Role of extracellular calcium in the metabolic and hemodynamic actions of sympathetic nerve stimulation, noradrenaline and prostaglandin F2 alpha in perfused rat liver. Differential inhibition by nifedipine and verapamil

In perfused rat liver hepatic nerve stimulation (10 Hz, 2 ms) caused an increase in glucose and lactate output, a decrease in flow and an overflow of noradrenaline into the hepatic vein. Noradrenaline (1 microM) (NA) and prostaglandin F2 alpha (5 microM) (PGF2 alpha), which are implicated as mediators of nerve action, elicited similar effects. 1) All actions of nerve stimulation and the hemodynamic but not the metabolic effects of noradrenaline and PGF2 alpha were largely dependent on extracellular calcium. 2) The dihydropyridine type calcium antagonist nifedipine (5 microM) inhibited the hemodynamic but not the metabolic actions of nerve stimulation, NA and PGF2 alpha, while the phenylalkylamine type calcium antagonist verapamil (5 microM) had no effect. These findings allow the following conclusions: Calcium influx into I nerve endings, necessary for the release of neurotransmitter, II parenchymal cells, for the display of metabolic effects induced by nerve stimulation, and III the actions of NA and PGF2 alpha, do not appear to be mediated by the normal affinity nifedipine- or the verapamil-sensitive channels. Calcium influx into vascular smooth muscle and/or endothelial cells for the display of hemodynamic action induced by nerve stimulation and the NA and PGF2 alpha effects, appear to occur through nifedipine-sensitive but verapamil-insensitive channels.     

Mechanism of action of arachidonic acid in the isolated perfused rat heart

The purpose of this study was to elucidate the mechanism of action of arachidonic acid in the isolated rat heart perfused with Krebs solution at a constant flow. Administration of arachidonic acid, 3.3-33 nmol, into the heart caused a small transient increase followed by a pronounced decrease in coronary perfusion pressure and increased myocardial tension, heart rate, and the output of prostaglandins (6-keto-PGF1 alpha, PGE2, and PGF2 alpha). Administration of structurally similar fatty acids, dihomo-gamma-linolenic acid, and 8,14,17-eicosatrienoic acid, produced vasoconstriction and decreased myocardial tension without affecting heart rate or the output of prostaglandins. Infusion of PGI2, PGF2 alpha, or PGE2 produced coronary vasodilation and increased myocardial tension, whereas PGF2 alpha increased heart rate, an effect which was not prevented by propranolol. Indomethacin blocked the effect of arachidonic acid on myocardial tension and heart rate, but only reduced the duration of coronary vasodilation. The initial component of arachidonic acid induced coronary vasodilation which was unaffected by indomethacin and also remained unaltered during the infusion of three structurally dissimilar lipoxygenase inhibitors, eicosatetraynoic acid, nordihydroguaiaretic acid, and 1-phenyl-3-pyrazolidone. Indomethacin did not alter the effects of the exogenously administered prostaglandins on perfusion pressure or myocardial tension; however, it blocked the effect of PGF2 alpha on heart rate. The effect of arachidonic acid or PGF2 alpha to increase heart rate was not blocked by thromboxane synthetase inhibitors, imidazole, or OKY-1581. We conclude that the cardiac effects of arachidonic acid are mediated primarily through its conversion to cyclooxygenase products.(ABSTRACT TRUNCATED AT 250 WORDS)     

Synergistic effect of prostaglandin F2alpha and cyclic AMP on glucose transport in 3T3-L1 adipocytes

The combined effect of prostaglandin F2alpha (PGF2alpha) and cAMP on glucose transport in 3T3-L1 adipocytes was examined. In cells pretreated with PGF2alpha and 8-bromo cAMP for 8 h, a synergy between these two agents on glucose uptake was found. Insulin-stimulated glucose transport, on the other hand, was only slightly affected. The synergistic effect of these two agents was suppressed in the presence of cycloheximide and actinomycin D. In concord, immunoblot and Northern blot analyses revealed that GLUT1 protein and mRNA levels were both increased in cells pretreated with both PGF2alpha and 8-bromo cAMP, greater than the additive effect of each agent alone. The synergistic action of PGF2alpha with 8-bromo cAMP to enhance glucose transport was inhibited by GF109203X, a selective protein kinase C (PKC) inhibitor. In addition, in cells depleted of diacylglycerol-sensitive PKC by prolonged treatment with 4beta-phorbol 12beta-myristate 13alpha-acetate, a PKC activator, the synergistic effects of PGF2alpha and 8-bromo cAMP on glucose transport and GLUT1 mRNA accumulation were both abolished. Taken together, these results indicate that PGF2alpha may act with cAMP in a synergistic way to increase glucose transport, probably through enhanced GLUT1 expression by a PKC-dependent mechanism.     

Effects of insulin and prior exercise on prostaglandin release from perfused rat muscle. Evidence that prostaglandins do not mediate changes in glucose uptake.

Prostaglandin generation and its inter-relation to the metabolic effects of insulin and prior exercise were examined in perfused muscle of fed rats. During a 60 min perfusion of the rat hindquarter, a substantial release of the prostaglandins PGF2 alpha, PGE2 and 6-oxoPGF1 alpha was observed. Blood cells present in the perfusate released these substances in negligible amounts indicating the prostaglandins were produced by the hindquarter. Addition of insulin to the perfusate increased both glucose uptake and the generation of PGE2 and 6-oxoPGF1 alpha. At 30 min after intense treadmill exercise, glucose and alpha-aminoisobutyric acid (AIB) uptake by the hindquarter were increased in the absence of added insulin, but prostaglandin release was not increased. Insulin further increased glucose and AIB uptake; however, in contrast with its effects in non-exercised rats, insulin no longer stimulated prostaglandin generation. Indomethacin (10 microM) added to the perfusate inhibited the release of PGF2 alpha and PGE2 by 90% and the release of 6-oxoPGF1 alpha by 54%. It had no effect on the stimulation of glucose uptake by either insulin or prior exercise. The data indicate that insulin increases prostaglandin synthesis by perfused rat muscle, and that prior exercise blocks this effect. They suggest that under the conditions studied prostaglandins do not mediate the effects of insulin or prior exercise on glucose uptake.     

A novel enhancing effect of platelet activating factor (PAF) on glucose oxidation in uteri from pregnant rats. Participation of prostaglandins and leukotrienes

The effects of platelet activating factor (PAF) on glucose oxidation in uterine strips isolated from rats in the 4 th and 5 th day of pregnancy, were explored. PAF, at a concentration of 10(-10) and 10(-8) M, augmented significantly the generation of 14CO2 from labelled glucose in uteri from pregnant rats in the 4 th day of pregnancy. When the tissue was obtained from 5 days pregnant rats, the addition of PAF at 10(-8) increased significantly more than PAF at 10(-10) M the metabolism of glucose. On the other hand, PAF at 10(-8) M failed to alter the uterine basal production of 14CO2 from labelled glucose in animals at estrus. BN52021, a specific PAF antagonist employed at 10(-5) M, blocked completely the action of PAF in the pregnant rat uterus. PGE1, PGE2 and PGF2 alpha enhanced significantly the formation of 14CO2 from labelled glucose in uteri from 5 days pregnant rats. Indomethacin, a well known inhibitor of prostaglandin synthesis, did not alter the basal glucose metabolism in uteri from 5 days pregnant rats, but antagonized completely the stimulating action of PAF on 14CO2 production from labelled glucose an effect that was partially reverted by the addition of PGE1, PGE2 or PGF2 alpha (10(-7) M). Furthermore, nordihydroguaiaretic acid (NDHGA), a specific inhibitor of 5-lipoxygenase at 10(-5) M, as well as FPL-55712, an antagonist of leukotrienes (LTs), at the same concentration, blocked the action of PAF on the metabolism of glucose. The action of NDHGA was partially counteracted by the addition of LTC4 at 10(-7) M.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of PGF2 alpha on in vivo cerebral arteriolar diameter in cats and rats

We compared the effect of topical application of PGF2 alpha on cerebral arterioles in cats and rats equipped with an acutely implanted cranial window. Arterial diameter was measured using a microscope and image splitting device. PGF2 alpha in a concentration ranging from 10(-7) to 10(-5) M had no effect on large (greater than or equal to 100 microns) or small (less than 100 microns) cat pial arterioles, but induced a dose dependent constriction of rat pial arterioles with a maximum constriction to 76% of control diameter. Dilation of cat large cerebral arterioles by topically applied PGE2 was not affected by simultaneous application of PGF2 alpha and PGE2 induced dilation of small arterioles was decreased 3% by PGF2 alpha. While we and others have previously shown that both cat and rat brain can synthesize PGF2 alpha, it appears that PGF2 alpha is not likely to normally be a major modulator of cerebral arteriolar resistance in all species.     

Requirement for prostaglandin F2 alpha in 17 beta-estradiol stimulation of DNA synthesis in rabbit endometrial cultures

We have hypothesized that two of the endogenously synthesized endometrial prostaglandins (PGs), prostaglandin F2 alpha (PGF2 alpha), and prostaglandin E1 (PGE1), play a regulatory role in growth control of the rabbit endometrium. PGF2 alpha increases DNA synthesis and PGE1 inhibits that effect. Primary cultures of rabbit endometrial cells were used to examine the possible role of these PGs in the mechanism of action of 17 beta-estradiol on DNA synthesis. Towards this end, binding, second messenger and DNA synthesis experiments were performed. 17 beta-estradiol stimulation resulted in a time dependent (optimal: approximately 6 h) and 17 beta-estradiol concentration dependent (optimal: approximately 10(-7) M 17 beta-estradiol in phenol red-containing medium) increase in [3H]PGF2 alpha binding. Scatchard type analysis of the binding data revealed an increase in receptor number while the receptor affinity for [3H]PGF2 alpha remained the same as in the control treated cultures. This 17 beta-estradiol stimulated increase in PGF2 alpha receptor allowed a suboptimal concentration of PGF2 alpha (10(-9) M) to increase intracellular levels of inositol polyphosphates, while by itself this concentration of PGF2 alpha caused no significant change in intracellular inositol polyphosphate levels. 17 beta-estradiol, alone among the several studied steroid hormones, could increase [3H]PGF2 alpha binding. Proliferation studies revealed that, in these primary cultures of rabbit endometrium, 17 beta-estradiol could increase DNA synthesis but not in the presence of indomethacin, unless PGF2 alpha was added to the medium at a concentration (10(-10) M) near or above what is normally accumulated in the medium by these cultures. In the absence of 17 beta-estradiol stimulation, addition of these same low concentrations of PGF2 alpha had no effect on DNA synthesis. Apparently, through its effect on the PGF2 alpha receptor, 17 beta-estradiol enhances the PGF2 alpha stimulated DNA synthesis response approximately 100 fold. The DNA synthesis induced by 17 beta-estradiol can be inhibited by PGE1, as can PGF2 alpha-induced DNA synthesis. We propose that 17 beta-estradiol may be mediating its mitogenic effect through an alteration of the prostaglandin agonist:antagonist control of proliferation in rabbit endometrial cultures. In addition we suggest that, if 17 beta-estradiol acts to increase PGF2 alpha, receptors as part of its mode of action, this may be of importance in other tissues possessing both prostaglandin and 17 beta-estradiol receptors.     

The effects of prostacyclin (PGI2) on tissues which detect prostaglandins (PG'S).

The effects of prostacyclin (PGI2) and its stable metabolite 6-oxo-PGF1alpha on various bioassay tissues are compared with those of PGE2 and PGF2alpha, using the cascade superfusion method. On vascular smooth muscle, PGI2 caused relaxation of all tissues tested except the rabbit aorta. PGE2 relaxed rabbit coeliac and mesenteric artery but contracted bovine coronary artery and had no effect on rabbit aorta. 6-oxo-PGF1alpha was ineffective at the concentrations tested. On gastro-intestinal smooth muscle, PGI2 contracted strips of rat and hamster stomach and the chick rectum. It was less potent than PGE2 or PGF2alpha. None of these substances contracted the cat terminal ileum. 6-oxo-PGF1alpha was inactive on these tissues at the doses tested. PGI2 was less active than PGE2 or PGF2alpha in contracting guinea-pig trachea and rat uterus; 6-oxo-PGF1alpha was active only on the rat uterus. Thus, PGI2 can be distinguished from the other stable prostaglandins using the cascade method of superfusion.     

Prostaglandin F2alpha increases glucose transport in 3T3-L1 adipocytes through enhanced GLUT1 expression by a protein kinase C-dependent pathway

The effect of prostaglandin F2alpha (PGF2alpha) on glucose transport in differentiated 3T3-L1 adipocytes was examined. Whereas PGF2alpha had little influence on insulin-stimulated 2-deoxyglucose uptake, it increased basal glucose uptake in a time- and dose-dependent manner, reaching maximum at approximately 8 h. The long-term effect of PGF2alpha on glucose transport was inhibited by both cycloheximide and actinomycin D. In concord, while the content of GLUT4 protein was not altered, immunoblot and Northern blot analyses revealed that both GLUT1 protein and mRNA levels were increased by exposure of cells to PGF2alpha. The effect of PGF2alpha on glucose uptake was inhibited by GF109203X, a selective protein kinase C (PKC) inhibitor. In addition, in cells depleted of diacylglycerol-sensitive PKC by prolonged treatment with 4beta-phorbol 12beta-myristate 13alpha-acetate (PMA), the stimulatory effects of PGF2alpha on glucose transport and GLUT1 mRNA accumulation were both inhibited. In accord, PMA was shown to stimulate GLUT1 mRNA accumulation. To further investigate if PKC may be activated by PGF2alpha, we tested several diacylglycerol-sensitive PKC isozymes and found that PGF2alpha was able to activate PKCepsilon. Taken together, these results indicate that PGF2alpha may enhance glucose transport in 3T3-L1 adipocytes by stimulating GLUT1 expression via a PKC-dependent mechanism.     

The effects of prostanoids on estrogen-dominated rat myometrial longitudinal muscle in vitro

The purpose of these experiments was to characterize the contractile response of longitudinal muscle from the estrogen-dominated rat uterus to natural and synthetic prostanoids. The biological significance is 1) to provide evidence for or against a physiological role for each natural prostanoid in the regulation of myometrial activity, 2) to determine if each prostanoid has pharmacological potential for the manipulation of myometrial activity, and 3) to understand the structural requirements for prostanoid action on the myometrium. All analogs tested produced excitation of the myometrium in vitro through what appeared to be a direct action on the muscle. The order of potency of the natural prostanoids was prostaglandin (PG) F2 alpha = PGD2 = PGE2 = PGE1 greater than PGA2 = PGB2 = 6-keto-PGF1 alpha. This order of potency was not consistent with any single currently recognized prostanoid receptor. Furthermore, PGF2 alpha had an EC50 (effective concentration that produces 50% of the maximal response) of 0.5 microM, which was low in comparison to other PGF2 alpha-sensitive tissues. There were large differences in the maximum tension developed in response to the prostanoids tested, only PGF2 alpha, PGE2 and 6-keto PGF1 alpha were full agonists. Although the simplest explanation of these data was that the rat uterus contains a single novel type of prostanoid receptor, the existence of multiple receptor subtypes could not be disproved. Evidence from the effect of synthetic analogs suggested that neither thromboxane A2 nor PGI2 are physiological regulators of activity in this tissue.     

Stimulation by prostaglandin F2 alpha of phosphatidic acid-phosphatidylinositol turnover in rat luteal cells

Prostaglandin F2 alpha (PGF 2 alpha) causes a rapid and marked increase of [32P]-orthophosphate incorporation into phosphatidylinositol (PI) and phosphatidic acid (PA) in rat luteal cells in culture. The incorporation of radioactivity is increased as early as 2 and 5 min after PGF 2 alpha addition into PA and PI, respectively, and by 10 min has reached a 2-fold stimulation over control in both lipid moieties. The labeling of other phospholipids is not affected. PGF 2 alpha exerts its stimulatory effect at an ED50 value of approximately 200 and 60 nM on PI and PA labeling, respectively. By contrast, human chorionic gonadotropin has no effect alone and does not interfere with the PGF 2 alpha-induced stimulation of PA-PI labeling. The striking similarity between the effects of PGF 2 alpha and LHRH on PA-PI labeling suggests that the two agents may exert their direct action on the corpus luteum via a common intracellular mechanism involving acidic phospholipid metabolism.     

Dissociation of hyperthermic and hyperglycemic effects of central prostaglandin F2 alpha.

We previously reported that intraventricular prostaglandins (PGs) produced hyperthermia and hyperglycemia in anesthetized rats. However, the relationship of them is little known. We examined the relationship between hyperthermia and hyperglycemia induced by intraventricular PGF2 alpha using curarized and adrenal demedullated rats. Iv curare completely prevented the PGF2 alpha-induced hyperthermia, but enhanced the hyperglycemic effect of PGF2 alpha. Adrenal demedullation completely prevented the hyperglycemia, but did not affect the hyperthermic effect of PGF2 alpha. To further assess the site of action concerned with PGF2 alpha-induced thermoregulation and glucoregulation in the central nervous system (CNS), we injected saline or PGF2 alpha into the preoptic area of the anterior hypothalamus (POA) in intact rats. After microinjection of PGF2 alpha into the POA, the rectal temperature rose, but the plasma glucose level did not increase significantly, as compared with saline-treated control rats. These results suggest that PGF2 alpha causes the central nervous system to produce hyperthermia via shivering, stimulated the somatic motor system, and to produce hyperglycemia by stimulating central sympathetic outflow to the adrenal medulla, but these operate independently under different neural regulation, and these sensitive sites are organically dissociated in the CNS.     

Inhibitory effects of interferon-gamma on myocardial hypertrophy

Prostaglandin F(2alpha) (PGF(2alpha)) plays an important role in pathologic cardiac growth. After testing several immune cytokines, we found that interferon-gamma (IFN-gamma) inhibited responsiveness of adult myocytes to PGF(2alpha). The present study was designed to test the hypothesis that IFN-gamma inhibits cardiac hypertrophy induced by PGF(2alpha). Incubation of cultured adult rat cardiac myocytes with PGF(2alpha) caused cell spreading, which was inhibited by IFN-gamma. The inhibitory effect was not affected by nitric oxide (NO) synthase inhibitors. In addition, administration of fluprostenol, a more selective agonist at the PGF(2alpha) receptor, induced cardiac hypertrophy in rats. Chronic treatment with IFN-gamma inhibited this myocardial growth, and the inhibitory effect of IFN-gamma was not accompanied by an increase in myocardial NO synthase gene expression. Further, abdominal aortic constriction resulted in a substantial increase in heart, ventricular and left ventricular weights to BW ratio that was significantly attenuated by treatment with IFN-gamma. The results demonstrate that IFN-gamma inhibits the in vitro and in vivo effects of PGF(2alpha) on cardiac hypertrophy, and that the mechanism of action is likely independent of NO production. IFN-gamma also attenuated cardiac hypertrophy induced by pressure overload, suggesting that PGF(2alpha) plays a role in the pathogeneses of this severe type of cardiac hypertrophy.     

Vascular actions of epidermal growth factor-urogastrone: possible relationship to prostaglandin production

Epidermal growth factor-urogastrone (EGF-URO), a polypeptide of about 6000 atomic mass units present in humans, mice, rats, and other mammals that is widely recognized for its mitogenic and acid-inhibitory activities, was observed to cause contraction of helical arterial strips of the rat ileocolic artery and to potentiate the action of KCl on helical strips from the superior (cephalic) mesenteric artery. The contractile effect of EGF-URO in ileocolic preparations displayed marked tachyphylaxis at high EGF-URO concentrations (100 ng/mL). The apparent mean effective concentration for EGF-URO in these tissues was about 10 ng/mL (1.7 nM); the detection of EGF-URO degradation in the organ bath indicated that a half-maximal response may have been achieved at a concentration as low as 50% of this value (i.e., about 0.9 nM). The actions of EGF-URO were abolished by indomethacin (3 microM) and were, in part, mimicked by prostaglandin F2 alpha (PGF2 alpha), which contracted the ileocolic preparation and potentiated the action of KCl in the superior mesenteric preparation. In the superior mesenteric preparation, PGF2 alpha alone, like EGF-URO, did not have an appreciable effect on resting tension. The time lag of the EGF-URO effect in the ileocolic preparation (5-6 min to reach peak contraction) corresponded closely with the time course of EGF-URO-stimulated calcium accumulation measured previously in other cell systems. Our results suggest that EGF-URO acts to modulate contractility in vascular tissue via a cyclooxygenase pathway product (possibly PGF2 alpha). Our data point to a role for EGF-URO and possibly other growth factors in the control of vascular function.     

High glucose levels modulate eicosanoid production in uterine and placental tissue from non-insulin-dependent diabetic rats during late pregnancy

Severe uterine and placental disturbances have been described in diabetes pathology. The relative severity of these changes appears to correlate with high glucose levels in the plasma and incubating environment. In order to characterize changes in eicosanoid production we compared uterine and placental arachidonic acid conversion from control and non-insulin-dependent diabetes mellitus (NIDDM) rats on day 21 of pregnancy, into different prostanoids, namely PGE2, PGF22alpha, TXB2 (indicating the production of TXA2) and 6-keto-PGF1 (indicating the generation of PGI2). PGE2, PGF2alpha and TXB2 production was higher and 6-keto-PGF1alpha was similar in diabetic compared to control uteri. PLA2 activity was found diminished in the NIDDM uteri in comparison to control. A role for PLA2 diminution as a protective mechanism to avoid prostaglandin overproduction in uterine tissue from NIDDM rats is discussed. Placental tissues showed an increment in TXB2 generation and a decrease in 6-keto PGF1alpha level in diabetic rats when compared to control animals. Moreover, when control uterine tissue was incubated in the presence of elevated glucose concentrations (22 mM), similar generation of 6-keto PGF1alpha and elevated production of PGE2, PGF2alpha and TXB2 were found when compared to those incubated with glucose 11 mM. Placental TXB2 production was higher and 6-keto PGF1alpha was lower when control tissues were incubated in the presence of high glucose concentrations. However, high glucose was unable to modify uterine or placental prostanoid production in diabetic rats. We conclude that elevated glucose levels induced an abnormal prostanoid profile in control uteri and placenta, similar to those observed in non-insulin-dependent diabetic tissues.     

An unexpected negative inotropic effect of prostaglandin F2alpha in the rat heart

Prostaglandin F(2alpha) (PGF(2alpha)) is produced during myocardial inflammation and many of the insults that trigger contractile dysfunction also activate prostaglandin synthesis and production. However, although PGF(2alpha) plays a significant role in the cardiac response to inflammation, the effect of this particular compound on the heart was largely studied at the cellular level and probably no due attention was paid to the effect of PGF(2alpha) on the whole heart contractility. Therefore, in the present study we have investigated the effect of PGF(2alpha) on isolated right ventricle of the rat heart. PGF(2alpha) (1nM-1microM) induced concentration-dependent decrease of the amplitude of contractions of the ventricular muscle. Real time RT-PCR has revealed that prostaglandin FP receptors are expressed in the rat myocardium and the level of expression was similar to those of creatine kinase and adenylate kinase, which are proteins abundantly present in the heart. An antagonist of FP receptors, PGF(2alpha) dimetilamide (10nM), abolished negative inotropic effect induced by PGF(2alpha). To examine the possibility that PGF(2alpha) could activate non-FP prostaglandin receptor, we have measured the level of expression of all known prostaglandin receptors in the rat heart. These experiments have shown that the order of expression of prostaglandin receptors in the rat heart is FP>EP1=TP>EP4>EP3>DP=IP. Based on the obtained results we conclude that PGF(2alpha) induces negative inotropic effect on rat heart by activating FP prostaglandin receptors. This effect of PGF(2alpha) could contribute to cardiac dysfunction in conditions of systemic and myocardial inflammation.     

Prostaglandin F2 alpha inhibition of epinephrine stimulated cyclic AMP and progesterone production by rat corpora lutea of various ages

Epinephrine can mimic the stimulatory effects of LH in vitro on cyclic AMP (cAMP) and progesterone production by isolated rat corpora lutea. The aim of the present study was to test whether the effects of epinephrine in vitro on the rat corpus luteum, as with LH, can be inhibited by prostaglandin F2 alpha (PGF2 alpha). The stimulatory effect of epinephrine on tissue levels of cAMP in 1-day-old corpora lutea was not inhibited by PGF2 alpha. A dose-dependent inhibition by PGF2 alpha (0.5-50 microM) was seen for 3-day-old corpora lutea and this inhibition could not be overcome by higher concentrations of epinephrine (0.165-165 microM). The stimulation by epinephrine on progesterone production was inhibited by PGF2 alpha (5 microM) in 3- and 5-day-old, but not in 1-day-old corpora lutea. Thus, PGF2 alpha can inhibit the stimulatory effect of epinephrine in 3- and 5-day-old corpora lutea, but not in the newly formed corpora lutea (1-day-old) and PGF2 alpha shows in this respect the same age dependent inhibitory pattern as in relation to LH stimulation.     

Prostaglandins E2 and F2 alpha affect glycogen synthase and phosphorylase in isolated hepatocytes.

Prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha) inactivated glycogen synthase and activated glycogen phosphorylase in rat hepatocytes in a dose- and time-dependent manner. These effects were dependent on the presence of Ca2+ in the incubation medium. When glycogen synthase was immunoprecipitated from cells incubated with [32P]Pi and then treated with PGE2 or PGF2 alpha, there was increased phosphorylation of the 88 kDa subunit of the enzyme. This phosphorylation affected two CNBr fragments of the glycogen synthase, CB-1 and CB-2, the same fragments that are phosphorylated by different glycogenolytic hormones. No phosphorylation of glycogen synthase by prostaglandins was observed in the absence of Ca2+. Thus the effect of PGE2 and PGF2 alpha on these glycogen-metabolizing enzymes supports a role for regulation by prostaglandins of glucose metabolism in parenchymal liver cells.     

Dual actions of prostacyclin (PGI2) on the rat pregnant uterus.

Using strips of rat pregnant uterus, treated with indomethacin to suppress spontaneous contractility, the oxytocic activity of prostacyclin was compared with other prostaglandins. A prostacyclin concentration of 32 ng/ml elicited uterine contractions in all experiments. In this respect prostacyclin was 80 times more active than 6-oxo-PGF1 alpha but less active than PGE2 or PGF2 alpha. Apart from a direct stimulant effect, prostacyclin also exhibited an indirect potentiating action. In threshold concentrations prostacyclin caused a 3-fold potentiation of threshold doses of oxytocin. A lesser 1.5-fold potentiation of PGE2 alpha was also observed. The implications of these findings in relation to prostacyclin playing a role in parturition are discussed.     

Histamine H1 receptors and prostaglandin-histamine interactions modulating contractility of rabbit and rat testicular capsules in vitro

The stimulatory effect of histamine on rabbit and rat testicular capsule was blocked by the H1 blocker, diphenhydramine, but not by the H2 blocker, cimetidine, suggesting the presence of H1 histamine receptors in both rabbit and rat testicular capsules. In the rabbit, both anti-prostaglandin F (PGF) and anti-prostaglandin E (PGE) effaced spontaneous autorhythmic contractions. They markedly inhibited PGF 2 alpha, PGE1 and histamine-stimulated contractions of the rabbit testicular capsule. In the rat, anti-PGF or anti-PGE had no inhibitory effects on the capsular tone, but they both inhibited the stimulatory effects of histamine. These data suggest that the action of histamine on the rabbit and rat testicular capsules could be due partly to a secondary release of the PG's, PGE2 and PGF2 alpha.