Inhibition of Human and Pig Ureter Motility in Vitro and in Vivo by the K+ Channel Openers PKF 217-744b and Nicorandil

Abstract
The present study was designed to examine the roles of protein kinase C (PKC) and phosphodiesterase (PDE) in modulating the action of κ receptor stimulation on cAMP accumulation in isolated iris-ciliary bodies (ICBs) of New Zealand White rabbits. The κ receptor agonist, (±)-1-(3,4-dichlorophenyl)acetyl-2-(1-pyrrolidinyl)methylpiperidine (BRL-52537) (BRL), and the PKC activator, phorbol 12,13-dibutyrate (PDBu), both caused a concentration-dependent inhibition of forskolin-stimulated cAMP production. The inhibitory effect of BRL on cAMP levels was significantly reduced in the presence of the selective κ receptor antagonist, norbinaltorphimine (10−6M), but the effect of PDBu was not, thus supporting the involvement of κ-opioid receptors in the response to BRL. In the presence of 3-isobutyl-1-methylxanthine or rolipram (10−5 M), the inhibitory effect of BRL or PDBu (10−6 M) on cyclic AMP accumulation was abolished. In the presence of the selective PKC antagonist, chelerythrine (10−6 M), the inhibitory effect of PDBu or BRL (10−6 M) was significantly reduced. Direct measurement of PDE activity demonstrated the ability of BRL and PDBu (10−6 M) to augment the activity of these enzymes. Preincubation of ICBs with rolipram (10−5 M) or chelerythrine (10−6 M) caused significant reversal of both BRL- and PDBu-induced increases in PDE activity. These results indicate that stimulation of PKC and PDE4 activity is part of the complex mechanism whereby κ-opioid receptor agonists reduce levels of cAMP in the rabbit ICB. This mechanism of action could contribute to the ability of κ-opioid agonists to suppress aqueous flow rate and to lower intraocular pressure.