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Effect of Serotonin Receptor Antagonist on Phosphate Excretion

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. 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 (FE_Pi) 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 FE_Pi 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 FE_Pi to 64 ± 3% (P < 0.05). The increase in FE_Pi during PTH infusion was similar in the absence (27 ± 5%, n = 7) and presence (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 FE_Pi during PTH infusion was significantly greater in the presence of methiothepin (1.3 ± 0.9 to 20.0 ± 4.0%, 18.7 ± 3.5%) than in the vehicle-infused rats (0.5 ± 0.2 to 8.8 ± 1.1%, 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.

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673