Comparison of calcium antagonist properties of antispasmotic agents

Several agents commonly employed for the treatment of detrusor hyperreflexia or instability are characterized as antispasmotics. Their mechanism of action is not completely understood but it has been proposed that their actions are dependent on anticholinergic activity, CNS mediated relaxation, or local anesthetic properties. The purpose of this study was to determine if imipramine, flavoxate HCl, or oxybutynin HCl possess any calcium antagonist properties. This was accomplished by determining the ability of these agents to inhibit a standard cholinergic stimulus (200 uM bethanechol) over a range of extracellular calcium concentrations (0.5 to 10.0 mM). In-vitro isolated smooth muscle strips of rabbit bladder dome were utilized. Control tissues displayed a reproducible response to bethanechol stimulation at different calcium concentrations with an ED50 of 0.4 mM calcium and a peak response of 5.0+/-0.4 grams tension. Flavoxate (2.5 mM), oxybutynin (2.5 uM), and imipramine 25 uM) all significantly reduced peak tension generation. The ED 50's for extracellular calcium in the presence of flavoxate and oxybutynin were not significantly different from controls. Imipramine at both 3 and 25 uM significantly increased the ED50 for calcium. The above data demonstrate that imipramine possesses competitive calcium antagonism. The relative contribution of calcium antagonism toward the inhibitory effects of imipramine is unknown but may play a significant role in its clinical activity.