Prostaglandin E₂ suppression of acetylcholine release from parasympathetic nerves innervating guinea‐pig trachea by interacting with prostanoid receptors of the EP₃‐subtype

Abstract

1 We have demonstrated recently that exogenous prostaglandin E 2 (PGE 2 ) inhibits electrical ®eld stimulation (EFS)-induced acetylcholine (ACh) release from parasympathetic nerve terminals innervating guinea-pig trachea. In the present study, we have attempted to characterize the pre-junctional prostanoid receptor(s) responsible for the inhibitory action of PGE 2 and to assess whether other prostanoids modulate, at a prejunctional level, cholinergic neurotransmission in guinea-pig trachea. 3 H]-ACh release when compared to receptors of the EP 3 -subtype. However, the relative importance of the dierent receptors will depend not only on the sensitivity of guinea-pig trachea to prostanoids but on the nature of the endogenous ligands released locally that have activity on parasympathetic nerves.

Immunohistochemical localization of prostaglandin EP3 receptor in the rat nervous system

“…These results indicate that EP3R may regulate the output mediated by those autonomic preganglionic neurons from the CNS. However, most of pharmacologic studies on the functions of PGE 2 in the autonomic nervous system have focused thus far on the EP3R that is located on peripheral terminals of the autonomic postganglionic nerve fibers (Mantelli et al, 1991;Molderings et al, 1992Molderings et al, , 1994Reinheimer et al, 1998;Spicuzza et al, 1998). Therefore, the distribution of EP3R-LI in this study may help to reveal the unknown roles of PGE 2 in the central autonomic system.…”

“…Many pharmacologic studies have indicated that EP3R functions as a presynaptic receptor (Mantelli et al, 1991;Molderings et al, 1992Molderings et al, , 1994Exner and Schlicker, 1995;Reinheimer et al, 1998;Spicuzza et al, 1998). From the above-mentioned results of the dorsal rhizotomy experiments, it is inferred that the EP3R protein in the spinal dorsal horn is supplied through axons from dorsal root ganglion cells and is located on the presynaptic membrane.…”

“…These various actions of EP3R have been thought to be induced by inhibition of adenylate cyclase or stimulation of Ca 2ϩ mobilization (Negishi et al, 1995). In addition to peripheral actions, EP3R also has been shown to have physiologic roles in the nervous system, such as fever induction (Ushikubi et al, 1998), pain modulation (Kumazawa et al, 1993;Minami et al, 1994;Oka et al, 1997), and regulation of the autonomic nervous system (Mantelli et al, 1991;Molderings et al, 1992Molderings et al, , 1994Yokotani et al, 1996;Reinheimer et al, 1998;Spicuzza et al, 1998). However, the neuronal mechanisms for the diverse functions of EP3R remain obscure.…”

Mediators of Chronic Obstructive Pulmonary Disease

“…Inflammatory cytokines may also activate sphingomyelinase in the cell membrane to generate ceramide, which may also upregulate COX-2 independently of NF-B (Newton et al, 2000). PGE 2 is a bronchodilator of human airways and inhibits the release of proinflammatory cytokines from monocytes (Meja et al, 1997) and acetylcholine release from airway cholinergic nerves (via prostaglandin E 3 receptors) (Spicuzza et al, 1998), suggesting that it may have beneficial effects in COPD airways. Furthermore, PGE 2 markedly enhances the anti-inflammatory actions of phosphodiesterase-4 inhibitors, which are in clinical development as anti-inflammatory therapy for COPD (Au et al, 1998).…”

Lipid Mediators and Lung Function

“…Activation of these receptors leads to protein kinase A-mediated phosphorylation of myosin light-chain kinase, which inhibits actinemyosin interactions and decreases muscle tone. PGE 2 also acts via EP 3 receptors to reduce the release of contractile neurotransmitters from parasympathetic neurons in the lung in animal models (Spicuzza et al, 1998). Similarly, prostacyclin relaxes airway smooth muscle.…”