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The Renal Excretion of Urodilatin in Humans is Related to Variations in the Renin–Angiotensin-Aldosterone System
Stephan Klaus, MD*
Horst Pagel, PhD†
Jens Sehested, MD, PhD‡
*Klinik für Anaesthesiologie
†Institut für Physiologie, Universität zu Lübeck, Lübeck, Germany
‡Klinisk Fysiologisk/Nuklearmedicinsk Afd., Esbjerg, Denmark
KEY WORDS: Natriuretic peptides, plasma renin activity, aldosterone, cardiorenal integration, hemodynamics
The precise mechanisms regulating production and excretion of the renal natriuretic peptide urodilatin, a member of the family of natriuretic peptides structurally related to atrial natriuretic peptide remains to be determined. We have recently shown that vasocontrictory concentrations of angiotensin II decrease renal urodilatin excretion in vitro. The present study was thus designed to determine excretion of urodilatin in humans, as well as levels of plasma renin activity and plasma aldosterone, during a body position-induced stimulation. Nine healthy volunteers were randomly studied during supine positioning (SUP-A) followed by a period in the sitting position (SIT-A): protocol A; and in the sitting position only (SIT-B): protocol B. Urodilatin excretion was significantly increased (P = .023) after supine positioning (139 ± 48 fmol*min-1) in comparison with the sitting only position (79 ± 46 fmol*min-1). This was accompanied by a significantly lower plasma-renin-activity (SIT-A: 1.00 ± 0.52 ng*ml-1*h-1; SIT-B: 1.44 ± 0.84 ng*ml-1*h-1; P = .016) and a plasma- aldosterone-concentration that had decreased from SUP-A to SIT-A (P = .003) and that tended (P = .059) to be lower during SIT-A than during SIT-B (SUP-A: 0.21 ± 0.08 nmol*l-1; SIT-A: 0.14 ± 0.07 nmol*l-1; SIT-B: 0.21 ± 0.10 nmol*l-1). This suggests that regulation of urodilatin excretion in humans may be linked with the activity of the renin-angiotensin-aldosterone system.
The precise mechanisms regulating production and excretion of the renal natriuretic peptide urodilatin, a member of the family of natriuretic peptides structurally related to atrial natriuretic peptide, remains to be determined. Urinary excretion of urodilatin [UUROV] has been shown to be influenced by nutritional sodium load,1–4 the cephalic concentration of sodium,5 and renal perfusion pressure.6 Additionally, controversial results regarding the effects of variations in thoracic blood volume and a possible role of ANP in the regulation of UUROV have been obtained.7–10
We have recently shown that vasoconstrictory concentrations of angiotensin II but not of endothelin-1 decrease UUROV in the isolated perfused rat kidney model,11 suggesting that the renal excretion of urodilatin may be influenced by variations in the renin-angiotensin–aldosterone system. The present study was thus designed to determine if stimulation of the renal urodilatin system is accompanied by variations in the levels of plasma renin activity and aldosterone.
The investigation conforms with the principles outlined in the Declaration of Helsinki. After institutional review board approval and informed written consent nine healthy nonsmoking male volunteers aged 34 ± 5 years on a customary sodium intake were investigated. Subjects were studied twice, around noon, in randomized order on different days at least 2 weeks apart after 2 different protocols.
Protocol A: After arrival at the laboratory, volunteers were requested to void for determination of baseline renal function and urodilatin excretion (U1A) and were seated in a recumbent position in a comfortable chair. A venous line (16 G) was inserted in an antecubital vein and an infusion of normal strength saline (2 ml*min-1) was started. After a period of 30 minutes, a blood sample for determination of hormones and plasma chemistry was taken (SUP-A) and hemodynamic measurements were performed. The volunteers remained in the supine position until data acquisition was completed (effective time in the supine position: 76 ± 22 min). Thereafter, body position was changed into an upright sitting position. Another blood sample was drawn (SIT-A), and hemodynamic measurements were performed after 15 minutes in the sitting position. Volunteers remained seated upright until voiding (U2A) was possible (effective time in the sitting position: 54 ± 21 min).
Protocol B: The protocol was comparable to protocol A except for the fact that the volunteers were immediately seated in the upright position. Hemodynamic measurements and sampling of blood was performed after 30 minutes in the sitting position (SIT-B). The volunteers remained seated until spontaneous voiding (U2B) was possible (effective time in the sitting position, protocol B: 95 ± 5 min).
Digital arterial blood pressure was measured with a FINAPRES blood pressure monitor (Ohmeda, Louisville, KY) connected to a digital storing device (DALO, Koralewsky, Celle, Germany). Mean arterial blood pressure (MAP) was calculated as diastolic plus one third of the pulse pressure (PP). Heart rate was recorded by precordial electrodes and stored in the DALO. Both parameters were recorded during periods of 10 minutes and analyzed off-line. Digital arterial blood flow (DBF) was determined by water plethysmography (Kaufmann, Berlin, Germany). Baroreceptor sensitivity (BRS) was measured by the phenylephrine injection method.12 Blood and urine was sampled in prechilled tubes, containing EDTA, aprotinin, and heparin, as appropriate, and immediately spun for 10 minutes at 4˚C. Supernatants were stored at –80˚C for further analyses.
Sodium (flame photometrically) and osmolality (freezing point depression) were determined on standard hospital analyzers. Atrial natriuretic peptide, urodilatin, endothelin-1, plasma renin activity, aldosterone, and noradrenaline were determined as described previously.8,13,14
If not stated otherwise, data are presented as mean ± standard deviation. Following a Kolmogorov-Smirnov test to determine if the data were distributed normally, a Student’s t-test for paired observations was performed. The level of statistical significance was set to P < .05.
Mean arterial blood pressure and pulse pressure tended to increase from SUP to SIT during protocol A (MAP: SUP-A: 79 ± 15 mm Hg; SIT-A: 87 ± 13 mm Hg; p = 0.06; PP: SUP-A: 52 ± 9 mm Hg; SIT-A: 61 ± 7 mm Hg; P = .08) and were higher during SIT-A than during SIT-B (MAP: SIT-B: 80 ± 9 mm Hg; P = 0.01; PP: SIT-B: 51 ± 5 mm Hg; P = .01). No significant variations in heart rate, digital arterial blood flow, and baroreceptor sensitivity were observed (data not shown).
Plasma osmolality was unchanged throughout the observation period (Osmp SUP-A: 305 ± 8 mosmol*kg-1; SIT-A: 302 ± 6 mosmol*kg-1; SIT-B: 301 ± 5 mosmol*kg-1; P = NS). Plasma sodium was unchanged from SUP to SIT during protocol A (Na: SUP-A: 140 ± 3 mmol*l-1; SIT-A: 138 ± 4 mmol*l-1) but lower during SIT-B than during SIT-A (SIT-B: 135 ± 1 mmol*l-1 ; P = .048).
Hormonal variations throughout the study are given in Table 1. They revealed a decrease in atrial natriuretic peptide and aldosterone levels from SUP to SIT during protocol A, different levels of plasma renin activity, and nearly significant differences in atrial natriuretic peptide and aldosterone in comparison between SIT-A and SIT-B. No significant variations in endothelin-1 and noradrenaline were noted throughout the procedure.
Renal Functional Parameters
Urine flow tended to increase during protocol A and was nearly significantly higher during SIT-A in comparison with SIT-B (UV: U1A: 1.2 ± 0.9 ml*min-1 ; U2A: 2.7 ± 1.5 ml*min-1; P = .09 for U1A vs. U2A; U1B: 1.4 ± 0.7 ml*min-1; U2B: 1.2 ± 0.7 ml*min-1; P = 0.059 for U2A vs. U2B). Renal excretion of sodium was significantly higher during U2A than during U2B (UNaV: U1A: 148 ± 139 mmol*min-1; U2A: 285 ± 111mmol*min-1; U1B: 132 ± 61 mmol*min-1; U2B: 160 ± 69mmol*min-1; P = 0.005 for U2A vs. U2B).
Urine osmolality was different at baseline, with significantly higher levels during protocol A in comparison with protocol B and decreased from U1A to U2A (OsmU: U1A: 788 ± 124 mosmol*kg-1; U2A: 575 ± 240 mosmol*kg-1; U1B: 542 ± 272 mosmol*kg-1; U2B: 776 ± 168 mosmol*kg-1; P = 0.03 for U1A vs. U1B; P = 0.01 for U1A vs. U2A). The course of urodilatin excretion is shown in Figure 1 and revealed significantly higher levels of this parameter during U2A in comparison with U2B.
The mechanisms regulating production and urinary excretion of the renal natriuretic peptide urodilatin15 are far from being understood. Several elegant studies have convincingly shown a close relationsship between nutritional or intravenous sodium loading, natriuresis and an increase in UUROV.1-4 This interaction is also present on the cellular level, because Lenz et al.16 have shown in vitro that HEK 293 cells, a human kidney cell line, are capable of increasing the production of URO on raising the sodium concentration in the perfusion medium. However, Emmeluth et al.5 have shown that an infusion of hypertonic saline into the cerebral circulation in a split-brain dog model increases the renal excretion of urodilatin despite an unchanged systemic sodium concentration and, most important, despite renal denervation, suggesting that the renal urodilatin system is additionally influenced by humoral factors.
We have recently shown that angiotensin II in vasoconstrictory concentrations is capable of decreasing UUROV in an isolated rat kidney model and that this effect is not attributable to vasoconstriction per se.11 The present cross-over study, with one protocol group (A) subjected to a period of supine positioning to increase thoracic blood volume, was thus designed to determine the levels of plasma renin activity and aldosterone in humans after a stimulus supposed to increase renal excretion of urodilatin.9 This assumption seems to be in contrast to our own observations, because we have observed a decrease in UUROV in water-loaded subjects during an increase in thoracic blood volume.8 However, subgroup analyses in these volunteers revealed that the decrease in UUROV was related to the increase in free-water clearance induced by water laoding and may hence be a physiologic response of a diuretic hormone on a marked increase in diuresis.17
Consequently, and based on observations made by Norsk et al.,9 we supposed stimulating UUROV by a combination of supine positioning and slow intravenous sodium loading. After this stimulation, comparisons between systemic hormones were performed in the sitting position to achieve comparable hemodynamics.
Our results show that the expected increase in UUROV in protocol group A was accompanied by a significantly lower plasma renin activity. Additionally, plasma levels of aldosterone had decreased significantly after supine positioning and tended to be lower (P = .06) during SIT-A in comparison with protocol B. No variations in endothelin-1 were observed. This suggests that the regulation of urodilatin excretion, also in humans, may be linked with the activity of the renin-angiotensin-aldosterone system.
Our findings during acute stimulation of the urodilatin system are in agreement with observations from Meyer et al.4 during long-term variations in nutritional sodium load. The authors studied the effects of three diets containing different amounts of sodium on UUROV and several hormones involved in the regulation of sodium and fluid homeostasis. Increased nutritional sodium induced an increase in UUROV that was accompanied by decreased plasma renin activity and urinary excretion of aldosterone.
Despite the comparisons that were made between protocol groups in the sitting position, to induce comparable hemodynamics and to rule out an immediate effect of positioning on the hormones of interest, arterial blood pressure was significantly higher during SIT-A than during SIT-B. With respect to our observations in the isolated kidney, showing increased UUROV upon an increase in renal perfusion pressure,6 and with respect to the fact that blood pressure variations are inversely related to the activity of the renin-angiotensin-aldosterone system, the higher UUROV and the lower plasma renin activity during SIT-1 may at least partially be explained by an increase in arterial blood pressure. Because digital arterial blood flow, baroreceptor sensitivity, and plasma noradrenaline were unchanged throughout the study, ruling out major alterations in peripheral hemodynamics, and ANP tended to be higher during SIT-A than during SIT-B, the increase in mean arterial blood pressue and pulse pressure was most likely attributable to an increase in thoracic blood volume during supine positioning that was maintained the sitting position.
In summary, we observed a decrease in plasma renin activity and a trend toward lower plasma aldosterone levels after acute stimulation of renal urodilatin excretion in healthy volunteers. Extending previous in vitro observations and in agreement with data from others during long-term stimulation of the urodilatin system, these findings suggest that the regulation of urodilatin excretion in humans may be linked with the activity of the renin-angiotensin-aldosterone system.
We gratefully acknowledge the help of Ernie Schmitzer (Deutsches Herzzentrum, Berlin, Germany) for performing the hormone analyses. We thank our institutional statistician for continuous support throughout the study.
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Table 1. Hormonal variations during different protocols designed to stimulate renal excretion of urodilatin
protocol A protocol B significance
Atrial natriuretic 28.2 ± 8.8 22.9 ± 10.9 17.3 ± 7.3
peptide (pg*1-1) *P = NS (.07) †P = .017
Aldosterone 0.21 ± 0.08 0.14 ± 0.07 0.21 ± 0.10
(nmol*1-1) *P = NS (.059) †P = .003
Plasma renin 1.25 ± 0.71 1.00 ± 0.52 1.44 ± 0.84
activity (ng*ml-1*h-1) *P = 0.016 †P = NS
Endothelin-1 20.5 ± 3.9 20.4 ± 3.3 17.2 ± 3.1
(pg*ml-1) *P = NS †P = NS
Noradrenaline 249 ± 144 303 ± 205 363 ± 173
(pg*ml-1) *P = NS †P = NS
Data are given as mean ± standard deviation. Plasma levels of hormones involved in the regulation of sodium and water homeostasis in nine healthy volunteers during different protocols. Protocol A was accompanied by an increase in renal excretion of urodilatin.
*denotes statistical differences between protocol A and B in the sitting position (SIT-A vs. SIT-B).
†denotes significant variations during protocol A. Student’s t-test for paired observations.
Figure 1. Renal excretion of urodilatin (UUROV) in healthy volunteers (n = 9) during baseline (U1) and during a period of supine positioning followed by the sitting body position (protocol A) and during sitting only (protocol B). Data are mean ± SEM. Paired t-test.
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