Infusion Of Prostaglandin D2 Research Articles

Early-life ruminal microbiome-derived indole-3-carboxaldehyde and prostaglandin D2 are effective promoters of rumen development

BackgroundThe function of diverse ruminal microbes is tightly linked to rumen development and host physiology. The system of ruminal microbes is an excellent model to clarify the fundamental ecological relationships among complex nutrient–microbiome–host interactions. Here, neonatal lambs are introduced to different dietary regimes to investigate the influences of early-life crosstalk between nutrients and microbiome on rumen development.ResultsWe find starchy corn-soybean starter-fed lambs exhibit the thickest ruminal epithelia and fiber-rich alfalfa hay-fed lambs have the thickest rumen muscle. Metabolome and metagenome data reveal that indole-3-carboxaldehyde (3-IAld) and prostaglandin D2 (PGD2) are the top characteristic ruminal metabolites associated with ruminal epithelial and muscular development, which depend on the enhanced ruminal microbial synthesis potential of 3-IAld and PGD2. Moreover, microbial culture experiment first demonstrates that Bifidobacterium pseudolongum is able to convert tryptophan into 3-IAld and Candida albicans is a key producer for PGD2. Transcriptome sequencing of the ruminal epithelia and smooth muscle shows that ruminal epithelial and muscular development is accompanied by Wnt and Ca2+ signaling pathway activation. Primary cell cultures further confirm that 3-IAld promotes ruminal epithelial cell proliferation depending on AhR-wnt/β-catenin signaling pathway and PGD2 accelerates ruminal smooth muscle cell proliferation via Ca2+ signaling pathway. Furthermore, we find that 3-IAld and PGD2 infusion promote ruminal epithelial and musculature development in lambs.ConclusionsThis study demonstrates that early-life ruminal microbiome-derived 3-IAld and PGD2 are effective promoters of rumen development, which enhances our understanding of nutrient–microbiome–host interactions in early life.

Adenosine A2A receptor deficiency attenuates the somnogenic effect of prostaglandin D2 in mice.

Prostaglandin D2 (PGD2) is one of the most potent endogenous sleep promoting substances. PGD2 activates the PGD2 receptor (DPR) and increases the extracellular level of adenosine in wild-type (WT) mice but not DPR knockout (KO) mice, suggesting that PGD2-induced sleep is DPR-dependent, and adenosine may be the signaling molecule that mediates the somnogenic effect of PGD2. The aim of this study was to determine the involvement of the adenosine A2A receptor (A2AR) in PGD2-induced sleep. We infused PGD2 into the lateral ventricle of WT and A2AR KO mice between 20:00 and 2:00 for 6 h, and electroencephalograms and electromyograms were simultaneously recorded. In WT mice, PGD2 infusion dose-dependently increased non-rapid eye movement (non-REM, NREM) sleep, which was 139.1%, 145.0% and 202.7% as large as that of vehicle-treated mice at doses of 10, 20 and 50 pmol/min, respectively. PGD2 infusion at doses of 20 and 50 pmol/min also increased REM sleep during the 6-h PGD2 infusion and 4-h post-dosing periods in WT mice to 148.9% and 166.7%, respectively. In A2AR KO mice, however, PGD2 infusion at 10 pmol/min did not change the sleep profile, whereas higher doses at 20 and 50 pmol/min increased the NREM sleep during the 6-h PGD2 infusion to 117.5% and 155.6%, respectively, but did not change the sleep in the post-dosing period. Moreover, PGD2 infusion at 50 pmol/min significantly increased the episode number in both genotypes but only enhanced the episode duration in WT mice. The results demonstrate that PGD2-induced sleep in mice is mediated by both adenosine A2AR-dependent and -independent systems.

Discrepancy between strong cephalic arterial dilatation and mild headache caused by prostaglandin D2 (PGD2)

Prostaglandins (PGs) are involved in nociception and mast cell degranulation. Prostaglandin D₂ (PGD₂) is a vasodilatator released during mast cell degranulation. The headache-eliciting effect of PGD₂ has not been studied in man. Twelve healthy volunteers were randomly allocated to receive intravenous infusion of 384 ng/kg/min PGD₂ over 25 min in a placebo-controlled, double-blind cross-over study. We recorded headache intensity and associated symptoms, velocity in the middle cerebral artery (V(MCA)) and diameter of the superficial temporal artery (STA) and radial artery (RA) using ultrasonography. In the period 0-14 h, 11 subjects reported headache on PGD₂ compared to one subject on placebo (P = 0.002). During the in-hospital phase (0-120 min), the area under the headache curve was larger on PGD₂ compared to placebo (P < 0.05). Median peak headache, 1 (0-1), occurred 10 min after start of PGD(2) infusion. There was no difference in incidence of headache in the post-hospital phase between PGD₂ (n = 3) and placebo (n = 1). There was a decrease in V(MCA) (P < 0.001), increase in STA (P < 0.001) and RA (P < 0.006) diameter during PGD₂ infusion compared to placebo. Peak decrease in V(MCA) was 28.3% after 10 min and peak increase in STA was 55.7% after 20 min on the PGD₂ day. The present study shows that PGD₂ is a very strong vasodilator of MCA, STA and RA, but causes only mild headache.

Tetranor PGDM, an Abundant Urinary Metabolite Reflects Biosynthesis of Prostaglandin D2 in Mice and Humans

Prostaglandin D(2) (PGD(2)) is a cyclooxygenase (COX) product of arachidonic acid that activates D prostanoid receptors to modulate vascular, platelet, and leukocyte function in vitro. However, little is known about its enzymatic origin or its formation in vivo in cardiovascular or inflammatory disease. 11,15-dioxo-9alpha-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor PGDM) was identified by mass spectrometry as a metabolite of infused PGD(2) that is detectable in mouse and human urine. Using liquid chromatography-tandem mass spectrometry, tetranor PGDM was much more abundant than the PGD(2) metabolites, 11beta-PGF(2alpha) and 2,3-dinor-11beta-PGF(2alpha), in human urine and was the only endogenous metabolite detectable in mouse urine. Infusion of PGD(2) dose dependently increased urinary tetranor PGDM > 2,3-dinor-11beta-PGF(2alpha) > 11beta-PGF(2alpha) in mice. Deletion of either lipocalin-type or hemopoietic PGD synthase enzymes decreased urinary tetranor PGDM. Deletion or knockdown of COX-1, but not deletion of COX-2, decreased urinary tetranor PGDM in mice. Correspondingly, both PGDM and 2,3-dinor-11beta-PGF(2alpha) were suppressed by inhibition of COX-1 and COX-2, but not by selective inhibition of COX-2 in humans. PGD(2) has been implicated in both the development and resolution of inflammation. Administration of bacterial lipopolysaccharide coordinately elevated tetranor PGDM and 2,3-dinor-11beta-PGF(2alpha) in volunteers, coincident with a pyrexial and systemic inflammatory response, but both metabolites fell during the resolution phase. Niacin increased tetranor PGDM and 2,3-dinor-11beta-PGF(2alpha) in humans coincident with facial flushing. Tetranor PGDM is an abundant metabolite in urine that reflects modulated biosynthesis of PGD(2) in humans and mice.

Activation of ventrolateral preoptic neurons by the somnogen prostaglandin D2.

Prostaglandin D2 (PGD2) is an extensively studied sleep-promoting substance, but the neuroanatomical basis of PGD2-induced sleep is only partially understood. To determine potential regions involved in this response, we used Fos immunohistochemistry to identify neurons activated by infusion of PGD2 into the subarachnoid space below the rostral basal forebrain. PGD2 increased nonrapid eye movement sleep and induced striking expression of Fos in the ventrolateral preoptic area (VLPO), a cluster of neurons that may promote sleep by inhibiting the tuberomammillary nucleus, the source of the ascending histaminergic arousal system. Fos expression in the VLPO was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus. PGD2 also increased Fos immunoreactivity in the basal leptomeninges and several regions implicated in autonomic regulation. These observations suggest that PGD2 may induce sleep via leptomeningeal PGD2 receptors with subsequent activation of the VLPO.

Reduction of bile secretion by prostaglandins in the rat in vivo

Bile secretion has been reported to be regulated by circulating hormones and by autonomic liver nerves. In the in situ perfused rat liver, prostaglandins reduce bile flow and bile acid secretion. The aim of this study was to investigate the regulation of bile secretion by prostaglandins in the in vivo situation. The bile duct and portal vein of anaesthetised Wistar rats were cannulated by polyethylene tubes. Bile flow was determined gravimetrically. Bile acids were quantified by the 3-α-hydroxy-steroid-dehydrogenase method and by high-pressure-liquid-chromatography (HPLC) separation. Administration of 1 μM prostaglandin F2α into the portal vein over 5 minutes reduced bile flow from 1.57 μl/min.g liver to 0.95 μl/min.g liver and bile acids secretion from 148 to 81 nmol/100g/min. The administration of different doses (0.1 μM, 1 μM, 10 μM) of prostaglandin F2α reduced hepatic bile secretion in a dose-dependent manner. Similar effects were observed after infusion of prostaglandin D2. However, the ratio of the bile acids (alpha-tauromuricholic acid, beta-tauromuricholic acid, taurocholic acid, taurochenodeoxycholic acid, and tauro-deoxycholic acid) was unchanged by prostaglandin F2α. In conclusion, infusion of prostaglandin F2α into the portal vein results in a reduction of bile flow and bile acid secretion in a dose-dependent manner. These results suggest that the effect is linked to canicular bile secretion.

Prostaglandin D2, a cerebral sleep-inducing substance in monkeys.

The sleep-inducing effect of prostaglandin D2 (PGD2) was studied in five conscious male rhesus monkeys (Macaca mulatta) maintained in a 12-hr light/dark cycle. PGD2 was infused into the lateral or the third ventricle of the cerebrum slowly and continuously for 6 hr in the light period. Infusion of PGD2 into the lateral ventricle at 15-2250 pmol/min induced natural sleep as identified by electroencephalogram, electromyogram, electrooculogram, body temperature, heart rate, and animal behavior. Although sensitivity to PGD2 was slightly different among individual animals, the amount of total sleep time increased maximally up to 3- to 4-fold over the control level. PGD2 infused into the third ventricle induced effects similar to those observed for the lateral ventricular route, but infusion into the third ventricle was about 1000 times more effective than infusion into the lateral ventricle. In three monkeys, PGD2 increased the amount of sleep in a dose-dependent manner. Bell-shaped dose-response curves were observed for the other two monkeys. Infusion of prostaglandin E2 or F2 alpha into the lateral ventricle caused sedation but slightly reduced the amount of slow-wave sleep and produced increases in heart rate and body temperature. These findings suggest that endogenous PGD2 may be involved in the regulation of sleep by acting on the brain structures surrounding the third ventricle in the rhesus monkey.

Effects of prostaglandin D2 on the activity of hypothalamic neurons in the rat.

The effects of electrophoretically applied prostaglandin D2 (PGD2) on neuronal activity in the rat lateral preoptic area (LPOA) and posterior hypothalamic area (PHA) were examined. In the LPOA, 20% of the tested neurons were excited, 26% inhibited, and 6% showed bidirectional response. The direct effects often showed desensitization after repeated applications. Neurons excited by PGD2 were significantly sensitive (excitation) to acetylcholine (ACh). The ACh excitatory effect was sometimes (38%) attenuated, blocked, or reversed by concurrent PGD2 application. Excitatory or inhibitory effect of noradrenaline (NA) was not related to the effects of PGD2; however, modulation of the NA responses by PGD2 was common (58%). Inhibition, the predominant NA response, was changed to no effect or to excitation during simultaneous PGD2 application. Changes of the NA responses from inhibition to excitation, or from excitation to inhibition-excitation sequences were observed after PGD2 infusion into the third cerebral ventricle at low concentrations. In 43% of the cells, neurotransmission in the LPOA following ventral noradrenergic bundle stimulation was modified by PGD2 application. PGD2 application tended to reduce the duration of inhibition and to extend that of excitation. The direct effects of PGD2 in the PHA were similar to those in the LPOA. Desensitization was also observed in the PHA, but no interrelations were observed among the effects of PGD2, ACh, and NA. Modulation of ACh and NA responses by PGD2 was rarely seen in the PHA. Possible contributions of PGD2 to sleep and thermoregulation are discussed.

Inotropic effects of prostaglandin D2 and E1 on the newborn rabbit heart.

This study determines the inotropic effects of prostaglandin D2 (PGD2) and prostaglandin E1 (PGE1) in the isolated, arterial perfused newborn (NB) and adult (A) rabbit heart. Significant positive inotropism of PGD2 was observed at all concentrations studied (1 X 10(-17) to 1 X 10(-7) M) in the two age groups; the effect in the NB was significantly greater (p less than 0.05) than that in the A at PGD2 concentrations higher than 1 X 10(-17) M. Significant positive inotropism of PGE1 was observed at PGE1 concentrations higher than 1 X 10(-8) M in the NB, and only at 1 X 10(-6) M in the A. In the NB, the relaxation parameters [1/2 RT and the ratio of +dT/dt (max) to -dT/dt (max)] decreased to 80% of control after PGE1 infusion, but not after PGD2 infusion. In contrast, relaxation parameters in the A were not different from control. Propranolol (1 X 10(-6) M) did not alter the positive inotropic action of PGD2 and PGE1 in the NB. These data indicate that: 1) the positive inotropic effects of PGD2 and PGE1 in NB are greater than that in the A, 2) PGE1 and not PGD2, enhances myocardial relaxation only in the NB, 3) the contractile effects of PGD2 and PGE1 are not mediated by beta-receptors.

Prostaglandin D2 in canine endotoxic shock: Hemodynamic, hematologic, biochemical, and blood gas analyses

This canine study was designed to evaluate the effects of the intravenous infusion of coliform endotoxin with a simultaneous infusion of prostaglandin D2 (PGD2) on hemodynamics, blood gas, blood chemistry, and some hematologic parameters. The information derived from the present study supports the view that the intravenous administration of PGD2 moderates the effects of endotoxin, with its main beneficial effect being on the renal vascular bed. Treatment with PGD2 did not change the endotoxin-induced hemoconcentration, or the reduction in the platelet and white blood cell counts. However, four of nine animals survived more than 7 days when treated with PGD2, whereas without it only one of nine animals survived the administration of the same dose of endotoxin. Although the mechanism of action is not clear, the correlation between PGD2 infusion and improved renal blood flow warrants further study in endotoxic shock.

Prostaglandin D2 induces release of luteinizing hormone from the rat pituitary gland without the modulation of hypothalamic luteinizing hormone releasing hormone.

The effect of prostaglandin D2 (PGD2) on release of LH and LH releasing hormone (LHRH) was studied in a sequential double-chamber superfusion system using the medial basal hypothalamus (MBH) and the pituitary gland from female rats at dioestrus. Infusion of PGD2 (5.7 or 57 mumol/l) caused a significant (P less than 0.05) increase in LH release to values 40-60% above the preinjection values from the pituitary gland superfused either alone or in series with the MBH. No release of LHRH in response to PGD2 was observed from the superfused MBH. These data demonstrate that PGD2 causes LH release from the pituitary gland not by inducing release of hypothalamic LHRH but by a direct action on the gland.

Prostaglandin D2, a cerebral sleep-inducing substance in rats.

We continuously monitored the circadian sleep patterns of unrestrained rats for more than 96 hr and infused various prostaglandins into their third ventricles for 10 hr to study the effects on inducing sleep. Prostaglandin D2 at 6 fmol/min had no effect on either slow wave sleep or paradoxical sleep. However, prostaglandin D2 at as little as 60 fmol/min caused a significant amount of excess slow wave sleep as compared with the control level during saline infusion. Paradoxical sleep was induced by prostaglandin D2 at doses greater than 600 fmol/min. Prostaglandin D2 (600 fmol/min) increased slow wave sleep by 33% and paradoxical sleep by 56%. Although prostaglandin F2 alpha (600 fmol/min) increased the amount of slow wave sleep, its activity was less than that of the same amount of prostaglandin D2. Prostaglandin E2 (600 fmol/min) had no effect on increasing the amounts of both slow wave sleep and paradoxical sleep. During the infusion of prostaglandin D2, rats were easily aroused by clap sound stimulation and their sleeping and waking postures remained normal. Further, their sleep was episodic, as observed in the physiological sleep of rats.

Effects of PGD2 on canine renal function.

IN many tissues, especially the mammalian kidney, prostaglandin D2 (PGD2) is a significant product in the metabolism of the bisenoic prostaglandin endoperoxides1,2. PGD2 was originally reported to have negligible biological activity1; but, subsequent workers noted that it produces vascular effects in several species3,4. Although the effects in the kidney of the precursor, arachidonic acid, and other prostaglandins (PGs)5–7 have attracted much interest, the effects of PGD2 have received little attention. Since PGD2 may be an important product of arachidonate metabolism in the kidney8,9, the renal response to an infusion of PGD2 in the dog was examined and compared with the response to an infusion of PGE2. Whereas both PGs produced an increase in renal blood flow, only PGE2 caused a diuresis and natriuresis. This suggests that PGD2 in the kidney is primarily involved in the control of renal haemodynamics, and does not participate in the regulation of fluid and electrolyte excretion.