ono-ae-248 and sulprostone

Topics: Acetates; Animals; Benzhydryl Compounds; Biphenyl Compounds; Dinoprostone; Drug Design; Humans; Hydrazines; Oxazepines; Receptors, Prostaglandin E

Human internal mammary arteries (IMA) and saphenous veins (SV) are frequently used for coronary artery bypass graft surgery. Intra- and postoperatively, the bypass grafts are exposed to inflammatory conditions, under which there is a striking increase in the synthesis of prostaglandin E(2) (PGE(2) ). In this context, the physiological response of these vascular grafts to PGE(2) is highly relevant. The aim of this study was thus to characterize the PGE(2) receptor subtypes (EP(1) , EP(2) , EP(3) or EP(4) ) involved in modulation of the vascular tone in these two vessels.. Rings of IMA and SV were prepared from 48 patients. The rings were mounted in organ baths for isometric recording of tension, and a pharmacological study was performed, together with associated reverse transcriptase PCR and immunohistochemistry experiments.. PGE(2) induced contractions of IMA (E(max) = 1.43 ± 0.20 g; pEC(50) = 7.50 ± 0.10); contractions were also observed with the EP(3) receptor agonists, sulprostone, 17-phenyl-PGE(2) , misoprostol or ONO-AE-248. In contrast, PGE(2) induced relaxation of the precontracted SV (E(max) =-0.22 ± 0.02 g; pEC(50) = 7.14 ± 0.09), as did the EP(4) receptor agonist, ONO-AE1-329. These results were confirmed by the use of selective EP receptor antagonists (GW627368X, L-826266, ONO-8713, SC-51322) and by molecular biology and immunostaining.. PGE(2) induced potent and opposite effects on the human vascular segments used for grafting, namely vasoconstriction of the IMA and vasodilatation of the SV via EP(3) and EP(4) receptors respectively. These observations suggest that EP(3) and EP(4) receptors could constitute therapeutic targets to increase vascular graft patency.

Topics: Acrylamides; Aged; Coronary Artery Bypass; Dinoprostone; Female; Humans; Isoindoles; Male; Mammary Arteries; Methyl Ethers; Misoprostol; Naphthalenes; Receptors, Prostaglandin E; Saphenous Vein; Sulfonamides; Vascular Grafting

Gastric emptying depends on functional coupling of slow waves between the corpus and antrum, to allow slow waves initiated in the gastric corpus to propagate to the pyloric sphincter and generate gastric peristalsis. Functional coupling depends on a frequency gradient where slow waves are generated at higher frequency in the corpus and drive the activity of distal pacemakers. Simultaneous intracellular recording from corpus and antrum was used to characterize the effects of PGE(2) on slow waves in the murine stomach. PGE(2) increased slow-wave frequency, and this effect was mimicked by EP(3), but not by EP(2), receptor agonists. Chronotropic effects were due to EP(3) receptors expressed by intramuscular interstitial cells of Cajal because these effects were not observed in W/W(V) mice. Although the integrated chronotropic effects of EP(3) receptor agonists were deduced from electrophysiological experiments, no clear evidence of functional uncoupling was observed with two-point electrical recording. Gastric peristalsis was also monitored by video imaging and spatiotemporal maps to study the impact of chronotropic agonists on propagating contractions. EP(3) receptor agonists increased the frequency of peristaltic contractions and caused ectopic sites of origin and collisions of peristaltic waves. The impact of selective regional application of chronotropic agonists was investigated by use of a partitioned bath. Antral slow waves followed enhanced frequencies induced by stimulation of the corpus, and corpus slow waves followed when slow-wave frequency was elevated in the antrum. This demonstrated reversal of slow-wave propagation with selective antral chronotropic stimulation. These studies demonstrate the impact of chronotropic agonists on regional intrinsic pacemaker frequency and integrated gastric peristalsis.

Topics: Alprostadil; Animals; Biological Clocks; Dibenz(b,f)(1,4)oxazepine-10(11H)-carboxylic acid, 8-chloro-, 2-acetylhydrazide; Dinoprostone; Membrane Potentials; Mice; Mice, Inbred BALB C; Mice, Mutant Strains; Muscle, Smooth; Peristalsis; Prostaglandins; Prostaglandins E, Synthetic; Pyloric Antrum; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP1 Subtype; Receptors, Prostaglandin E, EP2 Subtype; Receptors, Prostaglandin E, EP3 Subtype; Stomach

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

The pharmacologic actions of prostaglandin E(2) (PGE(2)) are mediated through specific E-prostanoid (EP)-1, EP-2, EP-3, and EP-4 receptors. In this study, we determined which PGE(2) receptor subtype(s) contribute to the prevention of allergen-induced bronchoconstriction.. We assessed the effects of these receptor agonists in ovalbumin (OA)-sensitized guinea pigs. The prostaglandin E receptor-subtype agonists tested were ONO-DI-004 (EP-1), ONO-AE1-259 (EP-2), ONO-AE-248 (EP-3), ONO-AE1-329 (EP-4), and sulprostone (EP-1 and EP-3) [Ono Pharmaceutical Company; Osaka, Japan]. We treated the animals with either PGE(2) or these agonists 15 min before OA challenge and measured respiratory resistance at 15 min, 1 h, and 3 h.. Allergen-induced bronchoconstriction was significantly (p < 0.01) suppressed at doses > 85 nmol/kg of PGE(2). The respiratory resistance elevations 15 min after OA challenge were significantly (p < 0.01) suppressed by preadministration of EP-2 and EP-4 agonists, but airway responsiveness to inhaled methacholine did not improve. EP-1, EP-3, or EP-1/EP-3 agonists had no effect on any parameter.. These results suggest that inhibition of OA-induced bronchoconstriction by PGE(2) acts through EP-2 and EP-4 receptors.

Topics: Alprostadil; Animals; Bronchial Provocation Tests; Bronchoconstriction; Bronchoconstrictor Agents; Dinoprostone; Guinea Pigs; Male; Methacholine Chloride; Methyl Ethers; Receptors, Prostaglandin E; Vasodilator Agents