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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2001 May;51(5):415–421. doi: 10.1046/j.1365-2125.2001.01373.x

Dopamine D2-like receptors and amino acid-induced glomerular hyperfiltration in humans

Gerd Luippold 1, Swetlana Schneider 1, Andreea Stefanescu 1, Peter Benöhr 1, Bernd Mühlbauer 1
PMCID: PMC2014470  PMID: 11421998

Abstract

Aims

In rodents, blockade of dopamine D2-like receptors abolishes both the physiological increase in glomerular filtration rate (GFR) induced by amino acids and the pathological hyperfiltration in experimental diabetes mellitus. This study addressed the contribution of dopamine D2-like receptors to changes in renal haemodynamics after amino acid infusion in humans.

Methods

Twelve healthy volunteers participated in this double-blind, randomized, cross-over study. GFR and renal blood flow (RPF) were assessed by renal clearance of inulin and p-aminohippuric acid (PAH), respectively. Following infusion of 0.45% saline at baseline, an electrolyte-balanced solution of mixed amino acids (10%) was infused. Prior to the experiments, the subjects received orally either placebo, or sulpiride (10 mg kg−1), a centrally and peripherally acting D2-like receptor antagonist, or domperidone (1 mg kg−1) which affects only peripheral D2-like receptors.

Results

In the placebo series, amino acid infusion significantly increased GFR and RPF by up to 15.8 ± 5.3% and 14.4 ± 6.1%, respectively, while mean blood pressure and heart rate remained unchanged. Pretreatment with domperidone only marginally altered the renal response to amino acids (maximal increase by 13.2 ± 5.6 and 11.9 ± 4.0% in GFR and RPF, respectively), while sulpiride completely abolished the renal haemodynamic changes induced by amino acids. Total and fractional urinary sodium excretion as well as urinary osmolality were similar at baseline and increased in response to amino acids, to the same extent, in all series. No changes in renal dopamine excretion occurred.

Conclusion

The results indicate that in man dopamine D2-like receptors are involved in the renal haemodynamic response to amino acid infusion. Whether dopamine D2-like receptor blockade diminishes glomerular hyperfiltration in pathological states requires clinical investigations.

Keywords: amino acids, dopamine D2-like receptors, glomerular hyperfiltration

Introduction

Increased protein intake is associated with elevated renal blood flow and glomerular filtration rate (GFR). This haemodynamic response of the kidney has been observed both in experimental animals [1, 2] and humans [3–5] and can be mimicked by an intravenous infusion of amino acids [6, 7]. Numerous investigations have been performed to clarify the mechanisms by which an increased plasma concentration of amino acids affects renal haemodynamics. The involvement of various humoral signals, e.g. insulin, glucagon, and prostaglandins, but also the renin-angiotensin system as well as intrinsic renal regulative mechanisms such as the tubuloglomerular feedback and changes in tubular electrolyte reabsorption have been proposed [8]. However, the mechanisms of the amino acid-induced changes in renal function still have to be defined. The physiological phenomenon of an amino acid-stimulated increase in renal blood flow and GFR has considerable clinical significance since a reduction in dietary protein intake decreased, although inconsistently, the progression of chronic kidney failure, most likely via modulation of renal haemodynamics [9]. Thus, pharmacological modulators of glomerular hyperfiltration due to amino acids might be useful in the management of progressive glomerular sclerosis.

Since amino acids are the natural source of endogenous dopamine and since exogenous dopamine affects renal haemodynamics, this catecholamine may be involved in amino acid-induced hyperfiltration. This hypothesis has been supported by experiments in rats in which the blockade of peripheral dopamine synthesis abolished the GFR response to amino acid infusion [10]. In addition, animal studies employing pharmacological antagonists showed that dopamine D2-like receptors contribute significantly to the amino acid-induced hyperfiltration [11–13]. The present investigation was designed to examine the potential role of dopamine D2-like receptors in this renal response in humans. In a three-way crossover study in healthy volunteers, glomerular hyperfiltration was induced by infusion of amino acids either without drug administration or after a single oral dose of sulpiride [14], a centrally and peripherally acting D2-like receptor antagonist, or domperidone that preferentially affects peripheral D2-like receptors for reasons of its inability to cross the blood–brain barrier [15]. In addition to GFR measurements, renal plasma flow (RPF), total and fractional sodium excretion and dopamine release into the urine were observed.

Methods

Subjects

Twelve healthy volunteers (six male), age range 24–38 years (mean ± s.e.mean: 28 ± 2 years) were enrolled in the study. Mean body weight was 78.5 ± 4.7 kg and calculated body mass index 25.0 ± 1.1 kg m−2. All subjects consumed food and fluid ad libitum prior to participation in the study. No participant was taking any medication, and none had a medical history of renal, endocrine, or cardiovascular disease. Each subject passed a screening examination that included medical history, physical examination, 12-lead electrocardiogram and a complete laboratory investigation. The purpose, nature, and potential risks of the study were explained to all subjects, and written informed consent was obtained before participation. The study protocol was approved by the local Ethics Committee.

Study protocol

The investigation was designed as a placebo-controlled, double-blind cross-over study. Twelve hours before each study day participants were asked to refrain from food, alcohol and caffeine consumption. Subjects received, in random order, at 08.00 h on the study day, a single oral dose of either placebo, or the D2-like receptor antagonists domperidone (1 mg kg−1 body weight; Motilium®, Byk Gulden, Konstanz, Germany) or sulpiride (10 mg kg−1 body weight; Dogmatil forte®, Synthelabo Arzneimittel GmbH, Puchheim, Germany). Domperidone is a highly potent and selective inhibitor of peripheral D2-like receptors [16]. Sulpiride, the classical dopamine D2-like receptor antagonist, consists of two enantiomers. In comparison with (R)-sulpiride, the (S)-enantiomer is characterized by higher selectivity for D2-like receptors [17]. However, the (S)-enantiomer is not available for clinical use. Therefore, the racemate of sulpiride was used in the present study. Since the enantiomers are present in the racemate to equal extents, a predominant D2-like receptor blockade by sulpiride racemate can be assumed. The single doses of both D2-like receptor antagonists used in the present study correspond to the maximal daily dose recommended for chronic treatment. Sufficient plasma concentrations during the clearance experiments following the single dose application can be assumed from the pharmacokinetic data of sulpiride (tmax = 2–4 h; terminal t½ = 6–8 h) and domperidone (tmax = 1–2 h and terminal t½ = 14 h). Prior to each study day, volunteers collected urine for 24 h and answered a questionnaire by which fluid and protein intake was quantified. During this urine collection period subjects were required to maintain the composition and amount of their normal daily food consumption.

Glomerular filtration rate (GFR) and renal plasma flow (RPF) were assessed by renal clearance of inulin and para-aminohippurate (PAH), respectively. Indwelling catheters were inserted into a vein of both forearms for infusion and contralateral blood sampling. Subjects received a priming dose of 113 mg inulin (Inutest®, Fresenius Pharma Austria, Linz, Austria) and 15 mg PAH (Aminohippurate sodium®, Merck, West Point, PA, USA) both expressed per kg body weight dissolved in 250 ml glucose solution (5%) infused from 08.30 h to 09.00 h. Thereafter, inulin and PAH were continuously infused at a rate of 313 mg and 72 mg kg−1 body weight, respectively, dissolved in 500 ml glucose solution at a rate of 80 ml h−1 to achieve plasma concentrations of approximately 400–500 mg l−1 for inulin and 15–20 mg l−1 for PAH. During the equilibration period of 1 h an intravenous 0.45% saline solution was infused (4 ml kg−1 body weight h−1) to induce sufficient and continuous urinary flow. Additionally, the volunteers were advised to drink tap water at a rate of 1 ml kg−1 per 45 min. Urine was collected by spontaneous voiding, urine samples were obtained every 45 min and blood samples were drawn at the midpoint of each urine collection period. Following an equilibration period of 1 h two urine collection periods of 45 min duration with concomitant blood sampling were performed, the average of which represents baseline (BAS). Thereafter, the 0.45% saline infusion was switched to an electrolyte-balanced 10% mixed amino acid infusion (Aminosteril KE®, Fresenius, Bad Homburg, Germany) at an identical infusion rate. Thereafter, three 45 min urine collection periods were performed which represent the amino acid infusion periods AA I, AA II, and AA III. The composition of the standard amino acid solution (in g l−1) was: l-isoleucine 4.7, l-leucine 7.1, l-lysine 6.0, l-methionine 4.1, l-phenylalanine 4.8, l-threonine 4.2, l-tryptophan 1.8, l-valine 5.9, arginine 10.6, l-histidine 2.9, aminoacetic acid 15.9, l-alanine 15.0, l-proline 15.0.

Analytical methods

In samples of 24 h urine, osmolality, sodium, dopamine and creatinine concentrations were determined. Degradation of dopamine was prevented by addition of 150 ml citrate-buffer (pH = 2.6) prior to the collecting periods. Aliquots of urine obtained from clearance experiments were placed in separate containers for measurement of sodium/osmolality, inulin/PAH and dopamine. The samples for the dopamine assay contained a citrate-buffer (pH = 2.6) and were frozen immediately at −80 °C until analysis. All other urine samples as well as serum samples, obtained by immediate centrifugation of blood samples at 4 °C, were kept frozen at −20 °C until determination of electrolytes, osmolality, inulin, and PAH.

Sodium was determined by flame photometry (ELEX 6361®, Eppendorf, Hamburg, Germany) and creatinine was measured photometrically using the Jaffé-reaction (Creatinine Analyser®, Beckman, Fullerton, CA, USA). Osmolality in urine was determined by using the freezing-point technique (Osmomat 030®, Gonotec, Berlin, Germany). Serum and urine concentrations of inulin and PAH were measured by colorimetric methods. Dopamine was analysed by high performance liquid chromatography (h.p.l.c.) with electrochemical detection (Sykam, Gilching, Germany) as previously described [12]. In brief, dihydroxybenzylamine was added to the urine sample as internal standard (ISTD). After adjustment to pH 8.6, neutral alumina oxide was added. Following this adsorption step, the samples were washed twice with bidistilled water and finally eluted with phosphoric acid. The eluate was applied onto the reversed phase h.p.l.c. system. The mobile phase consisted of a citrate-buffer, sodium salt of octane sulphonic acid, methanol and acetonitrile in bidistilled water. ISTD-corrected recovery of dopamine added to the urine averaged 96–104%.

Data analysis

Filtration fraction and fractional urinary excretion of sodium were determined by standard equations. The average of the two baseline periods was taken as the baseline value. Analysis of variance (anova) with Bonferroni's multiple comparisons test was performed to compare baseline with the experimental periods (amino acid infusion) in the same experiment and the baseline values between the three series. The confidence intervals (CI) for the differences of GFR and RPF to baseline were calculated. Results are expressed as mean±s.e. mean P values < 0.05 were considered to be statistically significant.

Results

24 h urine collection

The data of the 24 h urine collection prior to the clearance experiments showed no significant differences when comparing placebo, sulpiride, and domperidone series with respect to urinary flow rate, urine osmolality, sodium as well as dopamine excretion and creatinine clearance (Table 1). Likewise, 24 h protein intake and fluid consumption were not significantly different between the three series (Table 1) indicating similar basal conditions.

Table 1.

Analysis of 24 h urine and of questionnaire.

Series Placebo Sulpiride Domperidone
Fluid intake (ml 24 h−1) 2018 ± 172 1682 ± 165 1635 ± 165
Protein intake (g 24 h−1) 78 ± 11 77 ± 10 73 ± 8
Creatinine clearance (ml min−1 1.73 m−2) 109.0 ± 8.7 118.5 ± 10.9 111.9 ± 7.5
Urinary flow rate (ml 24 h−1) 1848 ± 213 1423 ± 232 1397 ± 208
Urinary osmolality (mosmol kg−1 water) 701 ± 48 741 ± 66 717 ± 67
Urinary sodium excretion (mmol 24 h−1) 206.1 ± 21.2 169.2 ± 16.4 184.1 ± 16.2
Urinary dopamine excretion (µg 24 h−1) 357.3 ± 36.2 401.5 ± 23.5 356.3 ± 36.0
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Values are expressed as mean ± s.e.mean. Note that prior to the three study days urine was collected and food as well as fluid intake was quantified for 24 h. *P < 0.05, vs placebo.

Blood pressure and heart rate

On the study days mean blood pressure in basal clearance periods averaged 85 ± 3 mmHg in the placebo, 80 ± 3 mmHg in the sulpiride, and 81 ± 3 mmHg in the domperidone series, while heart rate was 64 ± 2, 65 ± 3, and 61 ± 3 beats min−1, respectively. In addition, no significant changes from baseline were observed in blood pressure or heart rate during infusion of amino acids in either of the three series.

Renal haemodynamics

In the three series, GFR and RPF were not significantly different at baseline (Table 2). In the placebo series, a significant rise in GFR by up to 15.8 ± 5.3% (95% CI: 4.1, 27.4%; Figure 1) was observed during infusion of amino acids which was associated by a rise in RPF with a maximal increase of 14.4 ± 6.1% (95% CI: 1.0, 27.8%; Figure 2). In contrast, acute administration of sulpiride completely abolished this amino acid-induced rise in GFR and RPF in period AA I (GFR 95% CI: −13.5, 5.5%; RPF 95% CI: −9.8, 3.8%) and period AA II (GFR 95% CI: −15.1, 10.5%; RPF 95% CI: −10.5, 10.7%). In period AA III, only a slight but not significant increase in GFR and RPF was found (Figures 1 and 2). Following domperidone pretreatment, a similar renal haemodynamic response to infusion of amino acids was observed when compared with placebo, even though the effect was somewhat diminished: GFR rose by 11.1 ± 3.8, 12.5 ± 6.9, and 13.2 ± 5.6% (95% CI: 0.9, 25.5%) and RPF by 5.4 ± 4.6, 11.2 ± 3.0, and 11.9 ± 4.0% (95% CI: 3.1, 20.7%) during periods AA I, AA II, and AA III, respectively (Figures 1 and 2). Filtration fraction remained almost constant with 16.5 ± 0.7% at baseline and averaged 17.3 ± 1.0% in the experimental periods (Table 2). The administration of the D2-like receptor antagonists sulpiride or domperidone did not alter basal filtration fraction as compared with placebo (17.9 ± 1.3 and 17.5 ± 0.8%, respectively), similarly the infusion of amino acids in both series did not significantly change filtration fraction (Table 2).

Table 2.

Results of urinary measurements in clearance experiments.

Periods Placebo Sulpiride Domperidone
Glomerular filtration rate (ml min−1 1.73 m2) BAS 92.2 ± 3.7 99.4 ± 5.7 92.9 ± 5.4
AA I 104.9 ± 5.1* 94.6 ± 5.5 102.3 ± 3.6*
AA II 105.2 ± 6.8* 96.3 ± 7.6 102.8 ± 7.0*
AA III 106.7 ± 5.2* 100.5 ± 7.6 102.3 ± 3.4*
Renal plasma flow(ml min−1 1.73 m2) BAS 560.9 ± 28.9 562.8 ± 24.5 540.4 ± 31.7
AA I 620.9 ± 33.0* 541.3 ± 25.3 573.3 ± 43.6
AA II 604.5 ± 26.9 574.3 ± 22.7 613.2 ± 32.6*
AA III 636.4 ± 28.6* 592.3 ± 26.7 612.2 ± 25.0*
Filtration fraction(%) BAS 16.5 ± 0.7 17.9 ± 1.3 17.5 ± 0.8
AA I 16.9 ± 1.2 17.9 ± 1.2 18.6 ± 1.3
AA II 17.8 ± 1.3 17.5 ± 1.7 17.8 ± 1.2
AA III 17.2 ± 1.1 16.5 ± 1.2 17.3 ± 0.8
Urinary flow rate(ml min−1) BAS 12.5 ± 1.6 11.3 ± 1.8 10.4 ± 1.3
AA I 12.8 ± 1.0 8.7 ± 1.0 10.8 ± 1.1
AA II 9.1 ± 1.0 8.4 ± 1.0 10.1 ± 1.3
AA III 10.1 ± 0.9 9.9 ± 1.4 9.8 ± 1.2
Urine osmolality(mosmol kg−1 water) BAS 138 ± 13 166 ± 28 161 ± 21
AA I 136 ± 17 207 ± 24 183 ± 24
AA II 282 ± 40* 278 ± 28* 273 ± 22*
AA III 310 ± 42* 317 ± 42* 324 ± 42*
Urinary sodium excretion (µmol min−1) BAS 254 ± 46 279 ± 49 242 ± 35
AA I 267 ± 46 292 ± 43 304 ± 40
AA II 352 ± 47* 363 ± 55* 410 ± 52*
AA III 371 ± 39* 410 ± 50* 441 ± 50*
Fractional sodium excretion (%) BAS 1.9 ± 0.3 1.9 ± 0.3 1.8 ± 0.3
AA I 1.9 ± 0.3 1.8 ± 0.3 2.0 ± 0.3
AA II 2.4 ± 0.4 2.5 ± 0.3* 2.8 ± 0.5*
AA III 2.9 ± 0.5* 3.1 ± 0.4* 3.3 ± 0.6*
Urinary dopamine excretion (ng min−1) BAS 401 ± 29 407 ± 29 403 ± 48
AA I 417 ± 44 392 ± 44 443 ± 68
AA II 365 ± 35 352 ± 29 367 ± 48
AA III 343 ± 44 371 ± 22 370 ± 57
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Values are expressed as mean ± s.e.mean. BAS, basal period (0.45% saline infusion); AA, amino acid infusion (period I, II and III).

*

P < 0.05, vs BAS.

Figure 1.

Figure 1

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Effect of a single oral dose of placebo (solid squares), domperidone (open squares), or sulpiride (open circles) on the glomerular filtration rate (GFR) response to amino acid (AA) infusion in 12 healthy volunteers, expressed as percentage change (± s.e.mean) from baseline (BAS).* P < 0.05 vs baseline.

Figure 2.

Figure 2

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Effect of a single oral dose of placebo (solid squares), domperidone (open squares), or sulpiride (open circles) on the renal plasma flow (RPF) response to amino acid (AA) infusion in 12 healthy volunteers, expressed as percentage change (± s.e.mean) from baseline (BAS).* P < 0.05 vs baseline.

Urinary measurements

Basal urinary flow rate was similar in the three series. During infusion of amino acids, urinary flow rate remained constant in the domperidone series and was slightly but not significantly decreased in both the placebo and the sulpiride series (Table 2). Basal urinary output of sodium was similar in the three series and was significantly increased after amino acid infusion in period AA II and AA III by approximately 30–40% independent of pretreatment. In the three series mean fractional sodium excretion at baseline did not differ (range 1.8 ± 0.3–1.9 ± 0.3%) and was significantly enhanced by amino acids (Table 2). Urinary dopamine excretion at baseline showed no differences when comparing placebo, sulpiride, and domperidone series and did not significantly change during infusion of amino acids (Table 2). Urine osmolality in the three series was similar at baseline and significantly enhanced after amino acids, by approximately 50%, in period AA II and AA III (Table 2).

Discussion

It has been clearly documented that, in healthy subjects, both GFR and RPF increase by 10–20% following an infusion of amino acids [18–20]. Giordano et al. [21] showed, by administering a solution of 10% mixed amino acids at different infusion rates, a dose-dependent response of renal haemodynamics in humans. Compared with previous studies employing similar doses of amino acids, the present investigation demonstrated a quantitatively identical increase in GFR and RPF.

The mechanism underlying the amino acid-induced changes in renal haemodynamics is not completely understood. It is also unclear whether single or groups of amino acids may account for the changes in renal haemodynamics. In dogs, gluconeogenetic amino acids induced a significant rise in creatinine clearance, while an attenuated response was observed with dicarboxylic amino acids or valine [22]. In addition, in anaesthetized dogs infusion of the amino acids serine, alanine, and proline elevated renal blood flow and GFR to a similar extent [23]. In contrast, Claris-Appiani et al. [24] failed to observe alterations in the renal response to intravenous administration of branched-chain amino acids in humans. No single amino acid has been identified to be mainly responsible for the amino acid-induced glomerular hyperfiltration. In the present study amino acid infusion was used as a model for the physiological rise in GFR and RPF following an oral protein load [25] and thus a solution of mixed amino acids was employed.

In the kidney, dopamine is generated in the proximal tubular cells by decarboxylation of its precursor l-3,4-dihydroxyphenylalanine (L-DOPA) [26] which, in turn, derives from the amino acids l-phenylalanine and l-tyrosine [27]. Thus, considering the known renal effects of exogenous dopamine, the concept that the amino acid-induced glomerular hyperfiltration might result from an enhanced intrarenal dopamine synthesis appears to be an attractive hypothesis. This is supported by the observation that urinary dopamine excretion is increased in humans following an acute protein load [28]. Elevated renal dopamine excretion has been reported also in rats following oral [29, 30] or intraperitoneal [31] l-tyrosine administration. However, more recent experiments in rats questionned the idea that renal dopamine excretion and haemodynamics were functionally associated. In these studies, infusion of amino acids containing l-tyrosine increased both GFR and renal dopamine excretion while the same solution without l-tyrosine increased GFR but not urinary dopamine output; conversely, the infusion of l-tyrosine alone increased renal dopamine excretion but not GFR [12]. In the present study urinary output of dopamine was not significantly altered during infusion of amino acids. Since the content of dopamine precursors in the amino acid solution was not varied this observation cannot be directly compared with the former study in rats [12]. In addition, the dose of dopamine precursors administered might have been insufficient to increase the tubular dopamine release above the basal excretion rate. Taken together, the absence of changes in urinary dopamine release in spite of significant variations in GFR supports the view that renal dopamine excretion is not functionally linked to changes in renal haemodynamics.

In contrast with this obvious dissociation, the present experiments suggest dopaminergic mechanisms to be involved in the amino acid-induced glomerular hyperfiltration, most likely via activation of D2-like receptors. Interestingly, domperidone only slightly reduced while sulpiride completely abolished the amino acid-stimulated increase in GFR and RPF. This corresponds to previous experiments in anaesthetized rats [13] in which glomerular hyperfiltration due to amino acids was partly attenuated by domperidone and completely abolished by (S)-sulpiride. Since, in those experiments, even 5-fold higher doses of domperidone failed to further influence hyperfiltration, we assumed the different pharmacokinetic and pharmacodynamic profiles of domperidone and sulpiride to be the cause for the different modulation of the amino acid-induced hyperfiltration. Firstly, sulpiride is an inhibitor of D2-like receptors both in the CNS and the periphery, while domperidone does not cross the blood–brain barrier. Secondly, in binding studies domperidone showed a higher D2 over D3 selectivity as compared with sulpiride [32]. This might indicate that both central and peripheral effects of dopamine contribute to the renal haemodynamic changes induced by amino acids, or that other dopamine receptor subtypes, e.g. D3 receptors, might be involved. For safety reasons, no higher dose of domperidone could be used in the present clinical investigation. Therefore, the data cannot clarify whether the less pronounced effect of domperidone on renal haemodynamics resulted from an insufficient dose to completely block D2-like receptors or is due to the pharmacokinetic and pharmacodynamic differences of domperidone compared with sulpiride.

Since numerous amino acids undergo reabsorption in the proximal tubules by sodium-coupled transport it was proposed that the amino acid-induced hyperfiltration might be influenced by the tubuloglomerular feedback mechanism, in that increased tubular amino acid reabsorption might decrease the sodium load at the macula densa [8]. According to this hypothesis a decrease in sodium excretion during amino acid-induced hyperfiltration rather than an increase would be expected. However, in the present investigation renal sodium excretion was enhanced by infusion of amino acids corresponding to previous observations [10, 33, 34]. In addition, the amino acid-induced increase in renal sodium excretion was almost identical in the three experimental series in spite of the significant differences in the renal haemodynamic response. These data do not support the idea that the tubuloglomerular feedback mechanism is crucially involved in the amino acid-stimulated hyperfiltration. However, the present experiments were characterized by a continuously high urinary flow rate. Therefore it cannot be excluded that, under other experimental conditions, observations on renal sodium excretion during amino acid infusion might differ.

Pathological hyperfiltration contributes to the progression of diabetic nephropathy [35]. Recently, in a rat model of diabetic nephropathy, D2-like receptor antagonists have been demonstrated to completely abolish hyperfiltration [36]. Thus, the demonstrated functional role of dopamine D2-like receptors in the regulation of renal haemodynamics in humans offers hope that dopamine D2-like receptor blockade might be a new therapeutic concept for states of pathological glomerular hyperfiltration.

In summary, the data of the present investigation show that the previous observation in animals, that dopamine D2-like receptors contribute to the amino acid-induced renal haemodynamic changes, could be extended to humans. To what extent central and peripheral mechanisms are involved remains to be clarified. In addition, whether dopamine D2-like receptor antagonists will exert renoprotective effects in patients suffering from chronic renal disease must be addressed by clinical investigations.

Acknowledgments

The study was supported by the BMBF (Grant no. 01EC9405) and the IZKF Tübingen (Grant no. 01KS9602). G.L. is a fellow of the Deutsche Forschungsgemeinschaft (DFG-Grant Mu 1297/1–2).

The authors gratefully acknowledge the excellent technical assistance of Christine Piesch.

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