Renal and Endocrine Effects of Fenoldopam and Metoclopramide in Normal Man

Girbes, Arj; Smit, Andries J.; Meijer, S; Reitsma, Wd

doi:10.1159/000186129

Cited by 37 publications

(25 citation statements)

References 19 publications

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“…Fenoldopam increases renal plasma flow on HS 22,50,51 and normal 52 but not LS diets, 22 which was corroborated in the present study. Fenoldopam did not increase creatinine clearance on either diet, similar to previous studies that employed inulin clearance to measure GFR in normotensive humans.…”

Section: Discussionsupporting

confidence: 91%

“…Fenoldopam did not increase creatinine clearance on either diet, similar to previous studies that employed inulin clearance to measure GFR in normotensive humans. 22,51,52 Fenoldopam does increase inulin clearance in hypertensive humans. 53 Fenoldopam's natriuretic effect on a HS diet is related, perhaps, to decreased proximal and distal sodium transport, as shown previously.…”

Section: Discussionmentioning

confidence: 99%

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The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

Natarajan¹,

Eisner

Armando³

et al. 2016

Journal of the American Society of Nephrology

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The renin-angiotensin-aldosterone (RAAS) and renal dopaminergic systems interact to maintain sodium balance. High NaCl intake increases renal synthesis of dopamine and dopaminergic receptor activity, decreasing epithelial sodium transport, whereas sodium deficit activates the RAAS, increasing epithelial sodium transport. We tested the hypothesis that attenuation of the natriuretic effect of dopamine D 1 -like receptors during salt restriction results in part from increased RAAS activity in seven salt-resistant normotensive adults using a double-blind placebo-controlled balanced crossover design. All subjects attained sodium balance on low (50 mmol Na + /day) and high (300 mmol Na + /day) NaCl diets, administered 4 weeks apart. Sodium, potassium, lithium, para-aminohippurate, and creatinine clearances were measured before, during, and after a 3-hour infusion of fenoldopam, a D 1 -like receptor agonist, with and without pretreatment with enalapril, an angiotensin converting enzyme inhibitor. On the high NaCl diet, fenoldopam-induced natriuresis was associated with the inhibition of renal proximal and distal tubule sodium transport. On the low NaCl diet, fenoldopam decreased renal distal tubule sodium transport but did not cause natriuresis. The addition of enalapril to fenoldopam restored the natriuretic effect of fenoldopam and its inhibitory effect on proximal tubule sodium transport. Thus, on a high NaCl diet fenoldopam causes natriuresis by inhibiting renal proximal and distal tubule transport, but on a low NaCl diet the increased RAAS activity prevents the D 1 -like receptor from inhibiting renal proximal tubule sodium transport, neutralizing the natriuretic effect of fenoldopam. These results demonstrate an interaction between the renin-angiotensin and renal dopaminergic systems in humans and highlight the influence of dietary NaCl on these interactions. During salt depletion, sodium balance is maintained by increased activity of several systems, including the renin-angiotensin-aldosterone (RAAS) and sympathetic nervous systems.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

Natarajan¹,

Eisner

Armando³

et al. 2016

Journal of the American Society of Nephrology

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“…In our study, [5H]-dopexamine binding sites dis placed by SCH 23390, which correspond to DA-1 receptors, were found within the macula densa, proximal and distal tubules and the descending and the ascending limbs of the loop of Henle. The localization of DA-1 sites in the macula densa, where these receptors are probably involved in the control of renin secretion [26], and in the renal tubules, where they control natriuresis [26], confirms in the human kidney our previous observations in the rat kidney [15]. In contrast, the presence of DA-1 sites in the loop of Henle has not been previously reported.…”

Section: Discussionsupporting

confidence: 85%

Dopexamine Hydrochloride in the Human Kidney: Localization, Receptor Binding and Effect on 3’-5’-Cyclic Adenosine Monophosphate Generation

Napoleone

Cavallotti²,

Rícci³

et al. 1993

Nephron

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Dopexamine hydrochloride is a synthetic dopamine analogue recently developed to improve myocardial and renal performance in patients suffering from low cardiac output states. The present study was designed to assess the pharmacological profile and the anatomical localization of [³H]-dopexamine binding sites within the human nephron. The effects of dopexamine on the 3’-5’-cyclic adenosine monophosphate (cAMP)-generating system in membrane particles of the human kidney were also investigated. It was found that [³H]-dopexamine was specifically bound by sections of the human kidney. The binding was partly inhibited by the DA-1 receptor antagonist SCH 23390, by the β2-adrenoceptor antagonist ICI 118,551 and by the DA-2 receptor antagonist domperidone. The 3 antagonists in combination reduced [³H]-dopexamine binding to nonspecific values. Light microscope autoradiography revealed the accumulation of silver grains, corresponding to [³H]-dopexamine binding sites, within the different portions of the human nephron. The incubation of sections of the human kidney with [³H]-dopexamine plus SCH 23390 caused a remarkable reduction in the density of silver grains within the proximal tubule and the macula densa and a moderate decrease in the density of silver grains within the ascending and descending limbs of the loop of Henle as well as within the distal tubule. The incubation of sections of human kidney with [³H]-dopexamine plus ICI 118,551 caused a pronounced reduction in the density of silver grains within the glomerulus, the limbs of the loop of Henle, the distal tubule and the medullary collecting tubules and a moderate decrease in the density of silver grains within the macula densa and the proximal collecting tubule. The incubation of sections of the human kidney with [³H]-dopexamine plus domperidone caused a moderate decrease in silver grain accumulation within proximal and distal tubules as well as within medullary collecting tubules. Dopexamine caused a dose-dependent accumulation of cAMP levels in membrane particles of the human kidney. This effect was in part reduced by SCH 23390 or by ICI 118,551. A combination of SCH 23390 and ICI 118,551 reduced cAMP levels to basal values. The present results clearly show that dopexamine binds to dopamine DA-1 and DA-2 receptor sites and to β₂-adrenoceptors in various regions of the human kidney. Moreover, they demonstrate that dopexamine stimulates cAMP formation in the human kidney by activating both DA-1 receptors and β₂-adrenoceptors. Stimulation of some or all of these receptors may contribute to the renal actions of dopexamine in humans.

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“…1116 ' 32 In two studies in healthy volunteers, the same metoclopramide infusion schedule as used in the present study inhibited the natriuretic responses to a low dose of dopamine 33 and to the selective DA] agonist fenoldopam. 34 However, in another study, an infusion of approximately two thirds of our metoclopramide dose did not affect dopaminemediated natriuresis in salt-loaded healthy subjects. 35 These data might suggest that our metoclopramide dose was just high enough to block DA, receptor-mediated natriuresis.…”

Section: Discussionmentioning

confidence: 65%

Metoclopramide stimulates kaliuresis during felodipine without affecting its natriuresis.

et al. 1994

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Calcium entry blockers such as felodipine induce natriuresis without a parallel rise of potassium excretion. Previous studies with exogenous aldosterone and felodipine have suggested that the absence of kaliuresis might be explained by a felodipine-induced inhibition of aldosterone release. The natriuresis with calcium entry blockers could not be attributed to a similar mechanism but might be due to the stimulation of intrarenal natriuretic systems such as the dopaminergic system. We studied whether the aselective dopamine antagonist metoclopramide prevents the natriuresis with low and therapeutic felodipine doses and whether metoclopramide-induced aldosterone release promotes kaliuresis with felodipine. Twelve healthy male volunteers participated in a randomized, placebocontrolled, crossover study comparing felodipine infusion during metoclopramide with felodipine alone. Metoclopramide had no significant influence on the pronounced and dose-dependent increases of renal plasma flow and urinary sodium excretion with C alcium ehtry blockers (CEBs), especially dihydropyridines such as felodipine, are powerful vasodilating drugs useful for the treatment of hypertension.1 These drugs have short-term diuretic and natriuretic effects, 2 which may contribute to their antihypertensive action. Clearance studies in humans 3 "6 and some micropuncture studies in animals 79 have indicated that CEBs decrease proximal tubular sodium reabsorption. However, the mechanisms responsible for CEBmediated natriuresis remain unknown. Since selective administration of a CEB into the renal artery stimulates natriuresis, 10 an interaction with intrarenal natriuretic systems such as the dopaminergic system 11 could be involved.We and others have observed that the increased sodium excretion during calcium entry blockade is not accompanied by a parallel increase of potassium excretion. ,6,i2 This is rather surprising in view of the aforementioned CEB-mediated decrease of proximal tubular sodium reabsorption. We have previously demonstrated that simultaneous administration of exogenous aldosterone and felodipine was followed by a large increase of kaliuresis.13 Therefore, the attenuation of potassium excretion during calcium entry blockade might be explained by the well-known CEB-mediated inhibition of aldosterone release. © 1994 American Heart Association, Inc.felodipine. Metoclopramide increased plasma aldosterone concentration from 0.17±0.03 to 0.60±0.14 nmol/L, and subsequent felodipine infusion clearly increased urinary potassium excretion by 23 ±6 and 35±8 /xmol/min (low and therapeutic doses, respectively). In contrast, potassium excretion remained stable with felodipine alone (+5±4 and +7±5 /xmol/min, respectively). In conclusion, the natriuretic action of calcium entry blockers cannot be blocked by the aselective dopamine antagonist metoclopramide. This natriuresis is accompanied by kaliuresis only in the presence of elevated endogenous aldosterone concentrations. The ability of calcium entry blockers to prevent a rise of pl...

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Renal and Endocrine Effects of Fenoldopam and Metoclopramide in Normal Man

Cited by 37 publications

References 19 publications

The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

The Renin-Angiotensin and Renal Dopaminergic Systems Interact in Normotensive Humans

Dopexamine Hydrochloride in the Human Kidney: Localization, Receptor Binding and Effect on 3’-5’-Cyclic Adenosine Monophosphate Generation

Metoclopramide stimulates kaliuresis during felodipine without affecting its natriuresis.

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