title: Activation of renal calcium and water excretion by novel physiological and pharmacological activators of the calcium-sensing receptor.
abstract: Activated Ca(2+)-sensing receptors (CaR) play key roles in the regulation of whole-body calcium metabolism by inhibiting the secretion of the key calcitropic hormone parathyroid hormone and promoting urinary calcium excretion. We have now examined the effects of intravenous administration of novel calcium receptor activators on renal function in anaesthetized female Wistar rats. The type II calcimimetic NPS R-467 and the CaR-active amino acids l-Phe and l-Ala, which act at distinct binding sites on the receptor, all activated urinary flow rate, calcium and osmolar excretion and suppressed urinary osmolality. The effects of l-Phe and NPS R-467 on urine flow rate and calcium excretion were stereoselective, consistent with the idea that these effects were mediated by calcium-sensing receptors. However, d-Phe also suppressed urinary osmolality and promoted osmolar excretion, possibly by exceeding the transport maximum in the proximal tubule. The data indicate that novel activators of CaR, including l-amino acids at physiologically relevant serum concentrations, play a significant role in the regulation of urinary calcium and water excretion.
authors.affiliation: School of Molecular and Microbial Biosciences, University of Sydney, Sydney, New South Wales, Australia. a.conigrave@mmb.usyd.edu.au
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Conigrave
authors.forename: Hiu Chuen
authors.initials: HC
authors.lastname: Lok
mesh_terms: D000814:Aniline Compounds / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000819:agonists / Q000378:metabolism*; D005260:Female; D007668:Kidney / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D044169:Receptors, Calcium-Sensing / Q000819:agonists / Q000378:metabolism*; D014554:Urination / Q000187:drug effects / Q000502:physiology*; D014867:Water / Q000378:metabolism
chemical_list: D000814:Aniline Compounds; C111654:NPS R-467; D044169:Receptors, Calcium-Sensing; D014867:Water; D002118:Calcium