Vesicoureteral reflux is one of the more common disorders treated by pediatric urologists. In the past reflux was felt to be secondary to anatomic malpositioning of the ureters resulting in poor intramural tunnel length and therefore an incompetent flap valve mechanism. However many children outgrow their reflux with maturation, and the classic explanation was that the trigone also matures with growth. Reflux however has a physiologic or urodynamic component as is evidenced by numerous clinical studies documenting urodynamic abnormalities in children with reflux. One such study has shown that in neonates with high grade reflux, the voiding pressures exceeded 100 cm of H2O in 17/18 cases. The ontogeny of voiding function in normal children has not been clinically studied for ethical reasons (such studies are invasive), and thus we became interested in studying this in a laboratory model. Our preliminary data in a rabbit whole bladder model showed that the intravesical pressures that could be generated in neonatal rabbit bladders greatly exceeded those from mature animals. This work was carried over to a model using muscle strips which demonstrated that the neonatal smooth muscle was generating greater stresses in response to a variety of agonists. In further work we provided evidence that this may be in part due to differences in how free intracellular calcium rises during a stimulus induced contraction. Our evidence suggests that the neonatal rabbit bladder smooth muscle is far more dependent on extracellular calcium to generate force than its adult counterpart. The physiologic, pharmacologic, biochemical, metabolic, and histologic explanations for the differences in the ontogeny of bladder function will be the focus of this proposal. While elevated voiding pressures alone are unlikely to cause reflux, they could certainly be a contributing factor. A better understanding of bladder physiology with aging would be clinically useful to several disciplines. In addition to reflux, urologists see many children and adults with incontinence. The cost of incontinence is estimated to be in the billion dollar range nationally over a 1 year period and it is a leading cause for institutionalization of the elderly.
