Ex vivo modulation of muscarinically induced contractions by PGE2 and an EP1 receptor antagonist in the guinea pig urinary bladder

Abstract

A B S T R A C T OBJECTIVE:Mechanical and physical stimuli can evoke release of several substances by the urothelium, for example, prostaglandin E2 (PGE 2 ), nitric oxide, acetylcholine and adenosine triphosphate. It has been shown, that PGE 2 and acetylcholine seem to act in a positive feedback on molecular level. This feedback was located in the urothelial/ suburothelial layer. Therefore, the aim of our study was to investigate the role of PGE 2 and one of its receptors, EP1, on muscarinic induced contractions. METHODS:The urethra and bladder of 24 male guinea pigs were dissected after sacrifice of the animal. The bladder was catheterized transurethrally and placed into a preheated organ bath filled with Krebs buffer. The bladders were repeatedly stimulated with the muscarinic agonist arecaidine alone or in combination with a) acetylsalicylic acid, b) PGE 2 or c) the EP1 antagonist ONO-8713. All drugs were applied at the serosal side of the bladder. Intravesical pressure was measured and amplitude and frequency of the arecaidine induced response were analyzed. RESULTS:Adding PGE 2 before muscarinic stimulations induced an amplifying effect on muscarinically induced contractions and inhibition of the PGE 2 producing enzymes prior to an arecaidine stimulation decreased the amplitude during the initial phase of the response. Inhibition of EP1 resulted in a decreased frequency during the second phase of the arecaidine response. CONCLUSIONS:In summary, this study provides evidence that the cholinergic and prostanoid systems in the urinary bladder act in a positive feedback loop and that the EP1 receptor plays a subtle role in this process.