title: Ureteral relaxation through calcitonin gene-related peptide release from sensory nerve terminals by hypotonic solution.
abstract: OBJECTIVE
  To evaluate the influence of hypotonic solutions on ureteral relaxation mediated by the release of calcitonin gene-related peptide from intramural sensory nerve endings.
  
  
  METHODS
  Urine osmolarity of Sprague-Dawley rats drinking water low in salt content (Fiuggi water) or a reference water for 7 days was measured. Release of calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter and urinary bladder by hypotonic solutions was assessed by an immunometric assay. The mechanism through which hypotonic solutions inhibit neurokinin A-induced phasic contractions of isolated rat ureters was evaluated by organ bath studies.
  
  
  RESULTS
  A 7-day consumption of Fiuggi water in rats reduced urine osmolarity by ~40%. Exposure to hypotonic solutions released calcitonin gene-related peptide-like immunoreactivity from slices of rat ureter. This response was abated in a calcium-free medium, after capsaicin desensitization, and in the presence of the unselective transient receptor potential channel antagonist, ruthenium red. Exposure of isolated rat ureteral preparations to a hypotonic solution inhibited neurokinin A-evoked phasic contraction. This response was attenuated by capsaicin desensitization and in the presence of the calcitonin gene-related peptide receptor antagonist, calcitonin gene-related peptide8-37 . Transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4 antagonists did not affect the neurogenic and calcitonin gene-related peptide-dependent relaxation.
  
  
  CONCLUSIONS
  Present data show that hypotonic solution evokes calcitonin gene-related peptide release from capsaicin-sensitive intramural sensory nerves, thus inhibiting ureteral contractility, through a transient receptor potential-dependent mechanism. However, this mechanism does not involve transient receptor potential vanilloid 1 or transient receptor potential vanilloid 4. Future studies with appropriate in vivo models should investigate the hypothesis that hypostenuric urine diffusing into the ureteral tissue might favor ureteral relaxation through this novel mechanism.
authors.affiliation: Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.affiliation: Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Daiana
authors.initials: D
authors.lastname: Minocci
authors.affiliation: Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Gaetano
authors.initials: G
authors.lastname: De Siena
authors.affiliation: Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Benemei
authors.affiliation: Section of Clinical Pharmacology and Oncology, Department of Health Sciences, University of Florence, Florence, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism* / Q000494:pharmacology; D002211:Capsaicin / Q000494:pharmacology; D007038:Hypotonic Solutions / Q000494:pharmacology*; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D015288:Neurokinin A / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism*; D018689:Sensory System Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors; D046509:Tissue Culture Techniques; D014513:Ureter / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D016482:Urinalysis
chemical_list: D007038:Hypotonic Solutions; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D018689:Sensory System Agents; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; C486577:Trpv4 protein, rat; C508797:calcitonin gene-related peptide (8-37), propionyllysyl(24)-; D015288:Neurokinin A; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin
keywords: calcitonin gene-related peptide; nephrolithiasis; osmolarity; sensory nerves; ureteral relaxation