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relation between Dopamine and renal blood flow

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relation between Dopamine and renal blood flow

  1. 1. Clinical Science(1990)78,503-507 503 Renal tubular reabsorption of sodium and water during infusion of low-dosedopamine in normal man N. V. OLSEN", J. M. HANSEN?, S. D. LADEFOGEDt, N. FOGH-ANDERSENt AND P. P. LEYSSAcS Departments of tNephrology,$ClinicalChemistry and *ClinicalPhysiology,Herlev Hospital,Herlev,and $Instituteof Experimental Medicine,University of Copenhagen,Copenhagen, Denmark (Received 12June 1989/12 January 1990;accepted 17January 1990) SUMMARY 1. Using the renal clearance of lithium (CLi)as an index of proximal tubular outflow of sodium and water, together with simultaneous measurements of effective renal plasma flow, glomerular filtration rate (GFR) and sodium clearance (C,,), renal function and the tubular segmental reabsorption rates of sodium and water during dopamine infusion (3 pg min-' kg-') were estimated in 12normal volunteers. 2. CN,increased by 128% (P<O.OOl). Effective renal plasma flow and GFR increased by 43% (P<0.001)and 9% (P<0.01), respectively. CLiincreased in all subjects by, on average, 44% (P<0.001). Fractional proximal re- absorption [1-(CLi/GFR)] decreased by 13% after dopamine infusion (P<0.001), and 'estimated absolute proximal reabsorption rate (GFR- CLi)decreased by 8% ( P <0.01). Absolute distal sodium reabsorption rate [(CLi-CN,)x PNa,where P,, is plasma sodium concentra- tion] increased (P<0.001), and fractional distal sodium reabsorption [(cLi- cN,)/cLi] decreased ( P <0.001). 3. It is concluded that natriuresis during low-dose dopamine 'infusion is caused by an increased outflow of sodium from the proximal tubules that is not fully com- pensated for in the distal tubules. Key words: dopamine, glomerular filtration, lithium clear- ance, renal tubular function, sodium, water. Abbreviations: ADRN,, absolute distal reabsorption rate of sodium; APR, absolute proximal reabsorption rate; CLi and C,,, lithium and sodium clearances, respectively; DTPA, diethylenetriaminepenta-acetic acid; ERPF, effective renal plasma flow; FDRN,, fractional distal re- absorption of sodium; FEN,, fractional excretion of sodium; FF, filtration fraction; GFR, glomerular filtration rate; PFR, proximal fractional reabsorption. Correspondence: Dr N. V. Olsen, Department of Clinical Physiology, Herlev Hospital, Herlev Ringvej, DK-2730 Herlev, Denmark. INTRODUCTION Dopamine, an endogenous catecholamine, is known to cause an increasein renal blood flow, glomerular filtration rate (GFR), urine flow and sodium excretion [l-41. The rise in GFR and sodium excretionhas been interpreted as a consequence of increased renal blood flow secondary to an afferent and efferent arteriolar vasodilatation mediated by the action of dopamine on specific vascular receptors [4, 51. However, natriuresis after low-dose dopamine has been demonstrated in the absence of changes in renal blood flow and GFR, suggesting a specific tubular effect [2, 6, 71. Recently, specific dopamine DA,-receptors in the proximal tubule have been identified [8, 91, but previous studies have given conflicting results about the proximal tubular effects of dopamine. An unchanged [6], an increased [lo, 111 and a decreased [12] sodium re- absorption rate have been suggested by micropuncture studies and different techniques in vitro. Segmental tubular transport of sodium and water can be investigated in man by the lithium clearance (CLi) method [131. Evidence exists that lithium under normal physiological conditions is reabsorbed in the same pro- portion as sodium in the proximal tubules and is not reabsorbed or secreted in the distal tubules [13, 141. Under these conditions renal CLihas been shown to cor- relate reasonably with the delivery of sodium and water from the proximal tubules into the thin descending loop of Henle in experimental animals [15-171. Indirect evidence obtained by drug effect studies suggest a similar tubular handling of lithium in man [13, 181, and distal tubular reabsorption of lithium, suggested by an increase in CLiafter amiloride treatment, has only been found during extreme sodium depletion [18, 191. Simultaneous determinations of GFR, Cri, clearance of sodium (CNa) and urine flow may therefore allow an estimation of the proximal and distal reabsorption rates of sodium and water. The CLimethod has not previously been used to investigate the segmental transport of sodium during infusion of dopamine.
  2. 2. 504 N. V. Olsenet al. The purpose of the present study was to evaluaterenal tubular handling of sodium and water during intravenous infusion of low-dose dopamine (3 pg min-' kg-I) in normal man by simultaneous determination of the effectiverenal plasma flow (ERPF),GFR, CLiand CNa.In this dose dopamine only has minor, if any, effects on a- and p-adrenoreceptors [4]. MATERIALSAND METHODS Subjects The study was approved by the regional scientific ethical committee. Twelve healthy volunteers (seven males, five females, aged 18-48 years) entered the study after they had giventheir informed consent. Protocol In each subject the effects of dopamine (3 pg min-' kg-l) were investigated.In addition, in six of the subjects (four males, two females,aged 25-48 years)the effects of isotonic glucose (55 g/l) alone were investigated .on another occasion after an interval of at least 3 days. Lithium carbonate (600 mg; 16.2 mmol) was given orally on the evening before each investigation. After an over- night fast, a urine flow of at least 400 ml/h was maintained by orally administered tap water (200-250 ml every 20 min without initial load).Smoking and intake of caffeine- containing drinks were not allowed. Except for briefly standing when voiding, the subjectswere confined to bed. After a 1h control period (period l), an intravenous infusion (3 ml h-' kg-') of dopamine (60 mg in 1000 ml of isotonic glucose) or isotonic glucose alone (3 ml h-' kg-l) was started. The infusion continued during three 1 h clearance periods (periods 2, 3 and 4). ERPF and GFR were measured by a constant infusion technique with urine collections, using 1311-hippuranand YYmT~- diethylenetriaminepenta-aceticacid (yYmTc-DTPA)[20]in a total dose of, on average, 0.10 mCi (3.6 MBq) and 0.73 mCi (27.0 MBq), respectively. After an equilibration period of at least 1h, renal clearances of '311-hippuran, YYmT~-DTPA,lithium and sodium were determined for periods 1,2,3and 4, each calculated from the 1h urinary excretion rate and the plasma values from three samples drawn at the start, the middle and the end of each 1h period.The total volumeof blood samplesin each experi- ment was 260 ml. Blood pressure (measured manually by sphygmomanometry)and heart rate were recorded at the end of each period. Body weight was measured at the start of period 1and at the end of periods 2 and 4. Packed cell volume was measured at the middle of periods 1 and 4. Urine from all periods was tested for glucosuria by using Dip-Stix. Analytical methods 13'I-Hippuranand YYmT~-DTPAin plasma and urine were determined in a well-counter. Plasma sodium was measured with a Technicon SMAC instrument, and urinary sodium was determined with a Technicon RA 1000 instrument (Tarrytown, NY, U.S.A.). Plasma and urinary lithium were measured by atomic absorption spectrophotometry (model403; Perking-Elmer, Norwalk, CT,U.S.A.) [13]. Calculations Reabsorption and excretion rates of sodium and water were calculated based on the assumption that C, provides an accurate measurement of the rate of end- proximal deliveryof fluid and sodium [13]:absolute prox- imal reabsorption rate (APR)=GFR-CLPProximal fractional reabsorption (PFR)was calculated as 1-(CLi/ GFR). Absolute distal reabsorption rate of sodium (ADRN,) was determined as (CLi- CNa)x PNa,where PN, is plasma concentration of sodium. Fractional distal re- absorption of sodium (FDR,,) was calculated as (CLi-CNa)/CLi,and fractional sodium excretion (FEN,) was determined as CN,/GFR. Filtration fraction (FF)was calculated as GFR/ERPF. All clearance values were corrected to 1.73 m2 body surface area. Date were analysed by analysis of variance and paired t-tests. All data are expressedas meanskSEM. RESULTS There were no significant differences between baseline values (period 1) of any variable before infusions of isotonic glucose or dopamine (unpaired f-tests).None of the subjectshad glucosuria after any infusion. During infusion of isotonic glucose, no changes were observed in GFR, CLior C,, (Table 1).ERPF (Table 1) decreased significantly in periods 3 and 4, and FF (Table 1) increased in periods 3 and 4. Urine flow (Table 1) decreased in the last period. Packed cell volume decreased significantlyfrom 0.420 f0.010 in period 1to 0.404 f0.010 in period 4 (P<0.05). All other variables remained unchanged duringisotonic glucoseinfusion. During dopamine infusion, ERPF increased by 43% and GFR increased slightly, but significantly, by, on average, 9%. FF decreased by 24%. CLiincreased in all subjects by, on average, 14 ml/min (44%). Dopamine caused significant increases in urine flow (31%), C,, (128%) and FEN, (105O/0). Calculated segmental reabsorption rates are shown in Fig. 1. APR tended to decrease, but the change was only significant in period 3 (So/,). PFR decreased significantly by 9%, 13% and 13% in periods 2, 3 and 4, respectively. ADRN, increased by 42%, and FDRN, decreased by 2% from 96.5% to 94.5%. Packed cell volume remained unchanged. Mean arterial pressure decreased from 92+2 mmHg in period 1' to 91k 2 (not significant), 87& 3 (P<0.05) and 88f3 ( W 0 . 0 5 )mmHg in periods 2, 3 and 4, respectively. Heart rate increased from 62 f2 beats/min in period 1to 65 k 2 (not significant),65k 2 (not significant)and 67 f2 (P<O.O5) beats/min in periods 2, 3 and 4, respectively. Body weight decreased from 69.3 k 3.3 kg in period 1 to 68.4k3.3 kginperiod 4 (P<O.OOl). DISCUSSION Although the main assumptions for estimating proximal tubular outflow with CLimight be considered as being
  3. 3. Renalfunction after low-dose dopamine infusion 505 fulfilled in the present study, where young healthy subjects with normal sodium excretion were investigated, the data must be interpreted with some reservations,due to the lack of direct evidence supporting the validity of using CLiin man. The possibility, and contribution, of lithium reabsorption in the loop of Henle cannot be ignored. Water diuresis, used in the present study to facilitateurine collection, has been shown not to affect CLi [21].Recently,lithiumwas found to abolish the natriuresis produced by the dopamine prodrug gludopa [22]. How- ever, in another study lithium did not interfere with sodium excretion after administration of the dopamine agonistfenoldopam [23].In the present study, the sodium excretion rate more than doubled after dopamine in- fusion. Thus, although some interaction of lithium with the effects of dopamine cannot be entirely excluded from the present data, the renal effects of dopamine remained significantlyexpressed. The present finding of increased ERPF, GFR, urine flow and C,, during low-dose dopamine infusion is in accordance with previous investigations in normal humans [2, 4, 241. A change in renal vascular resistance, with a predominant efferent arteriolar vasodilatation as suggestedby the decreased FF in the present study, could explain the increased urine flow and sodium excretion,as previouslyproposed [4,5]. However, dopamine can produce diuresis and natriur- esis in both humans and experimental animals without significant changes in renal haemodynamics [2, 6, 7, 251. Specifictubular effects of dopamine are further suggested by the finding of greater diuresis and natriuresis during dopamine administration than during dobutamine administration, despite similar effects on cardiac output, ERPF and GFR by both drugs [26]. Although specific dopamine DA,-receptors have been characterized by radioligand-binding studies in the isolated proximal con- voluted tubule of the rabbit [S] and in renal cortical tubular tissue of the rat [9], the effects of dopamine on renal tubular sodium transport still remain unclear. Proximal tubular sodium reabsorption, as measured by a micropuncture technique, was found to be unchanged after dopamine infusion in dog kidneys, and it was inferred that the significantlyincreased sodium excretion rate was caused by an effect at a site distalto the proximal tubule [6].A similar conclusion was drawn from micro- puncture studies in the rat, in which the APR even increased after intratubular addition of dopamine [lo].In isolated proximal tubule cells dopamine stimulated sodium uptake [ll],but by the technique of microper- fusion of isolated pars recta segments of the rabbit proximal tubule in vitro, addition of dopamine was found to depress reabsorption rates of sodiumand fluid [12]. In the present study in normal humans, CLiwas used as an index of proximal tubular fluid outflow for calculating segmental tubular reabsorption rates of sodium and water. The estimated changein APR after dopamine infu- sion was so small that, although it transiently reached statistialsignificancein period 3,it should not be assigned any functional significance.Rather, the data suggest that the significantly increased CLireflects an increase in proximal fluid delivery due mainly to the vasodilating effect of'dopamine (increased ERPF) and the resulting Table 1. Effects of infusion of isotonic glucose (ISO: n=6) and dopamine (DA; n=12) on ERPF, GFR, FF, CLi,C,, ,FEN,and urine flow (V) Baseline=period 1,infusion=periods 2,3 and 4. Resultsare means kSEM.Statisticalsignificance: *P<O.O5,tP<O.Ol,$P<O.OOl compared with baseline. Periods.. . 1 2 3 4 ERPF (ml/min) IS0 DA I S 0 DA I S 0 DA IS0 DA IS0 DA IS0 DA IS0 DA GFR (ml/min) FF CLi(ml/min) CN,(ml/min) V (ml/min) 511f 16 498f 19 112k1 1083~4 0.221f0.007 0.218 f 0.007 31f 2 3 2 f l 1.19f0.22 1.10f0.24 1.05f0.19 1.04f0.12 1 4 f 1 1 3 f 1 499f 12 648It26* 112f2 113f3* 0.226f0.006 0.177 f0.007$ 31f 2 41 +2$ 1.24f0.24 2.31 f0.3It 1.11f0.21 2.05 f0.27t 13+1 1 7 f 2 t 477 f8* 692 f27$ 1 1 2 f 2 1 1 4 f 4 t 0.236 f0.007* 0.166f0.006$ 31f 2 44f2$ 1.I7f 0.23 2.48f0.21$ 1.04It0.20 2.24f 0.22$ 1 3 f 1 17+2* 468 f lot 711f 19$ 1 1 1 f 2 1 1 8 f 4 t 0.237f0.006* 0.166f0.004$ 3 1 f l 46f If 1.06 f0.14 2.51f0.24$ 0.96f0.12 2.13It0.21$ 1 2 f l * 1 6 f l t
  4. 4. 506 N. V. Olsen et al. 7000 3 - 4000 ** ** I I I i 1 2 3 4 Periods Fig. 1. Effects of infusion of dopamine ( A ; tz = 12)and isotonic glucose (0; tz=6) on APR, PFR, ADRN, and FDRN, in four consecutive 1 h periods (baseline =period 1;infusion =periods 2,3 and 4).Results are means fSEM. Statistical significance: *P<0.01, **P<0.001 compared with baseline. increase in GFR. The increased delivery of sodium and fluid to the distal tubular segments, as inferred from the increase in CLi,was associated with an increased ADR,, and a decreased FDR,,. The present data therefore indicate that sodium excretion increased because of an increased output of sodium from the proximal tubules which was not fully compensatedfor in the distal tubules. In summary, an intravenousinfusion of dopamine (3pg min-' kg-I) in normal man increased ERPF, GFR, urine flow and sodium excretion. CLi,used as an estimate of proximal delivery of fluid, increased in all subjects by, on average, 44%. PFR decreased significantly,but changes in APR were too small to be assigned any functional sig- nificance. ADR,, increased, but FDR,, decreased. It is concluded that natriuresis during low-dose dopamine infusion is caused by an increased outflow of sodium from the proximal tubules that is not fully compensated for in the distal tubules. ACKNOWLEDGMENTS This work was supported by grants from the Jacob Madsens and Olga Madsens Foundation, Copenhagen, and the Elin Hartelius Foundation, Copenhagen. REFERENCES 1. Goldberg, L.I., McDonald, R.H. & Zimmerman, A.M. Sodium diuresis produced by dopamine in patients with congestive heart failure. N. Engl. J. Med. 1963; 269, 1060-4. 2. McDonald, R.H., Goldberg, L.I., McNay, J.L. & Tuttle, E.P. Effect of dopamine in man: augmentation of sodium excre- tion, glomerular filtration rate, and renal plasma flow. J. Clin. Invest. 1964;43, 11 16-25. 3. Meyer, M.B., McNay, J.L. & Goldberg, L.I. Effects of dopamine on renal function and hemodynamics in the dog. J. Pharmacol. Exp. Ther. 1967; 156, 186-92. 4. Goldberg, L.I. Cardiovascular and renal actions of dopamine: potential clinical amlication. Pharmacol. Rev. 5. 6. 7. 8. 9. 10. 1 1 . 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. .. 1972; 24,1129. Chapman, B.J., Horn, N.M., Munday, K.A. & Robertson, MJ. The actions of dopamine and of sulpiride on regional blood flows in the rat. J. Physiol. (London) 1980; 298, Davis, B.B., Walter, M.J. & Murdaugh, H.V. The mechanism of the increase in sodium excretion following dopamine infusion. Proc. SOC.Exp. Biol. Med. 1968; 129,210-13. Wasserman, K., Huss, R. & Kullmann, R. Dopamine- induced diuresis in the cat without changes in renal hemo- dynamics. Arch. Pharmacol. 1980;312,77-83. Felder, R.A., Blecher, M., Calcagno, P.L. & Jose, P.A. Dopa- mine receptors in the proximal tubules of the rabbit. Am. J. Physiol. 1984;247, F499-505. Felder, R.A. & Jose, P.A. Dopamine, receptors in rat kidneys identified with 'ZSI-S~h23982. Am. J, Physiol. Greven, J. & Kline, H. Effects of dopamine on whole kidney function and proximal transtubular volume fluxes in the rat. Arch. Pharmacol. 1977; 296,289-92. Laradi, A., Sakhrani, L.M. & Massy, S.G. Effect of dopa mine on sodium uptake by renal proximal tubule cells of rabbit. Miner. Electrolyte Metab. 1986; 12,303-7. Bello-Reuss, E., Higashi, Y. & Kaneda, Y. Dopamine decreases fluid reabsorption in straight portions of rabbit proximal tubule. Am. J. Physiol. 1982; 242, F634-40. Thomsen, K. Lithium clearance: a new method for deter- mining proximal and distal tubular reabsorption of sodium and water. Nephron 1984;37,217-23. Hayslett, J.P. & Kashgarian, M. A micropuncture study of the renal handling of lithium. Pflugers Arch. 1979; 380, Thomsen, K., Holstein-Rathlou, N.H. & Leyssac, P.P. Com- parison of three measures ofproximal tubular reabsorption: lithium clearance, occlusion time, and micropuncture. Am. 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  5. 5. Renalfunction after low-dose dopamineinfusion 507 Lithium in renal physiology, Utrecht, The Netherlands, 1989'22. 24. Ter Wee, P.M., Smit, AJ., Rosman, J.B., Sluiter, WJ. & Donker, AJ.M. Effect of intravenous infusion of low-dose dopamine on renal function in normal individuals and in patients with renal disease.Am. J. Nephrol. 1986; 6,42-6. 25. McGiff,J.C. & Bums, C.R. Separation of dopamine natriur- esis from vasodilation: evidence for dopamine receptors [Abstract].J. Lab. Clm.Med. 1967;70,892. 26. Hilberman, M., Maseda, J., Stinson, E.B. et al. The diuretic properties of dopamine in patients after open-heart opera- tion. Anesthesiology 1984;61,489-94.

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