Effects of Propiverine and Its Metabolite Propiverine-N-Oxide on Bladder Contraction and Salivation in Mini Pigs

Abstract

Purpose: The objective of this study was to evaluate the influence of propiverine-HCl (P4) and propiverine-N-oxide (P4NO), one of the major metabolites of P4, on bladder contraction in a standardized in vivo model. Additionally, salivary flow measurements enabled the evaluation of hyposalivation, one of the most predominant anticholinergic side effects. Materials and Methods: Ten male mini pigs were anesthetized. P4 (0.4 mg/kg b.w.) and P4NO (0.422 mg/kg b.w.) were administered intravenously. Bladder contractions were induced through sacral anterior root stimulation and cystometrogram evaluation was performed. For stimulation-induced salivary flow measurements, the lingual nerve was exposed for neurostimulation. The effects of P4 and P4NO on stimulation-induced bladder contraction and salivation were evaluated in 5 mini pigs, respectively. Results: In all experiments, for each animal reproducible intravesical pressure values (Pves) were elicited during sacral anterior root stimulation before administration of the study drug. After administration of P4, Pves decreased by 64% whereas P4NO decreased Pves by 28%. Inhibition of salivary flow with P4 and P4NO was 71 and 32%, respectively. Directly following intravenous administration of P4, a short-term and reversible period of mild fluctuations in heart rate was observed. Administration of P4NO revealed no changes in either heart rate, or blood pressure. Conclusion: All of the investigated parameters revealed less anticholinergic effects for P4NO compared to P4. Under the experimental conditions described above, it may be assumed that P4NO behaves as a substance with poor anticholinergic effects with respect to side effects. As expected, P4 showed anticholinergic effects on bladder contraction and salivation.

Morphological changes in the salivary acini after in vivo cholinergic stimulation

“…However, muscarinic receptor antagonists have limited use because of side effects, which include dry mouth, headache, tachycardia, blurred vision, and constipation . Scheepe et al suggested most resulted from the drug being metabolized in the liver into active metabolites. For oxybutynin, N‐desethyloxybutynin has been shown as the active metabolite .…”

“…For oxybutynin, N‐desethyloxybutynin has been shown as the active metabolite . The effects of oxybutynin metabolites have been extensively studied in vitro, but not in vivo.…”