Synergistic relaxation of ureteral smooth muscle by doxazosin and vardenafil: experimental implications for medical expulsive therapy.

PURPOSE: This study aimed to investigate the relaxant effects of doxazosin (an α₁-adrenergic receptor blocker) and vardenafil (a phosphodiesterase type 5 inhibitor) on rabbit ureteral smooth muscle using an in vitro organ-bath model, and to determine whether sequential administration enhances relaxation, particularly in different ureteral segments.

METHODS

Ureteral segments (middle and distal) were obtained from 15 adult male New Zealand White rabbits and mounted in organ baths containing oxygenated Krebs-Henseleit solution at 37 °C. Each ureteral segment (middle and distal) obtained from the animals was treated as an independent experimental unit. Thus, a total of 15 middle and 15 distal ureteral segments were analyzed (n = 15 per group). Contractions were induced by 60 mmol/L KCl, and relaxation responses to doxazosin and vardenafil-applied separately or sequentially-were recorded isometrically. The degree of relaxation was expressed as a percentage of the initial KCl-induced contraction. Data were analyzed using one-way ANOVA followed by Tukey's post hoc test.

RESULTS

Both doxazosin and vardenafil produced significant relaxation in KCl-precontracted tissues (p < 0.001). In the middle ureter, relaxation responses were 47.3 ± 3.6% for doxazosin and 33.7 ± 3.5% for vardenafil. In the distal ureter, relaxation increased to 54.6 ± 2.2% and 40.8 ± 2.2%, respectively. Sequential administration of doxazosin followed by vardenafil yielded the greatest relaxation (84.1 ± 3.9% in middle, 88.4 ± 3.1% in distal segments; p < 0.001), whereas the reverse order produced a lower but still significant response (57.4 ± 4.8% and 80.5 ± 4.4%, respectively). Overall, distal segments exhibited greater pharmacologic sensitivity than middle ones.

CONCLUSION

Doxazosin and vardenafil both exert potent relaxant effects on ureteral smooth muscle, with enhanced efficacy when administered sequentially-especially in distal segments. These findings provide mechanistic insight into the synergistic interaction between α₁-adrenergic blockade and PDE5 inhibition and support the rationale for combination therapy in facilitating distal ureteral stone passage.