The muscarinic receptor antagonist propiverine exhibits α(1)-adrenoceptor antagonism in human prostate and porcine trigonum.

Abstract

PURPOSE:

Combination therapy of male lower urinary tract symptoms with α(1)-adrenoceptor and muscarinic receptor antagonists attracts increasing interest. Propiverine is a muscarinic receptor antagonist possessing additional properties, i.e., block of L-type Ca(2+) channels. Here, we have investigated whether propiverine and its metabolites can additionally antagonize α(1)-adrenoceptors.

METHODS:

Human prostate and porcine trigone muscle strips were used to explore inhibition of α(1)-adrenoceptor-mediated contractile responses. Chinese hamster ovary (CHO) cells expressing cloned human α(1)-adrenoceptors were used to determine direct interactions with the receptor in radioligand binding and intracellular Ca(2+) elevation assays.

RESULTS:

Propiverine concentration-dependently reversed contraction of human prostate pre-contracted with 10 μM phenylephrine (-log IC(50) [M] 4.43 ± 0.08). Similar inhibition was observed in porcine trigone (-log IC(50) 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 α(1)-adrenoceptor subtypes with -log K (i) [M] values ranging from 4.72 to 4.94, whereas the M-5 and M-6 did not affect [(3)H]-prazosin binding. In CHO cells, propiverine inhibited α(1)-adrenoceptor-mediated Ca(2+) elevations with similar potency as radioligand binding, again mainly by reducing maximum responses.

CONCLUSIONS:

In contrast to other muscarinic receptor antagonists, propiverine exerts additional L-type Ca(2+)-channel blocking and α(1)-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.

• Authors: Melinda Wuest, Lambertus P Witte, Martina B Michel-Reher, Stefan Propping, Manfred Braeter, Gerhard J Strugala, Manfred P Wirth, Martin C Michel, Ursula Ravens
• Journal: World journal of urology (World J Urol) Vol. 29 Issue 2 Pg. 149-55 (Apr 2011) ISSN: 1433-8726 [Electronic] Germany
• PMID: 21336600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adrenergic alpha-1 Receptor Antagonists
• Benzilates
• Calcium Channel Blockers
• Calcium Channels, L-Type
• Muscarinic Antagonists
• Receptors, Adrenergic, alpha-1
• propiverine
• Calcium

Topics

• Adrenergic alpha-1 Receptor Antagonists (pharmacology)
• Aged
• Animals
• Benzilates (pharmacology)
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Calcium Channels, L-Type (drug effects)
• Female
• Humans
• Male
• Middle Aged
• Models, Animal
• Muscarinic Antagonists (pharmacology)
• Muscle Contraction (drug effects)
• Muscle, Smooth (drug effects, metabolism)
• Prostate (drug effects, metabolism)
• Receptors, Adrenergic, alpha-1 (metabolism)
• Swine
• Urinary Bladder (drug effects, metabolism)