Ureteral Relaxation Through Calcitonin Gene-Related Peptide Release From Sensory Nerve Terminals By Hypotonic Solution

ObjectivesTo evaluate the influence of hypotonic solutions on ureteral relaxation mediated by the release of calcitonin gene-related peptide from intramural sensory nerve endings.MethodsUrine osmolarity of Sprague-Dawley rats drinking water low in salt content (Fiuggi water) or a reference water for 7days 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 neurokininA-induced phasic contractions of isolated rat ureters was evaluated by organ bath studies.ResultsA 7-day consumption of Fiuggi water in rats reduced urine osmolarity by similar to 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 neurokininA-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 peptide(8-37). Transient receptor potential vanilloid1 or transient receptor potential vanilloid 4 antagonists did not affect the neurogenic and calcitonin gene-related peptide-dependent relaxation.ConclusionPresent 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 vanilloid1 or transient receptor potential vanilloid 4. Future studies with appropriate invivo models should investigate the hypothesis that hypostenuric urine diffusing into the ureteral tissue might favor ureteral relaxation through this novel mechanism.