gr-63799x and sulprostone

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

We wished to determine whether any evidence indicates that the ductus arteriosus has prostanoid receptors coupled to contractile pathways and whether the sensitivity of the ductus to the dilator effect of prostaglandin E2 (PGE2) was inhibited by other prostanoids. Rings of ductus arteriosus were isolated from fetal New Zealand White rabbits (28 days of gestation) and mounted in vitro. In the presence of 1 microM indomethacin, the vessel was relaxed with either 300 nM forskolin or 10 nM PGE2, and cumulative concentration-contraction response curves to several synthetic prostanoids were obtained with or without a receptor antagonist when available. The vessel was also precontracted with 1 microM indomethacin and 25 mM K+ in 13-14.5 kPa O2, and cumulative concentration-relaxation response curves to PGE2 were obtained with and without addition of prostanoids. In 300 nM forskolin, both U46619 and sulprostone caused concentration-dependent contractions of the ductus in the nanomolar range (EC50 values, i.e., the interpolated molar concentration of the drug causing 50% of its own eventual maximum response of 33 and 42 nM, respectively). Responses to GR63799X and PGF2 alpha were complicated by the fact that these agonists caused relaxation at high concentrations (> or = 30 nM). The response to U46619 was shifted to the right by the thromboxane receptor antagonist EP 092. In 10 nM PGE2, U46619, sulprostone, and GR63799X elicited similar contractile responses, whereas PGF2 alpha had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Analysis of Variance; Animals; Colforsin; Dinoprost; Dinoprostone; Dose-Response Relationship, Drug; Ductus Arteriosus; Female; In Vitro Techniques; Indomethacin; Muscle Contraction; Muscle Relaxation; Muscle, Smooth, Vascular; Pregnancy; Prostaglandin Endoperoxides, Synthetic; Prostaglandins E, Synthetic; Rabbits; Receptors, Prostaglandin; Thromboxane A2; Thromboxanes; Vasoconstrictor Agents