INTRAURETHRAL MUSCLE-DERIVED CELL INJECTIONS INCREASE LEAK POINT PRESSURE IN A RAT MODEL OF INTRINSIC SPHINCTER DEFICIENCY CHRISTOPHER J. CHERMANSKY, TATUM TARIN, DONG-DUEK KWON, RONALD J. JANKOWSKI, TRACY W. CANNON, WILLIAM C. DE GROAT, JOHNNY HUARD, AND MICHAEL B. CHANCELLOR ABSTRACT Objectives. To determine whether allogenic muscle-derived cells (MDCs) could restore sphincter function in rats with intrinsic sphincter deficiency (ISD). ISD denotes a malfunction of the urethral sphincter. Methods. ISD was produced in 25 adult female Sprague-Dawley rats by cauterizing tissues lateral to the mid-urethra. One week after cauterization, 1.5  10 6 MDCs, genetically engineered for beta-galactosidase expression, was injected into the mid-urethra in 16 rats. Another 9 rats were injected with Hanks’ balanced salt solution after cauterization. As a control, 9 normal rats underwent a sham operation. Sphincter function was studied using the vertical tilt table/intravesical pressure clamp technique to measure leak point pres- sures (LPPs). The fate of the MDCs was assessed using LacZ staining. Results. The injection of MDCs increased the LPP without affecting bladder function. The mean LPP of the control rats 2, 4, and 6 weeks after the sham operation was 49.8  1.3, 51.2  1.5, and 51.6  2.0 cm H 2 O, respectively. The mean LPP of the rats 2, 4, and 6 weeks after cauterization and Hanks’ balanced salt solution injection was 17.2  1.4, 26.9  1.9, and 25.5  1.3 cm H 2 O, respectively. The mean LPP of the rats 2, 4, and 6 weeks after cauterization and MDC injection was 38.2  2.2, 43.1  2.6, and 51.5  0.9 cm H 2 O, respectively. LacZ staining confirmed that MDC had integrated within the striated muscle layer of the cauterized urethra. Conclusions. The injection of intraurethral MDCs improved sphincter function in rats with ISD and may provide an attractive alternative to current treatments. UROLOGY 63: 780–785, 2004. © 2004 Elsevier Inc. I ntrinsic sphincter deficiency (ISD) results from a malfunction of the external urethral sphinc- ter. 1 The most common cause of ISD is idiopathic, and it seems to be a product of aging. 2 ISD can also be acquired secondary to incontinence surgery or radical prostatectomy. In most patients with ISD, significant myogenic damage is present. 3 Such damage can result from direct injury to the sphinc- ter muscle or pudendal nerve, or both. Research into newer ISD treatments has focused on striated sphincter reconstruction. Recently, the injection of muscle-derived cells (MDCs) into normal rat urethra demonstrated greater persistence than bovine collagen. 4 Our ob- jective was to determine whether allogenic MDCs could restore sphincter function in rats with ISD. We have developed an ISD model that results in sphincter injury, demonstrated, functionally, by lower leak point pressures (LPPs) and, histologi- cally, by muscle and nerve damage. MATERIAL AND METHODS ANIMALS AND STUDY DESIGN We used three overall groups of normal female Sprague- Dawley rats (Hilltop Lab Animals, Scottsdale, Pa), weighing 250 to 300 g. In the first group, the urethra was cauterized, followed 1 week later by MDC injection. These rats were again divided into three groups that were evaluated 2 (n = 8), 4 (n = 5), or 6 (n = 3) weeks after MDC injection. In the second group, 9 rats underwent cauterization, followed 1 week later by injection with Hanks’ balanced salt solution (HBSS). These 9 rats were divided into three groups of 3 rats each that were evaluated 2, 4, or 6 weeks after HBSS injection. The third This study was supported by National Institutes of Health grants NIH K12 DK02656, NIH RO1 DK55387, and NIH RO1 AR049398. From the Departments of Urology, Orthopedic Surgery, and Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Reprint requests: Michael B. Chancellor, M.D., Department of Urology, University of Pittsburgh School of Medicine, Kaufmann Building, Suite 700, 3471 Fifth Avenue, Pittsburgh, PA 15213 Submitted: April 25, 2003, accepted (with revisions): October 8, 2003 BASIC SCIENCE © 2004 ELSEVIER INC. 0090-4295/04/$30.00 780 ALL RIGHTS RESERVED doi:10.1016/j.urology.2003.10.035