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J Am Soc Nephrol 11:1002-1007, 2000
© 2000 American Society of Nephrology

REGULAR ARTICLES

Effect of Serotonin Receptor Antagonist on Phosphate Excretion

JENNIFER M. GROSS, THERESA J. BERNDT and FRANKLYN G. KNOX

Departments of Medicine and Physiology and Biophysics, Mayo Clinic and Mayo Foundation, Rochester, Minnesota.

Correspondence to Dr. Franklyn G. Knox, Departments of Medicine and Physiology & Biophysics, Mayo Clinic and Foundation, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-2908; Fax: 507-266-4710; E-mail: knox.franklyn{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Abstract. To determine whether endogenous intrarenal 5-hydroxytryptamine affects phosphate excretion, the serotonin receptor antagonist methiothepin (20 µg/kg, +6 µg/kg per h) was infused into the renal interstitium of rats fed a normal phosphate diet (0.7% phosphate [Pi]) in the presence of endogenous parathyroid hormone (PTH). Renal interstitial infusion of methiothepin significantly increased fractional phosphate excretion (FEPi) from 23 ± 4 to 30 ± 4% (n = 8, P < 0.05). To determine whether serotonin modulates the phosphaturic response to PTH during conditions of dietary phosphate excess or deprivation, rats were fed either a high (1.8% Pi, HPD) or low (0.07% Pi, LPD) phosphate diet, and methiothepin (100 µg/kg, +30 µg/kg per h) or saline vehicle was infused intravenously before and during PTH infusion (33 U/kg, +1 U/kg per min). Methiothepin infusion significantly increased FEPi in thyroparathyroidectomized rats fed a HPD from 25 ± 4 to 32 ± 4% (n = 9, P < 0.05), and the subsequent administration of PTH further increased the FEPi to 64 ± 3% (P < 0.05). The increase in FEPi during PTH infusion was similar in the absence ({Delta}27 ± 5%, n = 7) and presence ({Delta}33 ± 6%) of methiothepin, P > 0.05. In thyroparathyroidectomized rats fed a LPD, methiothepin infusion did not increase phosphate excretion (0.8 ± 0.4 to 1.3 ± 0.9%, n = 7, P > 0.05). However, the increase in FEPi during PTH infusion was significantly greater in the presence of methiothepin (1.3 ± 0.9 to 20.0 ± 4.0%, {Delta}18.7 ± 3.5%) than in the vehicle-infused rats (0.5 ± 0.2 to 8.8 ± 1.1%, {Delta}8.3 ± 1.2%; n = 8, P < 0.05). In conclusion, these observations suggest that endogenous intrarenal serotonin enhances phosphate reabsorption in phosphate-replete rats, and attenuates the phosphaturic response to PTH in phosphate-deprived rats.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Serotonin is synthesized by the decarboxylation of 5-hydroxytryptophan to 5-hydroxytryptamine (serotonin, 5-HT), a process catalyzed by L-aromatic amino acid decarboxylase (1). In the kidney, L-aromatic amino acid decarboxylase activity has been localized to the proximal tubule (2,3), the primary nephron site of phosphate reabsorption.

In vitro studies using opossum kidney cells, a proximal tubule epithelial cell line, have suggested that serotonin synthesized by proximal tubule cells acts as a paracrine/autocrine modulator of phosphate (Pi) transport which stimulates sodium-dependent phosphate transport (4). In these studies, incubation of cultured opossum kidney cells, which express 5-HT1B receptors (5,6), with 5-hydroxytryptophan results in a time- and substrate-dependent accumulation of 5-HT. Furthermore, these studies showed that incubation of opossum kidney cells with 5-HT or 5-hydroxytryptophan stimulated sodium-dependent phosphate cotransport (4). These in vitro studies demonstrate that proximal tubule cells are able to synthesize 5-HT, and that 5-HT in turn stimulates Pi transport.

Parathyroid hormone (PTH) inhibits phosphate reabsorption in the proximal tubule and increases phosphate excretion. A study performed in opossum kidney cells reported that 5-HT blunted the PTH-induced increase in cAMP accumulation and attenuated the PTH-induced inhibition of sodium-dependent phosphate uptake (7), suggesting an interaction between PTH and 5-HT in the regulation of Pi reabsorption. Phosphate deprivation results in an attenuated phosphaturic effect of PTH by mechanisms not fully understood. Because in vitro studies have shown that 5-HT attenuates the inhibitory effect of PTH on Pi transport, it is possible that serotonin may contribute to the attenuated effect of PTH during phosphate deprivation.

Methiothepin is a nonselective 5-HT receptor antagonist that was previously reported to blunt the 5-HT1B-mediated inhibition of forskolin-induced cAMP formation in opossum kidney cells and in rat renal mesangial cells (8,9), and completely blocks the serotonin-induced increase in phosphate uptake in HeLa cells transfected with the human 5-HT1A receptor (10). In the present study, methiothepin was infused into the renal interstitium of rats fed a normal phosphate diet in the presence of endogenous PTH to determine whether endogenous intrarenal serotonin affects phosphate excretion. Furthermore, methiothepin was infused intravenously in conditions of dietary phosphate excess and deprivation in the presence and absence of PTH to determine whether serotonin modulates the phosphaturic response to PTH.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Group 1: Effect of Intrarenal Infusion of Methiothepin on Phosphate Excretion in Rats with Intact Parathyroid Glands Fed a Normal Phosphate Diet (n = 8)
All experiments were carried out according to the NIH Guidelines of the Institutional Animal Care and Use Committee of the Mayo Foundation. For infusion of methiothepin directly into the kidney to block intrarenal serotonin receptors, polyethylene matrixes were chronically implanted in the left kidney of male Sprague Dawley rats, as described previously (11), so that methiothepin could be preferentially delivered into the renal interstitium. Previous studies have demonstrated that infusion into the interstitium allows for distribution of the compound throughout the renal interstitium (11). After the matrix implantation surgery, the rats were allowed to recover for at least 4 wk. The animals were fed normal rat chow (0.7% Pi) before the acute experiment.

On the day of the acute experiment, rats (434 ± 24 g body wt) with implanted matrixes were anesthetized with an intraperitoneal injection (100 mg/kg body wt) of Inactin (Byk-Gulden, Konstanz, Germany) and were placed on a heated table to maintain temperature at approximately 37°C. After tracheostomy, a polyethylene (PE-50) catheter was inserted into the jugular vein for infusion, and in the carotid artery for arterial blood sampling and the monitoring of mean arterial pressure. A PE-10 catheter was placed in the ureter of the left kidney for urine collection. All animals received two separate intravenous infusions: 0.9% NaCl and 2% inulin in 0.9% NaCl. The infusion rate was 3 ml/h for each of these infusions (approximately 1.4% body wt). In addition, 0.9% NaCl was infused into the chronically implanted matrix at a rate of 10 µl/min. Two hours after completion of the surgical procedures, a 30-min control clearance was taken with a blood sample taken at midpoint. Then, the serotonin receptor antagonist methiothepin was administered (20 µg/kg, +6 µg/kg per h) into the renal interstitium. After a 30-min stabilization period, a final 30-min clearance was taken.

Group 2: Effect of Methiothepin and PTH Infusion on Phosphate Excretion in Thyroparathyroidectomized Rats Fed a High Phosphate Diet (n = 9)
Before the clearance experiment, the rats (300 to 400 g) were fed 12 g/d of high phosphate diet (HPD) (1.8% Pi) for 2 d. A commercially available diet (ICN Pharmaceuticals, Cleveland, OH) containing 0.07% phosphate was supplemented with a mixture of sodium and potassium phosphate (ratio of monobasic to dibasic salts was 1:4) to a final content of 1.8% Pi. Food consumption was confirmed daily. Animals that did not consume all of the diet were not included in the study.

The surgical procedures were the same as in group 1 except that the rats were thyroparathyroidectomized (TPTX) by heat cautery, and a PE-90 catheter was placed in the bladder for collection of urine samples. The animals received two separate intravenous infusions: normal saline (0.9% NaCl) and 2% inulin in 0.9% saline. The infusion rate was 2.5 ml/h for each of these infusions (approximately 1.4% body wt).

Two hours after the initiation of the infusions, a 30-min control clearance was taken. Then, the serotonin receptor antagonist methiothepin was administered (100 µg/kg, +30 µg/kg per h) intravenously. After a 30-min stabilization period, a second clearance was started. Subsequently, PTH was given as a bolus (33 U/kg) and was administered intravenously (1 U/kg per min) in the presence of methiothepin. After a 30-min stabilization period, a third clearance was taken. At the conclusion of the experiment in six rats, an intravenous 5-HT bolus (100 µg/kg) was given to determine efficacy of 5-HT receptor blockade, and a 5-min clearance was then taken.

Group 3: Effect of Vehicle and PTH Infusion on Phosphate Excretion in TPTX Rats Fed a HPD (n = 7)
This protocol is a time control for group 2 and is identical to group 2 except that 0.9% NaCl was infused instead of methiothepin. At the conclusion of the experiment in two rats, an intravenous 5-HT bolus (100 µg/kg) was administered, and a 5-min clearance was then taken.

Group 4: Effect of Methiothepin and PTH Infusion on Phosphate Excretion in TPTX Rats Fed a Low Phosphate Diet (n = 7)
This protocol is identical to group 2 except that the rats were fed a low phosphate diet (LPD). Before the experiment, the rats were fed 12 g/d of LPD (0.07% Pi) for 3 d. Sodium and potassium were supplemented in the diet to achieve the same concentrations as in the HPD. At the conclusion of the experiment, an intravenous 5-HT bolus (100 µg/kg) was given to determine efficacy of 5-HT receptor blockade, and then a 5-min clearance was taken. Urine samples were collected from six animals on ice and frozen at -30°C for later determination of cAMP.

Group 5: Effect of Vehicle and PTH Infusion on Phosphate Excretion in TPTX Rats Fed a LPD (n = 8)
This protocol is a time control for group 4 and is identical to group 4 except that 0.9% NaCl was infused instead of methiothepin. At the conclusion of the experiment, an intravenous 5-HT bolus (100 µg/kg) was administered, and then a 5-min clearance was taken. Urine samples were collected from seven animals on ice and frozen at -30°C for later determination of cAMP.

Analytical Procedures
GFR was determined from the clearance of inulin. Inulin concentrations in plasma and urine were determined by the anthrone method (12). Phosphate concentrations in urine and plasma were determined by the Chen method (13). Sodium concentrations in plasma and urine were measured by flame photometry (Instrumentation Laboratory, Wilmington, MA). cAMP concentrations in urine were determined by a cAMP enzyme immunoassay kit (Amersham Pharmacia Biotech, Piscataway, NJ).

Statistical Analyses
Results are expressed as mean ± SEM. Significance of changes within groups was evaluated using a paired t test, and an unpaired t test was used for statistical comparisons between groups. Statistical significance was defined as P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Renal interstitial infusion of methiothepin in rats fed a normal phosphate diet in the presence of endogenous PTH increased fractional excretion of phosphate (FEPi) from 23 ± 4 to 30 ± 4% ({Delta}7 ± 2%, P < 0.05). Urine flow rate and fractional excretion of sodium (FENa) were also increased after renal interstitial infusion of methiothepin from 12 ± 2 to 19 ± 4 µl/min and from 0.3 ± 0.1 to 0.6 ± 0.2%, respectively (P < 0.05). GFR (2.0 ± 0.2 to 2.2 ± 0.2 ml/min) and mean arterial pressure (MAP) (145 ± 5 to 139 ± 4 mmHg) remained stable throughout the experiment.

The effect of methiothepin and PTH infusion on clearance parameters in TPTX rats fed a HPD and a LPD are summarized in Tables 1 and 2, respectively, and in Figure 1. Methiothepin infusion increased the FEPi in rats fed a HPD, from 25 ± 4 to 32 ± 4% ({Delta}7 ± 2%, P < 0.05), while the FEPi was stable in the vehicle-infused control group fed a HPD (23 ± 4 to 24 ± 3%, {Delta}1 ± 1%). In the vehicle-infused control group fed a HPD, PTH infusion increased the FEPi from 24 ± 3 to 51 ± 5% ({Delta}27 ± 5%, P < 0.05). The administration of PTH in the presence of methiothepin increased the FEPi in rats fed a HPD from 32 ± 4 to 64 ± 3% ({Delta}33 ± 6%, P < 0.05). Although the phosphaturic response to PTH tended to be greater in rats administered methiothepin ({Delta}33 ± 6%) compared with vehicle-infused rats ({Delta}27 ± 5%), the changes were not significantly different from each other (P > 0.05). However, the maximal phosphate excretion following PTH administration in rats fed a HPD was greater in the presence of methiothepin (64 ± 3%) compared to vehicle-infused control animals administered a PTH infusion alone (51 ± 5%; P < 0.05).


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  		Table 1. Effect of methiothepin and PTH on clearance parameters in TPTX rats fed a high phosphate dieta
 

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  		Table 2. Effect of methiothepin and PTH on clearance parameters in TPTX rats fed a low phosphate dieta
 


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  		Figure 1. The effect of infusion of the serotonin receptor antagonist methiothepin (METH) or vehicle and parathyroid hormone (PTH) on the increase in fractional excretion of phosphate ({Delta}FEPi) in thyroparathyroidectomized rats fed a high phosphate diet (HPD) (Panel A) or a low phosphate diet (LPD) (Panel B). *, significant increase, P < 0.05, paired t test. {delta}, significant difference between methiothepin-infused rats and control rats after PTH administration, P < 0.05, unpaired t test.

 

In rats fed a LPD, the FEPi was stable in the vehicle-infused control group (0.5 ± 0.2 to 0.5 ± 0.2%, {Delta}0.1 ± 0.1%) and did not change in the presence of methiothepin infusion (FEPi 0.8 ± 0.4 to 1.3 ± 0.9%, {Delta}0.6 ± 0.8%). In the vehicle-infused group fed a LPD, subsequent PTH infusion increased the FEPi from 0.5 ± 0.2 to 8.8 ± 1.1% ({Delta}8.3 ± 1.2%, P < 0.05). The administration of PTH in the presence of methiothepin increased the FEPi in rats fed a LPD from 1.3 ± 0.9 to 20.0 ± 4.0% ({Delta}18.7 ± 3.5%, P < 0.05). The combined administration of methiothepin and PTH enhanced the phosphaturic response to PTH in rats fed a LPD because the change in FEPi was significantly greater in the methiothepin-infused rats ({Delta}18.7 ± 3.5%) than in the vehicle-infused rats ({Delta}8.3 ± 1.2%; P < 0.05).

In rats fed a LPD, methiothepin infusion did not affect cAMP excretion (38 ± 3 to 33 ± 3 pmol/ml · GFR) and was not significantly different from the vehicle-infused rats (36 ± 3 to 31 ± 5 pmol/ml · GFR). PTH infusion significantly increased cAMP excretion from 31 ± 5 to 184 ± 19 pmol/ml · GFR ({Delta}153 ± 19 pmol/ml · GFR, P < 0.05) in vehicle-infused rats, and from 33 ± 3 to 230 ± 9 pmol/ml · GFR ({Delta}197 ± 8 pmol/ml · GFR, P < 0.05) in methiothepin-infused rats. The increase in cAMP excretion following PTH administration tended to be greater in the presence of methiothepin ({Delta}197 ± 8 pmol/ml · GFR) compared to vehicle ({Delta}153 ± 19 pmol/ml · GFR; P = 0.07).

Methiothepin infusion significantly decreased MAP in rats fed a HPD and in rats fed a LPD, but the GFR did not change in either group. In addition, in rats fed a HPD, methiothepin infusion decreased the FENa from 2.4 ± 0.3 to 0.6 ± 0.2% (P < 0.05) and the urine flow rate from 39 ± 9 to 14 ± 2 µl/min (P < 0.05).

In the vehicle-infused control groups, the GFR and FENa remained stable throughout the experiment. In rats fed a HPD, urine flow rate decreased after PTH administration (P < 0.05). In rats fed a LPD, MAP and urine flow rate decreased after PTH administration (P < 0.05).

An exogenous serotonin bolus (100 µg/kg) was infused at the conclusion of the clearance experiments to confirm the effectiveness of serotonin receptor blockade. The infusion of exogenous serotonin into the systemic circulation of the rat causes a reduction in renal blood flow and GFR (14,15). Because the response elicited by the 5-HT bolus was the same in rats fed a HPD and a LPD, these data were combined. The 5-HT bolus decreased the GFR in vehicle-infused rats from 2.4 ± 0.2 to 1.3 ± 0.2ml/min (n = 9, P < 0.05). In contrast, in the presence of methiothepin, GFR was not altered following the 5-HT bolus (2.6 ± 0.2 to 3.1 ± 0.5 ml/min, n = 12). Thus, the dose of methiothepin used in the present study was effective in blocking the effects of exogenous serotonin, and presumably was adequate to block the effects of endogenous serotonin on the renal tubules.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The present study demonstrates that the renal interstitial infusion of the serotonin receptor antagonist methiothepin significantly increased phosphate excretion in rats fed a normal phosphate diet in the presence of endogenous PTH. Likewise, the intravenous infusion of methiothepin increased phosphate excretion in TPTX rats fed a HPD. The increases in phosphate excretion after infusion of methiothepin into the renal interstitium or the systemic circulation support the contention that the effect of methiothepin infusion on phosphate excretion is due to blockade of serotonin receptors in the kidney. Previous studies in opossum kidney cells demonstrated that serotonin selectively stimulates phosphate transport because sodium-dependent transport of alanine or glucose was unchanged (4,7). Furthermore, studies performed in HeLa cell lines transfected with the human 5-HT1A receptor demonstrated that the addition of serotonin enhanced sodium-dependent uptake, and this effect was completely blocked by methiothepin (10). A previous in vivo study has shown that intravenous infusion of 5-hydroxytryptophan decreased fractional phosphate excretion in rats (7). Taken together, these results provide evidence that endogenous intrarenal serotonin enhances phosphate reabsorption in vivo. The observation that methiothepin infusion did not increase phosphate excretion in TPTX rats fed a LPD suggests that stimulation of phosphate transport by serotonin is not the primary mechanism responsible for the markedly enhanced phosphate reabsorption observed during conditions of phosphate deprivation.

PTH inhibits phosphate reabsorption by the proximal tubule and increases phosphate excretion. Rats fed a LPD conserve phosphate and exhibit an attenuated phosphaturic effect to PTH (15,16,17,18). Similarly, in the present study, the phosphaturic response to PTH was significantly blunted in rats fed a LPD compared with rats fed a HPD. Infusion of the serotonin receptor antagonist methiothepin significantly enhanced the phosphaturic response to PTH in rats fed a LPD. Furthermore, the increase in excretion of cAMP following PTH administration tended to be greater in the presence of methiothepin. These results suggest that in vivo serotonin attenuates the inhibition of Pi reabsorption by PTH, at least in part, by attenuating cAMP generation. These observations are consistent with in vitro results demonstrating that exogenous administration of serotonin blunted PTH-induced cAMP accumulation and attenuated the inhibition of sodium-dependent phosphate uptake by PTH in cultured opossum kidney cells (7).

In rats fed a HPD, the phosphaturic effect of blockade of serotonin receptors by methiothepin infusion was additive to the phosphaturic effect elicited by PTH (FEPi 64 ± 3 versus 51 ± 5%, P < 0.05). However, when the effect of methiothepin on baseline phosphate excretion is taken into consideration, methiothepin did not significantly enhance the phosphaturic response to PTH in rats fed a HPD (FEPi {Delta}33 ± 6 versus 27 ± 5%). It is interesting to consider these results in the context of the antagonistic relationship between serotonin and dopamine as modulators of phosphate transport in the proximal tubule (4). Previous studies have shown that endogenously synthesized renal dopamine is phosphaturic (16,19,20). The additive phosphaturic response to the coadministration of methiothepin and PTH in rats fed a high phosphate diet may be attributable not only to the blockade of serotonin receptors by methiothepin infusion, but also to the increased endogenous intrarenal dopamine in rats fed a HPD (21,22). However, because methiothepin also has relatively potent antagonistic effects on dopamine receptors, a contribution of dopamine to this response is unlikely.

Previous studies have suggested the presence of serotonin receptors in the rat proximal and distal nephron (23,24). Furthermore, the 5-HT1B receptor subtype has been identified in cultured opossum kidney cells, a proximal tubule epithelial cell line (5,6). The present data are consistent with studies suggesting that functional serotonin receptors are present in the proximal tubule, because phosphate excretion was increased after the infusion of a serotonin receptor antagonist.

Intravenous methiothepin infusion decreased MAP in rats fed both a LPD and a HPD. Because serotonin is a vasoactive substance, the decreased BP after intravenous infusion of methiothepin is likely related to the blockade of serotonin receptors in the systemic circulation. Other investigators have reported similar decreases in BP following infusion of serotonin receptor antagonists (25,26,27,28). This decrease in MAP likely contributed to the decrease in sodium excretion in rats fed a HPD. Renal interstitial infusion of methiothepin through a chronically implanted matrix allows the serotonin receptor antagonist to be preferentially delivered to the kidney and avoids the systemic effects associated with infusing the serotonin receptor antagonist into the circulation (11). When methiothepin was infused into the renal interstitium, MAP and GFR remained stable while phosphate and sodium excretion increased. The observation that sodium excretion increased after renal interstitial infusion of methiothepin is consistent with other studies demonstrating that increased intrarenal serotonin synthesis reduces sodium excretion (29,30).

In conclusion, renal interstitial infusion of the serotonin receptor antagonist methiothepin significantly increased phosphate excretion in rats fed a normal phosphate diet in the presence of endogenous PTH. Likewise, the intravenous infusion of methiothepin increased phosphate excretion in TPTX rats fed a HPD in the presence and absence of PTH. In TPTX rats fed a LPD, methiothepin infusion enhanced the phosphaturic response to PTH. These observations suggest that endogenous intrarenal serotonin enhances phosphate reabsorption in phosphate-replete rats and attenuates the phosphaturic response to PTH in phosphate-deplete rats.


   Acknowledgments
 
This study was supported by National Institutes of Health Grant DK19715 and by the Mayo Foundation. The authors gratefully acknowledge the excellent secretarial assistance of Joanne Zimmerman and the technical assistance of Paul Odenbach, Azra Babar, and Amitpal Johal, who performed preliminary studies in support of this manuscript.


   Footnotes
 
This study was presented in part at the 30th Annual Meeting of the American Society of Nephrology, November 2-5, 1997, in San Antonio, TX.

Journal of the American Society of Nephrology


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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Received for publication July 19, 1999. Accepted for publication September 22, 1999.





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