The muscarinic receptor antagonist propiverine exhibits α1-adrenoceptor antagonism in human prostate and porcine trigonum

Abstract

PurposeCombination therapy of male lower urinary tract symptoms with α1-adrenoceptor and muscarinic receptor antagonists attracts increasing interest. Propiverine is a muscarinic receptor antagonist possessing additional properties, i.e., block of L-type Ca2+ channels. Here, we have investigated whether propiverine and its metabolites can additionally antagonize α1-adrenoceptors.MethodsHuman prostate and porcine trigone muscle strips were used to explore inhibition of α1-adrenoceptor-mediated contractile responses. Chinese hamster ovary (CHO) cells expressing cloned human α1-adrenoceptors were used to determine direct interactions with the receptor in radioligand binding and intracellular Ca2+ elevation assays.ResultsPropiverine concentration-dependently reversed contraction of human prostate pre-contracted with 10 μM phenylephrine (−log IC50 [M] 4.43 ± 0.08). Similar inhibition was observed in porcine trigone (−log IC50 5.01 ± 0.05), and in additional experiments consisted mainly of reduced maximum phenylephrine responses. At concentrations ≥1 μM, the propiverine metabolite M-14 also relaxed phenylephrine pre-contracted trigone strips, whereas metabolites M-5 and M-6 were ineffective. In radioligand binding experiments, propiverine and M-14 exhibited similar affinity for the three α1-adrenoceptor subtypes with −log Ki [M] values ranging from 4.72 to 4.94, whereas the M-5 and M-6 did not affect [3H]-prazosin binding. In CHO cells, propiverine inhibited α1-adrenoceptor-mediated Ca2+ elevations with similar potency as radioligand binding, again mainly by reducing maximum responses.ConclusionsIn contrast to other muscarinic receptor antagonists, propiverine exerts additional L-type Ca2+-channel blocking and α1-adrenoceptor antagonist effects. It remains to be determined clinically, how these additional properties contribute to the clinical effects of propiverine, particularly in male voiding dysfunction.

Refractory Urinary Incontinence in Girls: The Role of the Bladder Neck

“…Pharmacological treatment can be offered to those patients to reduce the voiding as well as the storage symptoms (25). Historically alpha 1 -blockers were mainly used to relieve the voiding symptoms, but the latest studies showed that non-selective antimuscarinics can reduce the storage symptoms acting through the M 3 receptor and voiding symptoms through the M 1–2 blockade (26–28). …”

Asiri Aktif Mesane Tedavisinde Karma Etkili Ajanların Etki Mekanizmasi ve Avantajlari

“…İnsan ve domuzlarda yapılan başka bir çalışmada propiverin metabolitlerinin yine alfa 1 reseptörlerini bloke ettiği gösteril-miştir (19). Propiverinin NANK mekanizmaya ait ATP bağımlı mesane aşırı aktivitesini de baskılamakta olduğu, ayrıca detrusor kasılmasından sorumlu faktörlerden biri olan purinerjik mekanizmayı da kısmen inhibe ettiği öne sürülmektedir (20).…”

Selectivity of pharmacological tools: implications for use in cell physiology. A Review in the Theme: Cell Signaling: Proteins, Pathways and Mechanisms

“…Such cross-reactivity can also be observed with targets less closely related to the primary binding partner of a ligand. For example, various histamine receptor antagonists bind to muscarinic receptors (54), and the muscarinic receptor antagonist propiverine binds with similar affinity to all subtypes of muscarinic receptors but also to all three subtypes of ␣ 1 -AR (206) and also inhibits L-type Ca 2ϩ channels (205). Interestingly, metabolites of propiverine exhibited a differential ratio of affinity for muscarinic receptors vs. ␣ 1 -AR and/or vs. L-type Ca 2ϩ channels ( Table 2).…”

“…Selectivity problems with transporter inhibitors have long been known from the group of monoamine uptake inhibitors Data are based on radioligand binding studies at M3 muscarinic receptors and ␣1A-adrenoceptor (AR) with similar affinities at other subtypes of these receptors as reported by Wuest et al (205,206). Data on L-type Ca 2ϩ channels are based on electrophysiological recordings in human urinary bladder smooth muscle cells as reported by Wuest et al (204).…”