Cellular mechanisms of pacemaking in the upper urinary tract: effects of sensory neuropeptides and prostaglandins

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The mammalian upper urinary tract (UUT) serves to propel urine from the renal pelvis within the kidney through the ureter to the bladder, where it is stored until micturition. This propulsion of urine from the renal pelvis to the bladder occurs by the means of spontaneous peristaltic contractions in the smooth muscle wall of the UUT, intimately dependent on the localized release of prostaglandins. Approximately 10% of the population suffer from renal calculi (kidney stones) at some stage of their lifetime, with men being 2-4 times more likely than women to have calculi. Pain management of renal colic usually involves the prescribing of strong analgesics, and antispasmodic and nonsteroidal anti-inflammatory agents. Most stones are expelled spontaneously if they are small. Larger stones require interventions such as fragmentation (extracorpereal lithotripsy), which is an out patient procedure, or physical removal, using ureterscopes or endoscopes or open surgery under general anesthesia; procedures usually requiring hospital stays of 2-7 days. This project will provide valuable information on the mechanisms by which sensory nerves and endogenous prostaglandins control motility in the mammalian UUT. In particular, these studies will contribute to the search of specific anti-inflammatory agents which will affect particular aspects of UUT motility. A clearer understanding of the cellular origin of UUT rhythmicity will lead to more informed non-surgical interventions to encourage the passing of painful calculi. Such information will also aid in the treatments of other forms of renal colic, during ureteric obstruction, and urinary tract infection. Ureteric stasis is an important condition to avoid, if left untreated permanent kidney damage usually occurs within 6 weeks.