Prostaglandin E1 increases myocardial contractility in the conscious dog

The systemic and inotropic properties of prostaglandin E1 (PGE1) were investigated in 20 unanesthetized dogs. Pairs of ultrasonic dimension gauges and a micromanometer were implanted in the subendocardium and the apex of the left ventricle (LV), respectively. Seven to ten days later, increasing doses of PGE1 were infused into the left atrium. To appreciate the inotropic effects of the agent, the heart rate was maintained constant at 150 beats/min in a subgroup of dogs while preload was modified by bleeding or saline infusion over matched ranges of end-diastolic segmental length (EDL) during placebo and PGE1 infusions (0.25 microgram . kg-1 . min-1). LV function curves (delta L: systolic segmental shortening versus EDL) were plotted. Increasing doses of PGE1 above 0.031 microgram . kg-1 . min-1 brought a progressive decrease of left ventricular end-diastolic pressure, EDL, delta L, and peak left ventricular systolic pressure. The heart rate increased significantly at dosages from 0.063 to 0.125 microgram . kg-1 . min-1, and peak positive dP/dt after an initial increase fell at the dose of 0.5 microgram . kg-1 . min-1. The LV function curves invariably showed a shift to the left when PGE1 was administered; as the basal EDL was restored during PGE1 infusion, delta L reached a 33% increase (p less than 0.001). Thus, in addition to its potent vasodilating properties that are more prominent on preload than afterload, PGE1 increases myocardial contractility in the conscious dog.     

Prostaglandin E2 and gestational hypotension in rabbits

Arterial levels of 13,14-dihydro-15-keto-PGE2 (PGE2-M), a stable metabolite of prostaglandin E2 (PGE2) were compared between unanesthetized pregnant (n = 12) and nonpregnant (n = 8) rabbits with the aim of elucidating the role PGE2 in the development of physiological hypotension associated with pregnancy. On the 20th and 22nd days of the 30 day gestation period the mean arterial concentrations of PGE2-M were about 10-times higher (p less than 0.05) and largely variable as compared to that of nonpregnant rabbits. Mean arterial pressure was not lower on either the 20th (69 +/- 4 mmHg, mean +/- SD) or the 22nd (70 +/- 3 mmHg) days of gestation (dg) than in nonpregnant rabbits (69 +/- 4 and 73 +/- 6 mmHg, respectively). On the 23rd dg hypotension was invariably present (61 +/- 5 mmHg vs 72 +/- 4 in nonpregnants, p less than 0.001), but arterial levels of PGE2-M (31.0 +/- 31.6 ng/ml) did not overcome those measured on earlier, normotensive days of gestation. Hypotension was also evident in a subgroup of pregnant rabbits (n = 4) with low PGE2-M concentrations in the nonpregnant range (3.2 +/- 1.5 ng/ml vs 1.9 +/- 1.2 in nonpregnant rabbits, ns). Since the arterial level of PGE2-M proved to correlate (p less than 0.001) with both the uteroplacental venous and renal venous PGE2 concentrations, we suggest that a key role of uteroplacental and renal PGE2 played in the development of gestational hypotension is not probable in rabbits.     

Prostaglandin E1 increases blood flow to the cervix uteri

PGE₁ occurs in high concentration in seminal fluid and is apparently necessary for normal fertility, although its specific function(s) is not known. We investigated the possibility that PGE₁, at seminal fluid concentration, could increase cervical blood flow and, thus, potentially alter cervical mucus properties, including 0₂ concentration. Fifteen μg PGE₁/ml placed directly on the cervix uteri increased cervical blood flow in anesthetized dogs from 0.8±0.7 to 5.7±5.1 ml/gomin 5 min following application without affecting arterial pressure or hepatic or renal blood flow. Seminal PGE₁ may have effects upon oxygen tension in the cervical mucus, as well as aiding leukocyte accumulation in the cervical canal, by increasing cervical blood flow.     

Prostaglandin E2 increases cardiac fibroblast proliferation and increases cyclin D expression via EP1 receptor

PGE(2) affects growth of many cell types. Thus, we hypothesized that PGE(2) would stimulate growth of cardiac fibroblasts. To test our hypothesis we used neonatal rat ventricular fibroblasts (NVF). RT-PCR demonstrated the presence of all 4 PGE(2) receptor (EPs) mRNAs in NVF. Using flow cytometry, we found that PGE(2) decreased the percentage of cells in G0/G1 and increased the number of cells in S phase. PGE(2) also increased expression of cyclin D3, a known regulator of the cell cycle and this effect was mimicked by the EP1/EP3 agonist sulprostone. Next, we found that treatment of NVF with PGE(2) increased phosphorylation of p42/44 MAPK and Akt and that PGE(2)-stimulation of cyclin D3 was antagonized with both a MEK inhibitor and a PI3 kinase inhibitor. In conclusion, PGE(2) stimulates cardiac fibroblast proliferation via EP1 and/or EP3, p42/44 MAPK and Akt-regulation of cyclin D3. These results may be relevant to cardiac fibrosis.     

Prostaglandin E2 enhances transforming growth factor-beta 1 and TGF-beta receptors synthesis: an in vivo and in vitro study

The aims of this study were to determine how Prostaglandin E2 (PGE2) locally applied affected the immunodistribution of latent transforming growth factor-beta 1 (TGF-beta1), and how the eicosanoid modified TGF-beta1 release and TGF-beta receptors gene expression in cultured osteoblasts. PGE2 locally delivered on the rat mandible at doses of 0.1 and 0.05 mg/day, but not 0.025 mg/day, over 20 days significantly increased latent TGF-beta1 immunodistribution (P<0.001), comparing with a placebo-treated group. Cultured osteoblasts stimulated with 10(-5) or 10(-7)M PGE2 significantly varied the level of activated TGF-beta1 released into supernatants at different experimental periods compared with negative and positive controls. TGF-beta receptor type I gene expression was significantly increased in osteoblasts (P<0.01) after 10 days of treatment with 10(-5) and 10(-7)M PGE2, whereas 10(-3) M PGE2 produced the opposite effect. It is concluded that PGE2 may stimulate bone deposition by affecting TGF-beta pathway. This effect on the pathway appears to be dose-dependent.     

Prostaglandin E synthase, a terminal enzyme for prostaglandin E2 biosynthesis

Biosynthesis of prostanoids is regulated by three sequential enzymatic steps, namely phospholipase A2 enzymes, cyclooxygenase (COX) enzymes, and various lineagespecific terminal prostanoid synthases. Prostaglandin E synthase (PGES), which isomerizes COX-derived PGH2 specifically to PGE2, occurs in multiple forms with distinct enzymatic properties, expressions, localizations and functions. Two of them are membrane-bound enzymes and have been designated as mPGES-1 and mPGES-2. mPGES-1 is a perinuclear protein that is markedly induced by proinflammatory stimuli, is down-regulated by antiinflammatory glucocorticoids, and is functionally coupled with COX-2 in marked preference to COX-1. Recent gene targeting studies of mPGES-1 have revealed that this enzyme represents a novel target for anti-inflammatory and anti-cancer drugs. mPGES-2 is synthesized as a Golgi membrane-associated protein, and the proteolytic removal of the N-terminal hydrophobic domain leads to the formation of a mature cytosolic enzyme. This enzyme is rather constitutively expressed in various cells and tissues and is functionally coupled with both COX-1 and COX-2. Cytosolic PGES (cPGES) is constitutively expressed in a wide variety of cells and is functionally linked to COX-1 to promote immediate PGE2 production. This review highlights the latest understanding of the expression, regulation and functions of these three PGES enzymes.     

Prostaglandin E2 increases growth and motility of colorectal carcinoma cells

Chronic use of nonsteroidal anti-inflammatory drugs results in a significant reduction of risk and mortality from colorectal cancer in humans. All of the mechanism(s) by which nonsteroidal anti-inflammatory drugs exert their protective effects are not completely understood, but they are known to inhibit cyclooxygenase activity. The cyclooxygenase enzymes catalyze a key reaction in the conversion of arachidonic acid to prostaglandins, such as prostaglandin E(2) (PGE(2)). Here we demonstrate that PGE(2) treatment of LS-174 human colorectal carcinoma cells leads to increased motility and changes in cell shape. The prostaglandin EP(4) receptor signaling pathway appears to play a role in transducing signals which regulate these effects. PGE(2) treatment results in an activation of phosphatidylinositol 3-kinase/protein kinase B pathway that is required for the PGE(2)-induced changes in carcinoma cell motility and colony morphology. Our results suggest that PGE(2) might enhance the invasive potential of colorectal carcinoma cells via activation of major intracellular signal transduction pathways not previously reported to be regulated by prostaglandins.     

Prostaglandin biosynthesis inhibitors and endometriosis

Prostaglandins (PGs) may be involved in the development of the symptoms of endometriosis. Therefore 18 patients with pelvic endometriosis were treated in placebo controlled double-blind trial with different prostaglandin biosynthesis inhibitors. These drugs were: acetylsalicylic acid (0.5 g x 3) exerting a weak PG-synthetase inhibition, indomethacin (25 mg x 3) inhibiting PG-synthetase, and as a representative of fenamates, tolfenamic acid (200 mg x 3), which both inhibits PG-synthetase and antagonizes PGs at the target level. The therapeutic effect was evaluated using a specific endometriosis score separately during menstruation and in premenstrum. Prostaglandin biosynthesis inhibitors did not alleviate premenstrual complaints better than placebo. During menstruation tolfenamic acid relieved endometriotic symptoms more effectively than placebo while indomethacin and acetylsalicylic acid did not differ from placebo. A drug which inhibit both the synthesis and action of PGs can thus be used in the alleviation of secondary dysmenorrhea due to endometriosis.     

Prostaglandin biosynthesis inhibitors and endometriosis

The prostaglandin biosynthesis inhibitors ketoprofen and indomethacin were compared in the treatment of primary dysmenorrhea in a double-blind, cross-over trial involving 23 patients. Each drug was used for 2–4 days during 3 consecutive menstruations in randomized order. Good or moderate overall relief was obtained in 60 of the 68 ketoprofen-treated menstruations (88 %) and in 60 of the indomethacin-treated cases (90 %). A dysmenorrhea score, based on subjective estimations of 8 symptoms, similarly decreased from a mean (±S.E.M.) basal level of 9.6 ± 0.6 to 3.6 ± 0.3 during ketoprofen treatment and to 4.0 ± 0.3 during indomethacin. Both drugs relieved pelvic and lower back pains and eliminated vomiting and diarrhea in 82–97 % of the cycles whereas headache, fatigue and nervousness were less frequently alleviated (40–67 %). Eighteen of the 23 women (78 %) had been unable to work during the first day of menstruation, the rate of working days lost was reduced to 4 % with ketoprofen and 9 with indomethacin. Mild side-effects occurred during 12 ketoprofen and 14 indomethacin therapies. Ketoprofen thus seems to be as effective and tolerable as indomethacin in the treatment of primary dysmenorrhea.     

Prostaglandin E1 specific binding in rhesus myometrium

Myometrial low speed supernatant prepared from non-pregnant rhesus uteri was incubated with ³H-Prostaglandin (PG)E₁ with or without addition of unlabelled prostaglandins. The uptake of ³H-PGE₁ was inhibited in a dose dependent fashion by PGE₂>PGE₁>PGA₁>PGF_2α=PGA₁>PGB₁=PGB₂≥PGD₂. PGE₁ metabolites inhibited ³H-PGE₁ binding in the following order: 13,14-dihydro-PGE₁>13,14-dihydro-15-keto-PGE₁=15-keto-PGE₁. The specific binding of ³H-PGE₁ and ³H-PGF_2α was similarly affected by the temperature and time of incubation. Equilibrium binding constants determined using rhesus uteri obtained during the luteal phase of the menstrual cycle indicate the presence of high affinity PGE₁ binding sites with an average (n=3) apparent dissociation constant of 2.2 × 10⁻⁹M and a lower affinity PGE₁ binding site with a K_d ≅ 1 × 10⁻⁸M. No high affinity — low capacity ³H-PGF_2α sites could be demonstrated.Relative uterine stimulating potencies of some natural prostaglandins and prostaglandin analogs tested after acute intravenous administration in mid-pregnant rhesus monkeys corresponded with the PGE₁ binding inhibition of the respective compound. The uterine stimulating potencies of the prostaglandin analogs tested were: (15S)-15-methyl-PGE₂=16,16-dimethyl-PGE₂>17-phenyl-18,19,20-trinor-PGE₂>16 phenoxy-17,18,19,20-tetranor-PGF_2α=PGE₂=PGE₁=(15S)-15-methyl-PGF_2α>PGF_2α.     

Prostaglandin synthesis and catabolism in the gastric mucosa: studies in normal rabbits and rabbits immunized with prostaglandin E2

Antral and fundic mucosal homogenates obtained from prostaglandin E2-immunized rabbits converted 14C-arachidonic acid to prostaglandin E2, 6-keto prostaglandin F1 alpha, prostaglandin F2 alpha, and prostaglandin D2. Percentage conversion of 14C-arachidonic acid to these prostaglandin products was not significantly different in prostaglandin E2-immunized rabbits compared with control rabbits (thyroglobulin-immunized and unimmunized rabbits combined). Synthesis of 6-keto prostaglandin F1 alpha, prostaglandin E2 and 13,14-dihydro 15-keto prostaglandin E2 from endogenous arachidonic acid after vortex mixing fundic mucosal homogenates was similar in prostaglandin E2 immunized rabbits and control rabbits. Both in prostaglandin E2-immunized rabbits and controls, 3H-prostaglandin E2 was catabolized extensively by the fundic mucosa, whereas 3H-6-keto prostaglandin F1 alpha, 3H-prostaglandin F2 alpha, and 3H-prostaglandin D2 were not catabolized to any appreciable extent. The rate of catabolism of PGs was not significantly different in prostaglandin E2-immunized rabbits and control rabbits, with the exception of prostaglandin F2 alpha which was catabolized slightly more rapidly in prostaglandin E2-immunized rabbits. These results indicate that development of gastric ulcers in prostaglandin E2-immunized rabbits is not associated with an alteration in the capacity of the gastric mucosa to synthesize or catabolize prostaglandins.     

Lipopolysaccharide increases resistin gene expression in vivo and in vitro

Although resistin has been thought to be an important link between obesity and diabetes, recent results do not support this hypothesis. We speculated that resistin may be involved in inflammatory processes and be induced by inflammatory stimuli. In this study, we tested whether lipopolysaccharide (LPS) induced resistin expression in rats. The results show that resistin mRNA levels in white adipose tissue and white blood cells were increased by LPS treatment. LPS also increased resistin mRNA levels in 3T3-L1 adipocytes and human peripheral blood monocytes. The results suggest that resistin is involved in insulin resistance and probably in other inflammatory responses.