Effect of co-administration of two different phosphodiesterase inhibitors and a β3-adrenoceptor agonist in an experimental model of detrusor overactivity.

Abstract

The purpose of this study was to evaluate in vitro the effect of the combination of BRL 37344 (ß3-adrenoceptor agonist) with tadalafil (phosphodiesterase type 5 inhibitor) or rolipram (phosphodiesterase type 4 inhibitor) in an experimental model of detrusor overactivity. The experiments were carried out in two phases using bladder strips of mice. In the first phase, on the top of 40 mM potassium-induced contraction, strips isolated from control mice were exposed to increasing concentrations of each study drug. In another series of experiments, prior to contraction, strips were incubated with either tadalafil or rolipram, followed by the addition of increasing concentrations of BRL 37344. In the second phase, the same protocols were performed with animals previously treated with L-NAME for 30 days. Chronic L-NAME administration leads to detrusor overactivity due to nitric oxide synthase inhibition. In phase one, preincubation with tadalafil enhanced relaxation response to BRL 37344 at two concentrations. Pretreatment with rolipram had no effect on BRL 37344-induced relaxation. In L-NAME-treated mice, rolipram induced more relaxation than the other drugs, enhancing relaxation response to BRL 37344 at almost all concentrations, but no synergistic effect with tadalafil was observed. The relaxant effect of BRL 37344 was enhanced by rolipram but not by tadalafil, suggesting that PDE4 inhibition, especially when associated with ß3-adrenoceptor stimulation, could represent a potential treatment for overactive bladder.

• Authors: Bruno Lima Linhares, Nilberto Robson Falcão Nascimento, Lúcio Flávio Gonzaga-Silva, Cláudia Ferreira Santos, Manoel Odorico Moraes, Lucas Bernardo Marinho, Ana Patrícia Gonçalves Silva, Manassés Claudino Fonteles, Ricardo Reges
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 833 Pg. 425-431 (Aug 15 2018) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 29913125 (Publication Type: Journal Article)
• Copyright: Copyright © 2018 Elsevier B.V. All rights reserved.

Chemical References

• Adrenergic beta-3 Receptor Agonists
• Ethanolamines
• Phosphodiesterase 4 Inhibitors
• Phosphodiesterase 5 Inhibitors
• BRL 37344
• Tadalafil
• Rolipram
• NG-Nitroarginine Methyl Ester

Topics

• Adrenergic beta-3 Receptor Agonists (pharmacology, therapeutic use)
• Animals
• Disease Models, Animal
• Drug Evaluation, Preclinical
• Drug Synergism
• Drug Therapy, Combination (methods)
• Ethanolamines (pharmacology, therapeutic use)
• Humans
• Male
• Mice
• Muscle Contraction (drug effects)
• Muscle Relaxation (drug effects)
• Muscle, Smooth (physiopathology)
• NG-Nitroarginine Methyl Ester (toxicity)
• Phosphodiesterase 4 Inhibitors (pharmacology, therapeutic use)
• Phosphodiesterase 5 Inhibitors (pharmacology, therapeutic use)
• Rolipram (pharmacology, therapeutic use)
• Tadalafil (pharmacology, therapeutic use)
• Treatment Outcome
• Urinary Bladder (drug effects, physiopathology)
• Urinary Bladder, Overactive (chemically induced, drug therapy, physiopathology)