First in vivo evaluation of pharmaceutical modulation of porcine ureteral distensibility

Background: Pharmacologic relaxation of ureteral smooth muscle may promote spontaneous stone passage via medical expulsive therapy (MET), reduce renal colic, and facilitate ureteroscopic access to the kidney. We evaluated the effects of six oral smooth-muscle relaxants on porcine ureteral distensibility using the novel University of California, Irvine (UCI) force sensor.

Methods: Thirty-five juvenile female Yorkshire swine contributed 59 evaluable ureters following seven days of oral treatment with placebo, fasudil, mirabegron, Rowatinex®, silodosin, tadalafil, or verapamil. Distensibility was measured as maximum dilator size passed and ureteral size scale (USS). Generalized estimating equations accounted for bilateral ureters and adjusted for age, baseline bacteriuria, and the corresponding day zero measurement. Primary analyses estimated within-group changes of ureteral distensibility due to fasudil, mirabegron, silodosin, tadalafil, and control, with a Holm correction performed across ten tests. Secondary analyses compared adjusted changes among groups and versus the control group.

Results: Untreated controls showed minimal change in ureteral size (+ 0.2 Fr, P = 0.842) or USS (+ 0.8 points, P = 0.734). In the primary, within-group analysis, and before multiplicity correction, fasudil increased ureteral size by 0.78 Fr (P = 0.018) and USS by 3.39 points (P < 0.001). After Holm correction, only the fasudil-associated USS increase remained significant (adjusted P = 0.003610). Sensitivity analysis using each group’s observed baseline characteristics supported increases with fasudil in size (+ 0.93 Fr) and USS (+ 3.48 points), both significant after correction. In the secondary analysis comparing medication groups to control, which was under-powered and had unbalanced baseline characteristics, no medication differed significantly from control after correction.

Conclusions: Oral fasudil showed the strongest association with increased porcine ureteral distensibility. These findings warrant an appropriately powered direct comparison between fasudil-treated and untreated control animals. Given the clinical tolerability and safety of fasudil, the findings could also support a clinical evaluation of ROCK inhibition for MET and ureteral colic in carefully selected patients.