Bladder injection of “naked” hSlo/pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo

Christ, G. J., N. S. Day, M. Day, C. Santizo, W. Zhao, T. Sclafani, J. Zinman, K. Hsieh, K. Venkateswarlu, M. Valcic, and A. Melman. Bladder injection of “naked” hSlo/ pcDNA3 ameliorates detrusor hyperactivity in obstructed rats in vivo. Am J Physiol Regulatory Integrative Comp Physiol 281: R1699–R1709, 2001.—The goal of these studies was to examine the potential utility of bladder instilled K channel gene therapy with hSlo cDNA (i.e., the maxi-K channel) to ameliorate bladder overactivity in a rat model of partial urinary outlet obstruction. Twenty-two female Sprague-Dawley rats were subjected to partial urethral (i.e., outlet) obstruction, with 17 sham-operated control rats run in parallel. After 6 wk of obstruction, suprapubic catheters were surgically placed in the dome of the bladder in all rats. Twelve obstructed rats received bladder instillation of 100 mg of hSlo/pcDNA in 1 ml PBS during catheterization, and another 10 obstructed rats received 1 ml PBS (7 rats) or 1 ml PBS containing pcDNA only (3 rats). Two days after surgery cystometry was performed on all animals to examine the characteristics of the micturition reflex in conscious and unrestrained rats. Obstruction was associated with a threeto fourfold increase in bladder weight and alterations in virtually every micturition parameter estimate. PBS-injected obstructed rats routinely displayed spontaneous bladder contractions between micturitions. In contrast, hSlo injection eliminated the obstruction-associated bladder hyperactivity, without detectably affecting any other cystometric parameter. Presumably, expression of hSlo in rat bladder functionally antagonizes the increased contractility normally observed in obstructed animals and thereby ameliorates bladder overactivity. These initial observations indicate a potential utility of gene therapy for urinary incontinence.