Contribution of prostaglandins to the activity of guinea-pig phrenic and chicken esophageal parasympathetic nerves

In order to clarify the role of prostaglandins (PGs) in the activity of cholinergic neurones other than the ileal myenteric plexus, the effects of indomethacin (IND) and PGE2 on the contractile responses and the release of acetylcholine (ACh) induced by electrical stimulation were investigated in isolated guinea-pig phrenic nerve-diaphragm and chicken parasympathetically innervated oesophagus preparations. In the guinea-pig phrenic nerve-diaphragm preparations, IND at 56 microM did not affect the twitch responses induced by direct or indirect electrical stimulation. PGE2 at 1 microgram/ml augmented the twitch responses induced by direct or indirect stimulation of submaximal, but not of supramaximal intensity. The amounts of ACh released from the phrenic nerve by electrical stimulation were unaffected by IND (56 microM). PGE2 (0.01-1 microgram/ml) inhibited the ACh release by the nerve stimulation of high frequency (50 Hz) in a concentration-dependent manner. The inhibitory effect of PGE2 was less clear on the ACh release by lower frequency (1 Hz). Neither IND nor PGE2 affected the ACh release induced by 40 mM-K+. In the chicken parasympathetically innervated oesophagus preparation, IND (2.8-5.6 5.6 microM) augmented the twitch responses induced by the nerve stimulation at a frequency of 0.017 Hz, but not those produced by train pulse (5 sec at a frequency of 1 or 10 Hz). This augmentation was reversed by the application of PGE2 at 10 ng/ml. PGE2 at 10 ng/ml produced a transient inhibition of the twitch responses induced by 0.017 Hz or train pulses.(ABSTRACT TRUNCATED AT 250 WORDS)     

The role of prostaglandins in the spontaneous and cholinergic nerve-mediated motility of guinea-pig gastric muscle

The role of PGE1, PGE2 and PGF2 alpha in the spontaneous and cholinergic nerve-mediated motility of guinea-pig gastric muscle strips was investigated. The prostaglandins (PGs) studied induce dose-dependent tonic activation in the longitudinal strips from fundus, corpus and antrum and inhibition of the phasic activity of circular strips from antrum and pyloric sphincter. These effects are not significantly changed in the presence of adrenergic and cholinergic blocking agents nor with tetrodotoxin, and are, therefore, direct effects on the smooth muscle. Indomethacin exerts effects opposite to those of PGs. The contractile responses of the longitudinal and circular smooth muscles to field stimulation (frequency of 10-20 Hz, duration of 0.5 ms and supramaximal voltage) are inhibited by atropine (1 X 10(-6) M), indicating that cholinergic transmission is involved. PGs potentiate the response of the longitudinal muscles but inhibit the response of the circular muscles to field stimulation. On the contrary, indomethacin (1 X 10(-6) to 1 X 10(-5) M) inhibits the response of the longitudinal and potentiates the response of the circular muscles to field stimulation. The data suggest that PGs may exert a negative feedback control over the excitatory transmission in the circular muscle of the guinea-pig stomach.     

The effects of prostaglandins E1, E2, F1alpha and F2alpha on guinea-pig ileal and colonic peristalis.

Prostaglandins (PGE1, E2, F1alpha and F2alpha) have been tested on the peristaltic reflex in isolated segments of guinea-pig ileum and colon using simultaneous recordings of fluid propulsion and longitudinal and circular muscle activity. Propulsion and circular muscle peristaltic activity were increased by serosally applied PGF compounds in the ileum and PGE or PGF compounds in the colon following initial contraction of the longitudinal muscle. This is consistent with a role for prostaglandins in peristalsis. Mucosally applied PGF compounds has no significant effect.     

Antagonism by fenamates of prostaglandin action in guinea-pig and human alimentary muscle.

1 Low concentrations of meclofenamate, flufenamate or mefenamate had little effect on contractions in response to acetylcholine in any tissue studied. 2 Sodium meclofenamate potently antagonized contractions of guinea-pig ileum longitudinal muscle to prostaglandin E2 (PGE2), PGF2 alpha or PGD2. 3 In guinea-pig colonic longitudinal muscle, contractions to PGE2 were reduced by sodium meclofenamate, but contractions of the longitudinal or circular muscle to PGF2 alpha or PGD2 were less effectively inhibited. 4 In human gastrointestinal longitudinal muscle, sodium meclofenamate or flufenamate potently inhibited contractions to PGF2 alpha, but not to PGE2. 5 Sodium mefenamate or mefenamic acid, even in high concentrations, had little effect on contractions to PGF2 alpha, but tended to inhibit PGE2-induced contractions of human gastrointestinal longitudinal muscle. 6 The therapeutic advantages of prostaglandin synthesis inhibitors which also antagonize responses to certain prostaglandins are discussed.     

The effects of prostaglandins E1, E2, F1α and F2α on guinea-pig ileal and colonic peristalsis

Prostaglandins (PGE₁, E₂, F_1α and F_2α) have been tested on the peristaltic reflex in isolated segments of guinea-pig ileum and colon using simultaneous recordings of fluid propulsion and longitudinal and circular muscle activity. Propulsion and circular muscle peristaltic activity were increased by serosally applied PGF compounds in the ileum and PGE or PGF compounds in the colon following initial contraction of the longitudinal muscle. This is consistent with a role for prostaglandins in peristalsis. Mucosally applied PGF compounds had no significant effect.     

Inhibitory effects of prostaglandin E1 and E2 on cholinergic transmission in isolated canine tracheal muscle.

The contractile response of the isolated canine tracheal muscle to the transmural nerve stimulation was depressed by atropine and augmented by physostigmine, indicating that the response was predominantly mediated via the parasympathetic nerve. The contractile response to the transmural nerve stimulation was inhibited by prostaglandin E1 (PGE1) and E2 (PGE2) (10(-7) to 10(-5) g/ml) and the inhibitory action of PGE1 was more potent than that of PGE2. On the other hand, the contractile response of the tracheal muscle to exogenously administered ACh was unaffected by 10(-6) g/ml of PGE1 and PGE2. These findings lend support to the hypothesis that the PGE series, in a manner similar to adrenergic transmission, are involved in a negative feed-back control mechanism for the transmitter release in cholinergic transmission.     

The contribution of prostaglandins in the muscle of human isolated small intestine to neurogenic responses

1. In stris cut parallel to the longitudinal or circular muscle, indomethacin (2--10 microgram/ml) usually lowered the tone, thus probably accounting for the reduction of nerve-mediated relaxations to electrical field stimulation. 2. In longitudinal muscle strips, indomethacin enhanced contractions which occurred during electrical stimulation, probably because tone fell, but antagonized after-contractions. By contrast, in the circular muscle indomethacin reduced initial contractions but enhanced after-contractions. 3. Prostaglandin E2 counteracted all of the effects of indomethacin in the longitudinal muscle and most of those in the circular muscle; prostaglandin F2alpha restored circular muscle tone. 4. The results suggest that prostaglandins affect the muscle directly and contribute to the regulation of tone. They may also mediate non-cholinergic contraction in longitudinal muscle and suppress contractility in the circular muscle.     

Effects of prostanoids and indomethacin on isolated smooth muscle from the human lower oesophagus.

Smooth muscle strips representing the longitudinal and the circular muscle layers of the oesophageal body and the oesophagogastric junction of the human oesophagus were mounted in organ baths and isometric tension recorded. Transmural field stimulation was applied to strips from both layers of the oesophageal body and to strips from the longitudinal muscle layer of the oesophagogastric junction. This resulted in contractions after cessation of the stimulus train in circular muscle, and in contractions during stimulation in longitudinal muscle preparations. Indomethacin lowered active tension in strips from the circular muscle layer of the oesophagogastric junction, and decreased responses to transmural field stimulation in all strips from the longitudinal muscle layer. The response to transmural field stimulation was increased in strips from the circular muscle layer of the oesophageal body, suggesting an inhibitory function of endogenous prostanoids in this muscle layer. Prostaglandin (PG) F2 alpha and the thromboxane A2 mimic U-46619 increased the responses to transmural field stimulation in all muscle types and the active tension in circular muscle from the oesophagogastric junction. PGE1 and PGE2 increased the responses to transmural field stimulation strips from the longitudinal muscle layer. In circular muscle strips from the oesophageal body responses to transmural field stimulation were inhibited. PGE1 decreased active tension in circular muscle strips from the oesophagogastric junction, whereas PGE2 produced inconsistent effects. These results suggest a role of prostanoids in the regulation of neuromuscular function in the human lower oesophagus. Moreover, exogenous prostaglandins may modulate oesophageal motor function.     

Prejunctional inhibition mediated via alpha 2-adrenoceptors in excitatory transmission of canine small intestine

Noradrenaline(NA) inhibited the contractile responses of longitudinal and circular muscles of canine small intestine to field stimulation (20 Hz, 1 ms, supramaximal voltage for 5 s). The purpose of this study was to see if NA-induced inhibitory action is mediated via alpha 1- or alpha 2-receptors and whether the inhibitory action involved prostaglandins. In both muscle layers the alpha 2-agonist, clonidine inhibited the contractile response to field stimulation more potently than did the alpha 1-agonists phenylephrine or methoxamine. It is suggested that NA-mediated prejunctional inhibition is mediated via alpha 2-receptors. Yohimbine, an alpha 2-adrenoceptor blocking drug antagonized NA-induced prejunctional inhibition, while E-643, an alpha 1-blocker, did not affect the inhibition. These results suggest that the inhibitory action of NA is mediated via alpha 2-receptors in both muscle layers. Indomethacin, an inhibitor of prostaglandin synthesis, did not affect NA-induced prejunctional inhibition in circular muscle, while augmenting it in longitudinal muscle. It is thought that NA-induced prejunctional inhibition is not mediated via prostaglandin release.     

Antagonism of prostanoid-induced contractions of rat gastric fundus muscle by SC-19220, sodium meclofenamate, indomethacin or trimethoquinol.

1 The effects of SC-19220, sodium meclofenamate, indomethacin or trimethoquinol were studied on contractions of the rat stomach longitudinal muscle to prostaglandin D2 (PGD2), PGE2, PGF2 alpha, PGH2, epoxymethano PGH2 analogues, PGI2, 6-keto-PGF1 alpha, 6,15-diketo-PGF1 alpha and thromboxane B2. All the drugs reduced contractions to all the prostanoids, but the degree of reduction differed widely. Selectivity of blockade was assessed by comparison with acetylcholine (ACh). 2 With SC-19220 5 micrograms/ml the effect on thromboxane B2, PGD2 or PGH2 and its epoxymethano analogues was not significantly different from the small effect on ACh, but the other prostanoids were blocked to greater extents. 3 The effect of the cyclo-oxygenase inhibitor sodium meclofenamate, 1 or 2 micrograms/ml, on 6,15-diketo-PGF1 alpha or thromboxane B2 was similar to the small antagonism of ACh, whereas the other prostanoids were blocked to greater extents. Indomethacin, 1 microgram/ml, also reduced contractions to the prostanoids, but antagonism of the PGH2 epoxymethano analogues was considerably less than with meclofenamate. 4 The beta-adrenoceptor stimulant trimethoquinol, 50 ng/ml, was the most potent prostanoid antagonist tested; all the prostanoids except PGE2 were antagonized more than ACh.     

Facilitation of sympathetic neurotransmission in the rat anococcygeus muscle by prostaglandins D2 and F2 alpha.

1 Investigations were made into the effects of prostaglandins D2 (PGD2) and F2 alpha (PGF2 alpha) on the responses of the rat anococcygeus muscle to field stimulation of intrinsic motor (sympathetic) and inhibitory nerves, and to exogenous noradrenaline. 2 PGD2 (2.8 X 10(-6) mol/1) substantially increased the motor responses to field stimulation at all frequencies tested (2 to 32 Hz), and caused a smaller increase in the responses to noradrenaline. 3 PGF2 alpha (2.8 X 10(-6) mol/1) strongly potentiated the motor responses to field stimulation (2 to 32 Hz) and also to noradrenaline. This prostaglandin had quantitatively similar effects on the responses to both types of stimulus. 4 PGD2 was without effect on the inhibitory responses evoked by field stimulation in the presence of guanethidine. PGF2 alpha seemed to reduce the inhibitory responses to low frequencies of stimulation (0.5 to 1.5 Hz), but this effect was marginal. 5 The results suggest that PGD2 facilitates sympathetic neurotransmission in this tissue by both pre- and post-junctional actions. The effect of PGF2 alpha seems likely to be mediated predominantly post-junctionally.     

Inhibition of peristalsis in guinea-pig isolated ileum and colon by drugs that block prostaglandin synthesis.

1 Methods of analysing peristaltic activity have been evaluated by the use of recordings of longitudinal and circular muscle activity and of propulsion in whole segments of guinea-pig ileum and colon. 2 Some prostaglandin synthesis inhibitors, and antagonists of prostaglandin action were tested for their suitability for studying the role of prostaglandins in peristalsis. Aspirin was suitable; at 10-200 mug/ml it had little effect on responses of longitudinal muscle strips of the guinea-pig ileum to acetylcholine (ACh), histamine, nicotine or prostaglandin E2. Indomethacin (1-4 mug/ml) reduced responses to nicotine and prostaglandin E2. The prostaglandin antagonists polyphloretin phosphate and SC-19220 reduced contractions of ileal longitudinal muscle caused by nerve excitation with either nicotine or transmural stimulation. 3 Aspirin (20-100 mug/ml) or indomethacin (1-4 mug/ml) applied serosally greatly inhibited all aspects of peristalsis in guinea-pig ileum and colon. Inhibition of peristalsis of the ileum by aspirin was antagonized by prostaglandin E2 and that by indomethacin was removed by prostaglandin F2alpha or ACh. Inhibition of colonic peristalsis by aspirin was antagonized by prostaglandin E2 but rarely by ACh, and that by indomethacin by prostaglandin E1 or E2. Mucosal application of aspirin had little effect on either ileum or colon but indomethacin caused some inhibition. 4 These results support the supposition that prostaglandins contribute to peristaltic activity.     

Prostaglandin receptors in NIH 3T3 cells: coupling of one receptor to adenylate cyclase and of a second receptor to phospholipase C.

In intact NIH 3T3 murine fibroblasts, prostaglandins (PGs) F2 alpha and E2 induce dose-dependent stimulation of inositol monophosphate generation. PGF2 alpha is greater than 50-fold more potent than PGE2 in eliciting this response. In streptolysin O-permeabilized NIH 3T3 cells, PGF2 alpha and PGE2 induced dose-dependent accumulations of inositol bis- and trisphosphates, which were dependent on the presence of the guanine nucleotide guanosine-5'-O-(3-thio)triphosphate (GTP gamma S) (10 microM). Pretreatment of cells for 16 hr with 100 nM PGF2 alpha resulted in a significant reduction of not only subsequent PGF2 alpha- and PGE2-induced but also GTP gamma S-induced stimulation of inositol phosphate formation in permeabilized cells. PGF2 alpha-induced accumulation of inositol phosphates was partially inhibited by pretreatment with pertussis toxin (1 microgram/ml, 4 hr). The inhibition by pertussis toxin was small but was not related to cyclic AMP formation, because forskolin, which activates adenylate cyclase, did not mimic pertussis toxin-induced inhibition. In the same cell line, PGF2 alpha and PGE2 induced a dose-dependent accumulation of cAMP and a dose-dependent potentiation of 0.5 microM forskolin-stimulated cAMP formation. PGF2 alpha and PGE2 were almost equipotent in eliciting both responses. However, PGF2 alpha was less efficacious than PGE2 and, in the presence of forskolin, PGF2 alpha at 10 microM induced an inhibitory effect on cAMP accumulation. Such inhibition may be related to PGF2 alpha-mediated phospholipase C activation and subsequent stimulation of protein kinase C, because the phorbol ester phorbol 12-myristate-13-acetate, which directly activates protein kinase C, also inhibited forskolin- and PGE2-induced cAMP accumulation. Pretreatment with PGF2 alpha for 16 hr did not reduce subsequent stimulation of cAMP accumulation by PGF2 alpha or PGE2. The results indicate that in NIH 3T3 cells two receptors for PGs are present, one that couples to adenylate cyclase, probably through Gs, and does not exhibit selectivity between PGF2 alpha and PGE2 and a second receptor that couples to phospholipase C through a guanine nucleotide-binding protein that is not sensitive to pertussis toxin pretreatment. The latter shows at least 40-fold selectivity towards PGF2 alpha over PGE2. Because long treatment with PGF2 alpha resulted in desensitization of the GTP gamma S-induced response, it is possible that long exposure to PGF2 alpha may down-regulate the guanine nucleotide-binding involved in phospholipase C signal transduction.     

Cyclo-oxygenase inhibitors antagonize indirectly evoked contractions of the guinea-pig isolated ileum by inhibiting acetylcholine release

The effects of indomethacin, sodium meclofenamate and ketoprofen on the contractile responses of the guinea-pig isolated ileum to directly and indirectly evoked stimuli were investigated. The effects of the cyclo-oxygenase inhibitors on acetylcholine (ACh) release from plexus containing longitudinal muscle strips were also studied. The cyclo-oxygenase inhibitors reduced contractile responses to transmural stimulation (TMS) and nicotine at concentrations which had no effect on ACh-induced contractions. In whole ileum preparations (WIP) indomethacin and ketoprofen (40 micrograms ml-1) reduced TMS responses by 17 +/- 1.8% and 12 +/- 1.8% (n = 6), respectively (30 min incubation). In longitudinal muscle strips (LMS) in which Auerbach's plexus is exposed, indomethacin and ketoprofen (1 microgram ml-1) reduced TMS responses by 28 +/- 2.3% and 34 +/- 2.7% (n = 6), respectively (10 min incubation). Thus the cyclo-oxygenase inhibitors were up to 80 times more effective in LMS than in WIP. The drugs were similarly more effective in blocking nicotine contractions in LMS than in WIP. The cyclo-oxygenase inhibitors reduced basal and stimulated ACh release from LMS. For example, indomethacin (1 microgram ml-1) reduced stimulated ACh release by 35% after 10 min incubation. The percentage inhibition increased to 79% after 40 min incubation (n = 6). Prostaglandin E2 (PGE2) (0.1-2.5 ng ml-1) restored the contractile responses and ACh release depressed by the cyclo-oxygenase inhibitors but not the contractile responses depressed by atropine. PGF2 alpha had no effect on mechanical responses or ACh release depressed by the cyclo-oxygenase inhibitors.(ABSTRACT TRUNCATED AT 250 WORDS)     

EFFECTS OF PROSTAGLANDIN(PG) E2, D2 I2, 6-KETO-PGF1α AND ARACHIDONIC ACID ON EXCITATORY TRANSMISSION OF CANINE SMALL INTESTINE

• 1 Effects of prostaglandin(PG) E₂, D₂, I₂, 6-keto-PGF_1α and arachidonic acid on the excitatory transmission were examined in the separated longitudinal and circular muscles of canine small intestine in vitro.
• 2 Both muscles contracted in response to electrical field stimulation (1 msec, 20 Hz, 100 pulses, supramaximal voltage: indirect stimulation). The contractions were abolished by treatment with tetrodotoxin (0.3 μM). In the presence of tetrodotoxin, the muscle contracted in response to stimulation using a pulse duration of 20msec (direct stimulation). Sites of action of drugs were determined by the difference in their effects on the responses to indirect and direct stimulation.
• 3 PGE₂ strongly inhibited the contractile response of circular muscle to indirect stimulation whilst slightly inhibiting that to direct stimulation. The data suggest that PGE₂ may act on the transmission prejunctionally and reduce the transmitter release in circular muscle.
• 4 PGD₂ and PGI₂ in high concentrations slightly inhibited the contractile responses of circular muscle to both indirect and direct stimulations, indicating that PGD₂ and PGI₂ slightly inhibited the transmission postjunctionally. 6-keto-PGF_1α did not inhibit the transmission of circular muscle.
• 5 Arachidonic acid inhibited the contractile response of circular muscle to indirect stimulation, and indomethacin attenuated the arachidonic acid-induced inhibition. PGE₂, biosynthetized from arachidonic acid, may act on the transmission of circular muscle.
• 6 In the longitudinal muscle, none of PGE₂, PGD₂, PGI₂ or 6-keto-PGF_1α inhibited the contractile response to indirect stimulation. 7 Arachidonic acid slightly inhibited the contractile response of longitudinal muscle to indirect stimulation. However, indomethacin did not antagonize this effect. 8 The results suggest that the transmission of circular muscle in canine small intestine is prejunctionally regulated by PGE₂, and that of longitudinal muscle is slightly affected by arachidonic acid or by metabolites through lipoxygenase.

     

Modification of dyskinesias following the intrastriatal injection of prostaglandins in the rodent.

The abilities of prostaglandin E1 (PGE1), PGE2, PGD2 and PGF2 alpha to antagonize striatal dopamine function were assessed following bilateral and unilateral injections into the striata of the rat and guinea-pig. Three tests were used to assess the effects of the bilateral injections, ability to antagonize dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin (0.025 mg kg-1 s.c.), ability to antagonize stereotyped behaviour induced by apomorphine (0.5 or 2 mg kg-1 s.c.) and ability to induce catalepsy. Asymmetry/circling behaviour revealed on challenge with apomorphine (0.25 mg kg-1 s.c.) was measured following unilateral injection into the striatum. In the rat, dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by PGE1 (0.001-1 micrograms) and PGE2 (0.00001-1 micrograms) but not by PGD2 or PGF2 alpha (1 microgram). Stereotyped behaviour induced by apomorphine was not antagonized by any of the prostaglandins. A weak catalepsy was induced by PGE1 (1 microgram only), PGE2 (0.001-1 micrograms) and PGD2 (0.001-1 micrograms) but not by PGF2 alpha. Asymmetry and circling behaviour was only observed following the unilateral injection into the striatum of PGE1 and PGD2 (0.01-1 microgram) and challenge with apomorphine. In the guinea-pig the actions of PGE1 and E2 were compared with those of PGF2 alpha. Dyskinetic biting induced by 2-di-n-propylamino-5,6-dihydroxytetralin was antagonized by bilateral injections into the striatum of PGE2 (0.001-1 microgram), but not PGE1 (0.5 micrograms) and PGF2 alpha (1 microgram) but not PGE, (0.5 micrograms) and PGF2 alpha (1 microgram).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of nerve stimulation and of administration of noradrenaline or potassium chloride upon the release of prostaglandins, I2, E2, and F2 alpha from te perfused mesenteric arterial bed of the rabbit

1 The release of prostaglandin I2 (PGI2), PGE2 and PGF2 alpha from the perfused mesenteric arterial bed of the rabbit was examined at rest, following nerve stimulation and following noradrenaline (NA) or potassium chloride (KCl) administration. 2 Stimulation of adrenergic nerves at 10 Hz caused a significant increase in the release of both PGI2, (assayed in terms of 6-oxo-PGF1 alpha) and PGE2 but a significant decrease in the release of PGF2 alpha. 3 Exogenous Na (2 micrograms) increased the output of PGI2 and PGE2 but left the output of PGF2 alpha unaffected. 4 KCl (15 mg) significantly increased the output of PGF2 alpha but left the output of PGF2 unaffected. 5 It is concluded that PGI2 and PGE2 output from the mesenteric arterial bed of the rabbit increases following stimulation of adrenoceptors. The sympathetic nervous system may therefore modulate PGI2/platelet interaction. 6 Prostaglandins released from the blood vessels by sympathetic nerve stimulation may also modulate adrenergic transmission to the blood vessels.     

The role of prostaglandins in cholinergic neurotransmission in the guinea pig.

Prostaglandins have contrasting effects on neurotransmission at different cholinergic nerve endings. This is a report on the role of prostaglandins in a number of cholinergic preparations from the guinea pig. In the isolated ileum PGE1 (2 X 10(-10) to 5 X 10(-8) M) potentiated the response to electrical stimulation of the cholinergic nerves. PGE1 (10(-7 M) caused an increase in tone followed by a period of transient inhibition of twitch height. Responses to simulation of the ileum with drugs were not potentiated by PGE1. Responses of atropinized or plexus-free muscle to electrical stimulation were also not potentiated by PGE1. Acetylsalicylic acid (2.5 X 10(-4) M) diminished the twitch response and the output of acetylcholine from the ileum. Both effects were reversed by PGE1. Qualitatively similar observations were made on the trachea. It is concluded that prostaglandins facilitate acetylcholine release in the ileum and trachea. PGE1 diminished the effect of vagal stimulation on the heart rate. The response to stimulation of the phrenic nerve was not affected.     

Modulation of eicosanoid-induced contraction of mouse and rat blood vessels by gingerols

The effects of the active principles of crude ginger (a traditional Sino-Japanese medicine), the gingerols, on the contractile responses to eicosanoids were compared using isolated mouse and rat blood vessels. Leukotrienes (LT) C4 and D4, a thromboxane (TX) A2 derivative (U-46619), prostaglandins (PG) F2 alpha, PGI2-Na, PGE2, the stable PGI2 derivative TRK-100, and PGD2 induced contraction in longitudinal segments of mouse mesenteric veins in that order of potency. Exogenous arachidonic acid and PGE1 did not cause contraction. The mesenteric veins also contracted in response to noradrenaline (NA) and phenylephrine (PhE), but not to clonidine. The gingerols alone relaxed the muscle transiently and then augmented the response to PGF2 alpha, PGE2, PGI2-Na, and TRK-100, but suppressed the response to PGD2, U-46619, LTC4, LTD4, NA and PhE. (+/-)-[6]-Gingerol also potentiated the PGF2 alpha-induced contraction in longitudinal segments of rat mesenteric vein and vena cava, but inhibited it in circular segments of rat aorta and longitudinal segments of mouse mesenteric arteries. These results showed that (+/-)-[6]- and (+/-)-[8]-gingerols potentiated the contraction induced by prostanoids (except PGD2) and inhibited that produced by PGD2, TXA2, and LT, suggesting the modulation of eicosanoids-induced responses by (+/-)-[6]- or (+/-)-[8]-gingerol.     

The action of prostaglandins on ureter smooth muscle of guinea-pig

Prostaglandins of the E type (PGE) relaxed guinea-pig ureter but prostaglandins of the F type (PGF) did not affect smooth muscle contraction. Hyperpolarization and relaxation of the muscle cells caused by the PGEs were achieved at concentrations in a different range, a feature also observed in the presence of forskolin or iso-butyl-methyl-xanthine (IBMX). Hyperpolarization was inhibited in the presence of k-strophanthoside. The c-AMP content of ureter smooth muscle cells was increased in the presence of PGE2. These observations suggest that the PGE-induced hyperpolarization is caused by activation of the sodium-potassium pump and that enhancement of the cellular c-AMP level plays a major role in the PGE-induced relaxation.