ono-ae-248 and cicaprost

The hyperalgesic response to prostaglandin E2 (PGE2) is thought to be mediated by activation of the cAMP/protein kinase A pathway in primary sensory neurones. The aim of this study was to investigate the relative contribution of different PGE2 (EP) receptor subtypes to the overall activity of adenylyl cyclase in adult rat isolated dorsal root ganglion (DRG) cells, in vitro. PGE2 and the prostanoid EP4 receptor agonist ONO-AE1-329 increased [3H]cAMP production with EC50 values of 500 nM and 70 nM, respectively, and showed similar efficacies. No combination of prostanoid EP1, EP2, EP3 or EP4 receptor selective agonists produced synergistic increases in [3H]cAMP. The prostacyclin mimetic cicaprost increased [3H]cAMP production with an EC50 value of 42 nM and produced a significantly greater maximal response compared with PGE2. No evidence for prostanoid EP3 receptor-dependent inhibition of adenylyl cyclase activity could be obtained to account for the relatively weak effect of PGE2 compared with prostacyclin receptor agonists. Interestingly, sulprostone (prostanoid EP3/EP1 receptor agonist) caused a Rho-kinase-dependent retraction of neurites, suggesting an alternative role for prostanoid EP3 receptors in DRG cells. In conclusion, PGE2 mediated increases in adenylyl cyclase activity in primary sensory neurones is likely to be mediated by activation of prostanoid EP4 receptors, and is not under inhibitory control by prostanoid EP3 receptors.

Topics: Adenylyl Cyclases; Alprostadil; Amides; Animals; Cell Line; Cells, Cultured; Cyclic AMP; Dinoprostone; Dose-Response Relationship, Drug; Enzyme Activation; Enzyme Inhibitors; Epoprostenol; Ganglia, Spinal; Humans; Intracellular Signaling Peptides and Proteins; Male; Methyl Ethers; Neurites; Prostaglandin D2; Protein Serine-Threonine Kinases; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Receptors, Prostaglandin E, EP4 Subtype; rho-Associated Kinases; Time Factors; Tritium

In order to characterize prostanoid receptors present in the non-pregnant porcine uterus, the effects of naturally occurring prostaglandins (D2, E2, F2alpha, I2) and synthetic prostanoid receptor agonists on contractility of the longitudinal and circular muscles were examined in vitro. The potent contractile actions of prostaglandin F2alpha and cloprostenol indicate the presence of excitatory FP receptors in the porcine uterus. The longitudinal muscle was more sensitive to FP receptor agonists than was the circular muscle. Prostaglandin D2 produced an excitatory response in the longitudinal muscle but completely inhibited the spontaneous contraction of the circular muscle. BW-245C (5-(6-carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl)hydantoin, 1 nM-10 microM, a DP receptor agonist) inhibited the spontaneous contractions of both muscles, but the inhibition was conspicuously stronger in the circular muscle. Prostaglandin I2 caused excitatory and inhibitory responses in the longitudinal and circular muscles, respectively, at relatively high concentrations (10-100 microM). Cicaprost, an IP receptor agonist caused inhibition of the contraction in the circular muscle but contracted the longitudinal muscle. Iloprost, an EP(1)/IP receptor agonist, caused excitatory responses in both muscles at relative high concentrations. Prostaglandin E2 caused excitatory responses at 1-100 nM and inhibitory responses at 100 nM-10 microM in both muscle layers. ONO-DI-004 ((17S)-2,5-ethano-6-oxo-17,20-dimethyl prostaglandin E1, an EP1 receptor agonist) and ONO-AE-248 ((16S)-9-deoxy-9beta-chloro-15-deoxy-16-hyfroxy-17,17-trimethylene-19,20-didehydro prostaglandin F2, an EP3 receptor agonist) contracted the longitudinal muscle but had little effect on the circular muscle. ONO-AE1-259 (11,15-O-dimethyl prostaglandin E2, an EP2 receptor agonist) inhibited the spontaneous contractions of both muscle layers to almost the same degree, but ONO-AE1-329 (16-(3-methoxymethyl)phenyl-omega-tetranor-3,7-dithia prostaglandin E1, an EP4 receptor agonist) did not inhibit the myometrial contraction. The present results indicate that contractile (FP, EP1, EP3) and relaxatory (DP, IP, EP2) prostanoid receptors are present in the non-pregnant porcine uterus. There are marked muscle layer-related differences in the degree of responsiveness of prostanoid receptor agonists, and these differences suggest that there is a heterogeneous distribution of prostanoid receptors in the longitudinal and circular m

Topics: Animals; Cloprostenol; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Epoprostenol; Female; Hydantoins; Iloprost; In Vitro Techniques; Muscle Contraction; Myometrium; Prostaglandin D2; Receptors, Prostaglandin; Swine