title: The muscarinic receptor antagonist propiverine exhibits α(1)-adrenoceptor antagonism in human prostate and porcine trigonum.
abstract: OBJECTIVE
  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.affiliation: Department of Pharmacology and Toxicology, Dresden University of Technology, Dresden, Germany.
authors.forename: Melinda
authors.initials: M
authors.lastname: Wuest
authors.forename: Lambertus P
authors.initials: LP
authors.lastname: Witte
authors.forename: Martina B
authors.initials: MB
authors.lastname: Michel-Reher
authors.forename: Stefan
authors.initials: S
authors.lastname: Propping
authors.forename: Manfred
authors.initials: M
authors.lastname: Braeter
authors.forename: Gerhard J
authors.initials: GJ
authors.lastname: Strugala
authors.forename: Manfred P
authors.initials: MP
authors.lastname: Wirth
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
authors.forename: Ursula
authors.initials: U
authors.lastname: Ravens
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000494:pharmacology*; D000368:Aged; D000818:Animals; D001561:Benzilates / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism*; D011467:Prostate / Q000187:drug effects / Q000378:metabolism*; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D013552:Swine; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D001561:Benzilates; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018727:Muscarinic Antagonists; D018340:Receptors, Adrenergic, alpha-1; C015586:propiverine; D002118:Calcium