and distribution of blood flow. In J. Orloff and R. W. Berliner (Eds.). Handbook ofphysiology, Washington D.C.: American Physiological Society, 1973. Pp. 249-313. 62. Stein, J. H., Boonjaren, S., Wilson, C. B., and Ferris, T. F. Alterations in renal blood flow distribution. Methods of measurement and relationship to sodium balance. Circ. Res. 32-33(Suppl.): I6 1, 1973. 63. Chapman, B. J., Horn, N. M., Munday, K. A., and Robertson, M. J. The actions of dopamine and of sulpride on regional blood flows in the rat kidney. J. Physiol. 298: 437, 1980.

64. Hardaker, W. T., and Wechsler, A. S. Redistribution of renal intracortical blood flow during dopamine infusion in dogs. Circ. Res. 33: 437, 1973. 65. Neiberger, R. E., and Passmore, J. C. Effects of dopamine on canine intrarenal blood flow distribution during hemorrhage. Kidney Int. 15: 219, 1979.

585

66. Te-tse, L., Tsin-tsing, C., and Chung-tang, W. Clinical observations of dopamine: Cardiotonic and Diuretic Action. Clin. Med. J. 4: 241, 1978. 67. Parker, S., Carlon, G. C., Issacs, M., Howland, W. S., and Kahn, R. C. Dopamine administration in oliguria and oliguric renal failure. Crit. Care Med. 9: 630, 1981. 68. Beukhof, H. R., ter Wee, P. M., Sluiter, W. J., and Donker, A. J. M. Effect of low dose dopamine on effective renal plasma flow and glomerular filtration rate in 32 patients with IgA glomerulopathy. Am J. Nephrol. 5: 267, 1985. 69. Tulassay, T., Seru, I., Machay, T., Kiszel, J., Varga, J., and CsSmGr, S. Effects of dopamine on renal functions in premature neonates with respiratory distress syndrome. Int. J. Pediatr. Nephrol. 4: 19, 1983. 70. Smith, H. W. Principles of Renal Physiology. New York: Oxford Univ. Press, 1956. Pp. 51-61. 71. Atuk, N. O., Ayers, C. R., and Westfall, V. Effect of dopamine on blood pressure and urinary catecholamines in man. Clin. Res. 16: 90, 1968. 72. Henderson, 1.S., Beattie, T. J., and Kennedy, A. C. Dopamine hydrochloride in oliguric states. Lancet 18: 827, 1980. 73. Merin, G., Bitran, D., Uretzky, G., Superstine, E., Cotev, S., and Borman, J. B. The hemodynamic effects of dopamine following cardiopulmonary bypass. Ann. Thorac. Surg. 23: 361, 1977. 74. Sulyok, E., Seri, I., Tulassay, T., Kiszel, J., and Ertl, T. The effect of dopamine administration on the activity of the renin-angiotensin-aldosterone system in sick preterm infants. Eur. J. Pediatr. 143: 191, 1985. 75. Beukhof, H. R., ter Wee, P. M., Sluiter, W. J., and Donker, A. J. M. Effect of low dose dopamine on effective renal plasma flow and giomentlar filtration rate in 32 patients with IgA glomemlopathy. Amer. J. Nephrol. 5: 267, 1985. 76. Goldberg, L. I., McDonald, R. H., and Zimmerman, A. M. Sodium diuresis produced by dopamine in patients with congestive heart failure. N. Engl. J. Med. 269: 1060, 1963. 77. Bar&o, G., Ferrari, F., Guarini, S., Sandrini, M., and Ferrari, W. Diuretic effect of dopaminomimetic agents. In G. L. Gessa,G. U. Corsini (Eds.), Apomorphine

and Other Dopaminomimetics.

New

York: Raven Press, 1981. Vol. 1, pp. 285-295. 78. Hilberman, M., Maseda, J., Stinson, E. B., Derby, G. C., Specter, R. J., Miller, C., Oyer, P. E., and Myers, B. D. The diuretic properties of dopamine in patients after open-heart operation. Anesthesiologybl: 489, 1984. 79. Tulassay, T., Rascher, W., Hajdu, J., Land, R. E., Toth, M., and Seri, I. Influence of dopamine on atria1 natriuretic peptide level in premature infants. Acta Pediatr. Stand. 76: 42, 1987.

586

JOURNAL OF SURGICAL RESEARCH: VOL. 45, NO. 6, DECEMBER 1988

80. Levinson, P. D., Goldstein, D. S., Munson, P. J., Gill, J. R., and Keiser, H. R. Endocrine, renal, and hemodynamic responses to graded dopamine infusions in normal men. J. Clin. Endocrinol. Metab. 60: 821, 1985. 81. Imbs, J. L., Schmidt, M., and Schwartz, J. Catecholamines and the kidney: The role of dopamine. In Proceedings, 8th In?. Gong. Nephrol, 1981. Pp. 1067-1074. 82. Imbs, J. L., Schmidt, M., and Schwartz, J. Renal vascular effects of dopaminomimetics. In G. L. Gessa and G. U. Corsini (Eds)., Apomorphine and Other Dopaminomimetics. New York: Raven Press, 1981. Vol. I, pp. 265-271. 83. Imbs, J. L., Schmidt, M., Erhardt, J. D., and Schwartz, J. The sympathetic nervous system and renal sodium handling: Is dopamine involved? J. Cardiovasc. Pharmacol. 6(Suppl. I): S 171, 1984. 84. Lindheimer, M. D., Lalone, R. C., and Levinsky, N. G. Evidence that an acute increase in glomerular filtration has little effect on sodium excretion in the dog unless extracellular volume is expanded. J. Clin. Invest. 46: 256, 1967. 8.5. McGrath, B. P., Leversha, L., Jablonski, P., Matthews, P. G., Howden, B., and Marshell, V. C. Natriuretic and diuretic effects of dopamine in the isolated perfused rat kidney. Aust. N.Z. J. Med. 10: 481, 1980. 86. Wasserman, K., Huss, R., and Kullman, R. Dopamine-induced diuresis in the cat without changes in renal hemodynamics. Naunyn Schmiedebergs Arch. Pharmacol. 312: 77, 1980. 87. Davis, B. B., Walter, M. J., and Murdaugh, H. V. The mechanism of the increase in sodium excretion following dopamine infusion. Proc. Sot. Exp. Biol. Med. 129: 210, 1968. 88. McGiff, J. C., and Burnes, C. R. Separation of dopamine natriuresis from vasodilation: Evidence for dopamine receptors. J. Lab. Clin. Med. 70: 892, 1967. 89. Early, L. E., and Frielder, R. M. Changes in renal blood flow and possibly the intrarenal distribution of blood during natriuresis accompanying saline loading in the dog. J. Clin. Invest. 45: 542, 1966. 90. Schoeppe, W. Effects of dopamine on kidney function. Proc. R. Sot. Med. ‘IO(Suppl. 2): 36, 1977. 9 1. Baines, A. D., and Rowffignac, C. Functional heterogeneity of nephrons. II. Filtration rates, intraluminal flow velocities and fractional water reabsorption. Pluegers Arch. 308: 260, 1969. 92. Hoister, M., and Thurau, K. Micropuncture studies on the filtration rate of single superficial and juxtamedullary glomeruli in the rat kidney. Pjluegers Arch. 301: 162, 1968. 93. Jamison, R. L. Micropuncture study of superficial and juxtamedullary nephrons in the rat. Amer. J. Physiol. 218: 46, 1970.

94. Jamison, R. L. Intrarenal heterogeneity: The case for two functionally dissimilar populations of nephrons in the mammalian kidney. Amer. J. Med. 54: 281, 1973. 95. Britton, K. E. The measurement of intrarenal blood flow distribution in man. Clin. Sci. 56: 101, 1979. 96. Rowe, J. W., Shelton, R. L., Helderman, H., Vestal, R. E., and Robertson, G. L. Influence of the emetic reflex on vasopressin release in man. Kidney In?. 16: 729, 1979. 97. Ball, S. G., Tree, M., Morton, J. J., Inglis, G. C., and Fraser, R. Circulating dopamine: Its effect on the plasma concentrations of catecholamines, renin, angiotensin, aldosterone, and vasopressin in the conscious dog. Clin. Sci. 61: 4 17, 1981. 98. Lightman, S. L., and Forsling, M. Evidence for dopamine as an inhibitor of vasopressin release in man. Clin. Endocrinol. 12: 39, 1980. 99 Carey, R. M., Thorner, M. O., and Ortt, E. M. Dopaminergic inhibition of metoclopramide-induced aldosterone secretion in man: Dissociation of responses to dopamine and bromocriptine. J. Clin. Invest. 66: IO, 1980. 100. Noth, R. H., McCallum, W., Contino, C., Havelick, J. Tonic dopaminergic suppression of plasma aldosterone. J. Clin. Endocrinol. Metab. 51: 64, 1980. 101. Norbiato, G., Bevilacqua, M., Raggi, U., Micossi, P., and Moroni, C. Metoclopramide increases plasma aldosterone in man. J. Clin. Endo. Metab. 45: 1313,1977. 102. Campbell, D. J., Mendelsohn, F. A. O., Adam, W. R., and Funder, J. W. Is aldosterone secretion under dopaminergic control? Circ. Res. 49: 1217, 1981. 103. Ganguly, A. Dopaminergic regulation of aldosterone secretion: how credible? Clin. Sci. 66: 631, 1984. 104. deBold, A. J., Borenstein, H. B., Veress, A. T., and Sonnenberg, H. A rapid and potent natriuretic response to intravenous injection of atria1 myocardial extract of rat atrium. L@ Sci. 28: 89, 1981. 105. Sonnenberg, H. On the physiological role of atria1 natriuretic factor. Klin. Wochenschr.65(Suppl. 8): 8, 1987. 106. Kiberd, B., Larson, T., and Jamison, R. L. Effect of atria1 natriuretic factor on medullary blood flow. Kidney In?. 29: 337, 1986. 107. Struthers, A. D., Anderson, J. V., Payne, N., Causn, R. C., Slater, J. D. H., and Bloom, S. R. The effect of atrial natriuretic peptide on plasma renin activity, plasma aldosterone, and urinary dopamine in man,” J. Clin. Pharmacol. 31: 223, 1986. 108. Uehlinger, D. E., Weidmann, P., Gnldinger, M. P., Hasler, L., Bachmann, C., Shaw, S.,

SCHWARTZ AND GEWERTZ: RENAL RESPONSE TO DOPAMINE Hellmiiller, B., and Lang, R. E. Increase in circulating insulin induced by atria1 natriuretic peptide in normal humans. J. Curdiovusc. Pharmacol. 8: 1122, 1986. 109. Weidmann, P., Hasler, L., Gntidinger, M. P., Lang, R. E., Uehlinger, D. E., Shaw, S., Rascher, W., and Reubi, F. C. Blood levels and renal effects of atria1 natriuretic peptide in normal man. J. C/in. Invest. 77: 134, 1986. 110. Schnermann, J., and Brigs, J. P. Renal effects of atria1 natriuretic peptides. Klin. Wochenschr. 65(Suppl. 8): 92, 1987. 111. Hansell, P., Fasching, A., Sjiiquist, M., Anden, N. E., and Ulfendahl, H. A. The dopamine receptor antagonist haloperidol blocks natriuretic but not hypotensive effects of the atrial natriuretic factor. Acta Physiol. Scund. 130: 40 I, 1987. 112. Katoh, T., Matsunaga, H., Ohnuma, N., and Kurokawa, K. Renal effectsof atria1 natriuretic peptide (ANP) may be mediated by dopamine in the rat. Kidney Int. 29: 337, 1986. 113. Marin-Ghrez, M., Angchanpen, P., Gambaro, G., Schnermann, J., Schubert, G., and Briggs, J. P. Evidence for an involvement of dopamine receptors in the natriuretic response to atria1 natriuretic peptide. Klin. Wochenschr.65(Suppl. 8): 97, 1987. 114. Petterson, A., Hedner, J., and Hedner, T. The diuretic effect of atria1 natriuretic peptide (ANP) is dependent on dopamine activation. Acta Physiol. &and. 126: 619, 1986. 115. Webb, R. L., Della Puca, R., Manniello, J., Robson, R. D., Zimmerman, M. B., and Ghai, R. D. Dopaminergic mediation of the diuretic and natriuretic effects of ANF in the rat. Life Sci. 38: 2319, 1986. 116. Felder, R. A., Blecher, M., Eisner, G. M., and Jose, P. A. Cortical tubular and glomerular dopamine receptors in the rat kidney. Amer. J. Physiol. 246: F557, 1984. 117. Felder, R. A., Blecher, M., and Jose, P. A. Dopamine receptors in the proximal tubule of the rabbit: Adenylate cyclase studies and radioligand binding. Clin. Res. 30: 447a, 1982. 118. Bello-Reuss, E., Higashi, Y., and Kaneda, Y. Dopamine decreases fluid reabsorption in straight portions of rabbit proximal tubule. Amer. J. Physiol. 242: F634, 1982. 119. Greven, J., and Kline, H. Effects of dopamine on whole kidney function and proximal transtubular volume fluxes in the rat. Arch. Pharmncol. 296: 289, 1917.

120. Lanadi, A., Sakhrani, L. M., and Massry, S. G. Effects of dopamine on sodium uptake by renal proximal tubule cells of rabbit. Min. Elect. Met& 12: 303, 1986. 121. Goldberg, L. I., and Weder, A. B. Connections between endogenous dopamine, dopamine recep-

587

tors, and sodium excretion: Evidence and hypotheses.In P. Turner, and D. Shand (Eds.), Recent Advances in Clinical Pharmacology. New York: MacMillan, 1981. Pp. 149-166. 122. Kuchel, O., Buu, N. T., and Unger, T. Dopaminesodium relationship: Is dopamine a part of the endogenous natriuretic system?Contrib. Nephrol. 13: 27, 1978.

123. Talley, R. C., Forland, M., and Belier, B. Reversal of acute renal failure with a combination of intravenous dopamine and diuretics. Clin. Res. 18: 5 18, 1970.

124. Dasta, J. F., and Kirby, M. A. Pharmacology and therapeutic usesof low-dose dopamine. Pharmacotherapy 6: 304, 1986. 125. Docci, D. Dopamine-furosemide in oliguric acute renal failure. Nephron 36: 74, 1984. 126. Graziani, G., Cairo, G., Tarantino, F., and Ponticelli, C. Dopamine and frusemide in acute renal failure. Lancet 13: 1301, 1980. 127. Graziani, G., Casati, S., Cantaluppi, A., Citterio, A., Aroldi, A., Scalamonga, A., Brancaccio, D., and Ponticelli, C. Dopamine-frusemide therapy in acute renal failure. Proc. EDTA 19: 319, 1982. 128. Graziani, G., Cantaluppi, A., Casati, S., Citterio, A., Scalamonga, A., Aroldi, A., Silenzio, R., Brancaccio, D., and Ponticelli, C. Dopamine and frusemide in oliguric renal failure. Nephron 37: 39, 1984. 129. Lindner, A. Synergism of dopamine and furose-

mide in diuretic-resistant, oliguric acute renal failure. Nephron 33: 121, 1983. 130. Tulassay, T., and Seri, I. Acute oliguria in preterm infants with hyaline membrane disease: Interaction of dopamine and furosemide. Acta Pediatr. Stand. 75: 420, 1986. 131. Abbott, W. M., Cooper, J. D., and Austen, W. G. The effect of aortic clamping and declamping on renal blood flow distribution. J. Surg. Res. 14: 385, 1973. 132. Nanson, E. M., and Noble, J. G. The effect on the

kidneys of cross-clamping the abdominal aorta distal to the renal arteries. Surgery 46: 388, 1959. 133. Gamulin, Z., Forster, A., Morel, D., Simonet, F., Aymon, E., and Favre, H. Effects of intrarenal aortic cross-clamping on renal hemodynamics in humans. Anesthesiology 61: 394, 1984. 134. Paul, M. D., Mazer, C. D., Byrick, R. J., Rose, D. K., and Goldstein, M. B. Influence of mannitol and dopamine on renal function during elective infrarenal aortic clamping in man. Amer. J. Nephrol. 6: 427, 1986. 135. Salem, M. G., McLaughlin, G. A., Crooke, J. W., Middle, J. G., and Taylor, W. H. Effect of dopamine on renal function during aortic cross-clamping. Clin. Sci. 71(Suppl. 15): 45P, 1986. 136. Poison, R. J., Park, G. R., Lindop, M. J., Farman, J. V., Caine, R. Y., and Williams, R. The preven-

588

JOURNAL OF SURGICAL RESEARCH: VOL. 45, NO. 6, DECEMBER 1988 tion of renal impairment in patients undergoing orthotopic liver grafting by infusion of low dose dopamine. Anuesthesia 42: 15, 1987.

137. Bosch, J. P., Saccaggi, A., Latter, A., Ronco, C., Belledonne, M., and Glabman, S. Renal functional reserve in humans: Effects of protein intake on glomerular filtration rate. Amer. J. Med. 75: 943, 1983. 138. Hostetter, T. H. Renal hemodynamic responseto a meat meal in humans. Kidney Int. 25: 168, 1984. 139. Raftery, A. T., and Johnson, A. W. G. Dopamine pretreatment in unstable kidney donors. &it. Med. J. 87: 522, 1979. 140. Dhabuwala, C. B., Bird, M., and Salaman, J. R. Relative importance of warm ischemia, hypoten-

sion, and hypercarbia in producing renal vasospasm. Transplantation 21: 238, 1919. 141. Gnmdmann, R., Kammerer, B., Franke, E., and Pichlmaier, H. The effect of hypotension on the results of kidney storage and the use of dopamine under these conditions. Transplantation 32: 182, 1981. 142. Grundmann, R., Kindler, J., Meider, G., Stowe, H., Sieberth, H. G., and Pichlmaier, H. Dopamine treatment of human cadaver kidney graft recipients: A prospectively randomized trial. Klin. Wochenschr.60: 193, 1982. 143. DeLosAngeles, A., Baquero, A., Bannett, A., and Raja, R. Dopamine and furosemide infusion for prevention of post transplant oliguric renal failure. Kidney Int. 27: 339, 1985.