BERKELEY, CA (UroToday.com) - Spinal cord injury (SCI) is a devastating disease that affects about 2.5 million people worldwide; it has a profound impact on quality of life and life expectancy, causing a great economic burden to society. The disruption of coordinated control between the brain, spinal cord, and peripheral nervous system caused by SCI leads to several secondary pathological conditions, including lower urinary tract dysfunctions. As a consequence, individuals develop overactive urinary bladder (OAB), a syndrome characterized by exacerbated contractions of the urinary bladder during the filling phase, associated with detrusor sphincter dyssynergia (DSD) and inefficient voiding.
Overactive urinary bladder syndrome affected approximately 450 million people worldwide in 2008. It has been projected that this number will increase substantially by 2018. Hence, there is an enormous and urgent medical need for the development of novel therapeutic strategies that target improvements in OAB, especially following SCI. Therefore, we investigated the role played by kinin B1 and B2 receptors in overactive urinary bladder, after SCI, in male Wistar rats. The spinal cord injury procedure was performed as previously described by Vanický et al. (2001) and Andrade et al. (2011). As it is well known, kinins are a group of peptides formed in plasma and tissues during different physiological states and in response to inflammation, infection, and tissue trauma. Once formed and released, kinins exert their biological effects through the activation of two G-protein coupled receptors, the kinin B1 and B2 receptors.
Our group assessed the involvement of such receptors on the means of RNAm levels, protein expression, and localization, in vitro and in vivo studies, with agonists and antagonists. One of the main results is the urodynamic study. It revealed that during the urinary bladder filling phase, SCI animals showed more non-voiding contractions (NVCs) (10.0 ± 2.6) than sham-operated animals (0.5 ± 0.3). In comparison to sham-operated animals, the SCI animals showed significant alterations such as: reductions in the intercontraction interval, voided volume, and voiding efficiency, as well as an increase in threshold pressure and urinary bladder capacity. On the other hand, the treatment of SCI animals with the B2 selective antagonist Icatibant reduced the amplitude and number of NVCs. The B1 antagonist des-Arg9-[Leu8]-bradykinin reduced the number of NVCs while the non-peptide B1 antagonist SSR240612 reduced the number of NVCs, the urinary bladder capacity, and increased the voiding efficiency and voided volume.
In summary, we provided evidence that the basal expression of B2 receptors in the urinary bladder suggests that bradykinin may play a role in normal urinary bladder functioning. The up-regulation of B1 receptors in SCI urinary bladders might be associated with the alterations in urinary bladder reflex pathways, in OAB, caused by SCI. Moreover, the B1 and B2 receptor antagonism improves urodynamic parameters associated to the OAB in SCI animals. Thus, kinin receptor-selective antagonists might constitute an attractive pharmacological tool for the treatment of urinary bladder overactivity in neurogenic diseases such as SCI.
Stefânia Forner, Edinéia L. Andrade, Alessandra C. Martini, Allisson F. Bento, Rodrigo Medeiros,1 Janice Koepp, and João B. Calixto as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Departamento de Farmacologia, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, 88049-900, Florianópolis, SC, Brazil
1Current address: Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697-4545 USA.