Action Of Prostaglandin E1 Research Articles

Pentoxifylline and prostaglandin E1 action on ischemia and reperfusion of small intestine tissue in rats. An immunohistochemical study.

To investigate the action of pentoxifylline (PTX) and prostaglandin E1 (PGE1) on ischemia and reperfusion of small intestine tissue in rats, using immunohistochemical analysis. Thirty-five Wistar rats were distributed as follows: group A (n=10): subjected to intestinal ischemia and reperfusion for 60 min, with no drugs; group B (n=10): PTX given during tissue ischemia and reperfusion; group C (n=10): PGE1 given during tissue ischemia and reperfusion; group D (n=5): sham. A segment of the small intestine was excised from each euthanized animal and subjected to immunohistochemical examination. Mean number of cells expressing anti-FAS ligand in the crypts was highest in Group A (78.9 ± 17.3), followed by groups B (16.7 ± 2.8), C (11.3 ± 1.8), and D (2.5 ± 0.9), with very significant differences between groups (p<0.0001). The use of pentoxifylline or prostaglandin E1 proved beneficial during tissue reperfusion. The immunohistochemical results demonstrated a decrease in apoptotic cells, while protecting other intestinal epithelium cells against death after reperfusion, allowing these cells to renew the epithelial tissue.

Prostaglandin e1 action on canine isolated tracheal muscle.

Abstract Prostaglandin E1 (PGE1) inhibits contractions of dog isolated tracheal muscle stimulated by different agents, but the degree of inhibition varies with the agent used. Low concentrations of PGE1 completely block the stimulant effect of 5-hydroxytryptamine, but even large concentrations of PGE1 do not completely antagonize the contractions caused by acetylcholine. The inhibitory effect of PGE1 is blocked by methysergide and not by propranolol, morphine or dihydroergotamine. PGE1 does not relax depolarized smooth muscle, although bradykinin and isoprenaline do. It is concluded that in tracheal smooth muscle, PGE1 interacts with cell membranes close to the 5-hydroxytryptamine D receptors. This causes activation of the smooth sarcoplasmic reticulum, leading to accumulation of calcium ions and relaxation.

Improved transdermal delivery of prostaglandin E1 through hairless mouse skin: combined use of carboxymethyl-ethyl-beta-cyclodextrin and penetration enhancers.

The optimal prescription of transdermal preparations of prostaglandin E1 (PGE1) for treatment of peripheral vascular diseases has been investigated. The chemical stability of PGE1 in fatty alcohol/propylene glycol (FAPG) ointment was markedly improved by carboxymethyl-ethyl-beta-cyclodextrin (CME-beta-CyD). Application of a PGE1 ointment containing the penetration enhancer, 1-dodecylazacycloheptane-2-one (Azone) or 1-[2-(decylthio)ethyl]azacyclopentane-2-one (HPE-101), onto the skin of hairless mice showed the increase of blood flow in the skin due to the vasodilating action of PGE1. In particular, the ointment containing a PGE1-CME-beta-CyD complex supplemented with HPE-101 showed the most prominent increase of the blood flow. Compared with other ointments, this ointment was found to show significantly greater transfer of HPE-101 into in-vitro preparations of the skin of hairless mice. Transfer of PGE1 into the skin was thought to be facilitated by this increased transfer of HPE-101. These results suggest that a combination of CME-beta-CyD and HPE-101 is useful for designing PGE1 ointments for topical application with good chemical stability and percutaneous permeability.

Pharmacologic Preconditioning Effects: Prostaglandin E 1 Induces Heat-Shock Proteins Immediately After Ischemia/Reperfusion of the Mouse Liver

Prostaglandin E1 (PGE1) has several potential therapeutic effects, including cytoprotection, vasodilation, and inhibition of platelet aggregation. This study investigates the protective action of PGE1 against hepatic ischemia/reperfusion injury in vivo using a complementary DNA microarray. PGE1 or saline was continuously administered intravenously to mice in which the left lobe of the liver was made ischemic for 30 minutes and then reperfused. Livers were harvested 0, 10, and 30 minutes postreperfusion. Messenger RNA was extracted, and the samples were labeled with two different fluorescent dyes and hybridized to the RIKEN set of 18,816 full-length enriched mouse complementary DNA microarrays. Serum alanine aminotransferase and aspartate aminotransferase levels at 180 minutes postreperfusion were significantly lower in the PGE1-treated group than in the saline-treated group. The cDNA microarray analysis revealed that the genes encoding heat-shock protein (HSP) 70, glucose-regulated protein 78, HSP86, and glutathione S-transferase were upregulated at the end of the ischemic period (0 minutes postreperfusion) in the PGE1 group. Our results suggested that PGE1 induces HSPs immediately after ischemia reperfusion. HSPs might therefore play an important role in the protective effects of PGE1 against ischemia/reperfusion injury of the liver.

Unique regulation profile of prostaglandin e1 on adhesion molecule expression and cytokine production in human peripheral blood mononuclear cells.

In the present study, we examined the effects of prostaglandin E1 (PGE1) on the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40, and CD40 ligand (CD40L) on peripheral blood mononuclear cells (PBMC) using fluorescence-activated cell sorting analysis as well as its effects on cytokine production using enzyme-linked immunosorbent assay. Whereas no inhibitor of spontaneous expression of adhesion molecules was reported, we found that PGE1 inhibited spontaneous ICAM-1, B7.2, and CD40 expression on monocytes in a concentration-dependent manner but had no effect on the expression of B7.1 and CD40L. Although interleukin (IL)-18 induced the expression of ICAM-1, B7.2, CD40, and CD40L, PGE1 prevented IL-18-induced expression of ICAM-1, B7.2, and CD40. We examined the involvement of five subtypes of PGE1 receptors (IP, EP1, EP2, EP3, and EP4) in the effect of PGE1 on the expression of these adhesion molecules using subtype-specific agonists. Among EP receptor agonists, EP2 and EP4 receptor agonists inhibited IL-18-elicited ICAM-1, B7.2, and CD40 expression. ONO-1301 (IP receptor agonist) prevented the expression of ICAM-1, B7.2, and CD40 regardless of the presence of IL-18 with the same potency as PGE1. The effect of a combination of ONO-1301 and 11-deoxy (D)-PGE1 (EP2/EP4 receptor agonist) on ICAM-1, B7.2, and CD40 expression mimicked that of PGE1. Moreover, PGE1 inhibited the production of IL-12 and interferon-gamma in PBMC in the presence and absence of IL-18, whereas PGE1 induced IL-10 production. In conclusion, IP receptor and EP2/EP4 receptor play an important role in the action of PGE1 on the expression of adhesion molecules on monocytes and cytokine production.

Prostaglandin E1 and peptide growth factors stimulate neonatal pulmonary artery smooth muscle cell proliferation in a synergistic manner. † 1544

Abnormal pulmonary artery smooth muscle cell (PASMC) proliferation is involved in the pathogenesis of pulmonary vascular remodeling. Several peptide growth factors stimulate smooth muscle proliferation, while some vasodilators(e.g. nitric oxide) have an inhibitory effect. The action of prostaglandins is less clearly defined, and the effect has been reported to be different for adult aortic and pulmonary artery smooth muscle cells. We evaluated the effects of basic fibroblast growth factor (bFGF, a competence factor), insulin-like growth factor-1 (IGF-1, a progression factor), and prostaglandin E1 (PGE1) on neonatal PASMC proliferation. We used PASMC isolated from the main pulmonary artery of newborn piglets and assessed cellular proliferation by chemosensitivity assays after 24 hours of exposure to different combinations of these factors (5ng/ml bFGF, 20ng/ml IGF-1, 1mg/ml PGE1) in serum free media. As expected. bFGF and IGF-1 stimulated PASMC proliferation. PGE1 also increased PASMC proliferation and its action was synergistic with both growth factors (p<0.05 by ANOVA). To further evaluate the mechanism involved in this action, we tested the hypothesis that PGE1 stimulates the local production of IGF-1 in PASMC (as happens in osteoblasts). The experiment was repeated with the addition of angiopeptin (a somatostatin analogue that inhibits the synthesis of IGF-1). The effect of PGE1 on PASMC proliferation was not changed by angiopeptin, suggesting that PGE1 action is not due to an increased production of IGF-1 by PASMC. These results, if applicable to in vivo conditions, suggest that the administration of PGE1 to newborns with congenital heart defects may contribute to the development of abnormal pulmonary vascular remodeling and chronic pulmonary hypertension.Table

Effect of prostaglandin E1 on leukotriene C4-induced increases in vascular permeability of hamster cheek pouch.

Our goal was to determine whether there is a synergistic effect of prostaglandin E1 (PGE1) on leukotriene C4 (LTC4)-induced increases in vascular permeability of the hamster cheek pouch in vivo. Changes in permeability were quantified by counting venular leaky sites (LS) and calculating clearance (CLR) of fluorescein isothiocyanate (FITC)-dextran 70kDa, during suffusion of the cheek pouch with LTC4 in the absence or presence of PGE1. LTC4 produced a dose-related increase in LS and CLR, and PGE1 (0.01 microM) significantly potentiated the effect of LTC4. During suffusion with LTC4 (15.0 nM) in the absence of PGE1, LS increased from 0 to 19 +/- 3/0.11 cm2 and CLR increased from 0.3 +/- 0.1 to 1.0 +/- 0.2 x 10(-6) ml/sec. During superfusion with LTC4 (15.0 nM) in the presence of PGE1, LS increased from 0 to 40 +/- 3/0.11 cm2, and CLR increased from 0.4 +/- 0.1 to 2.1 +/- 0.5 x 10(-6) ml/sec. To determine whether the effect of PGE1 on LTC4-induced increases in vascular permeability was related to the vasodilatory effect of PGE1, we examined the effect of isoproterenol (ISO). In contrast to that observed with PGE1, ISO decreased LTC4-induced increases in LS and CLR. Our data suggest that there is a synergistic effect of PGE1 on LTC4-induced increases in venular permeability that is not mediated by a vasodilatory action of PGE1.

Differential sensitivity in the sites of fever production by prostaglandin E1 within the hypothalamus of the rat.

1. The febrile sensitivity of male Sprague-Dawley rats to microinjections of prostaglandin E1 (PGE) was investigated at three different locations in the rostromedial hypothalamic region. These were the preoptic anterior hypothalamic area (PO-AH), the organum vasculosum laminae terminalis (OVLT) and the rostral third ventricle (3V). 2. Stainless-steel cannula guide tubes were implanted in the OVLT region of one group of animals, within the PO-AH area of a second group and into the third ventricle of a third group of rats. After their recovery, the febrile response of each group was tested to a variety of doses of PGE, each administered in a volume of 1 microliter sterile 0.9% saline, via a sterile cannula inserted into the implanted guide tubes. Metabolic, vasomotor and rectal temperature changes were monitored continuously for the duration of the fevers. 3. Surprisingly, not only did the introduction of PGE into the OVLT region produce fevers, but the sensitivity of this region to PGE in the production of fever greatly exceeded that of the PO-AH area and the third ventricle. Fevers produced by microinjection of PGE into the PO-AH and 3V were identical. 4. Doses of PGE as low as 0.5 ng injected into the OVLT produced fevers of 0.5 degrees C. The fever dose threshold for the OVLT region was one-fifth those of the PO-AH area and the 3V, and the slope of the OVLT dose-response curve was twice those of the PO-AH and the 3V dose-response curves. 5. This study demonstrates that there is an anatomically distinct, regional sensitivity in the febrile responsiveness to PGE within the hypothalamus. These results are interpreted as evidence that the site of action of PGE in the production of fever is located within or immediately adjacent to the OVLT region, rather than within the medial PO-AH neuropil as has been believed previously.

Effects of cold and capsaicin desensitization on prostaglandin E hypothermia in rats

Intraperitoneal injection of prostaglandin E1 (PGE) produces a transient hypothermia in rats that lasts 1-2 h. Rats exposed to an ambient temperature (Ta) of 26 degrees C displayed a decrease in rectal temperature (Tre) of 0.95 +/- 0.12 degrees C (SE) after injection with PGE (100 micrograms/kg ip). Hypothermia was produced mainly by heat losses, as indicated by increases in tail blood flow. At Ta of 4 degrees C, PGE produced a comparable fall in Tre of 1.00 +/- 0.14 degrees C. However, in the cold the hypothermia was caused solely by decreases in heat production. These results indicate that the PGE-induced hypothermia is not the result of a peripheral vasodilation induced by the direct action of PGE on the tail vascular smooth muscle but is a central nervous system-mediated response of the thermoregulatory system induced by PGE within the peritoneal cavity. Capsaicin injected subcutaneously induces a transient hypothermia in rats because of stimulation of the warm receptors. If administered peripherally in sufficient amounts, it is reputed to impair peripheral warm receptors so that they become desensitized to the hypothermic effects of capsaicin. We measured PGE-induced hypothermias in rats both before and after capsaicin desensitization at Ta of 26 degrees C. Before desensitization the hypothermia was -1.14 +/- 0.12 degrees C, whereas after capsaicin treatment the PGE-induced hypothermia was -0.34 +/- 0.17 degrees C. The biological effects of capsaicin are diverse; however, based on current thinking about the thermoregulatory effects of capsaicin desensitization, our results indicate that peripheral warm receptor pathways are in some manner implicated in the hypothermia induced by intraperitoneal PGE.

Vasodilator action of prostaglandin E1 on microcirculation of rat cremaster muscle

Vascular spasm is often present after microsurgical procedures, and its presence or absence can greatly influence the success rate of such operations. Prostaglandin E1 (PGE1) is known to be a potent vasodilator and antiaggregator of small blood vessels. Using intravital videomicroscopy in the rat cremaster model, this study visually and quantitatively monitored changes in vessel diameter to observe the effect of PGE1 on the microcirculation and compared its action with that of 1% lidocaine. The results suggest that PGE1 (10 micrograms/ml) can significantly relieve epinephrine-induced vasoconstriction at the terminal arteriole, arteriole, and small artery level (vessel diameters 10-50 microns). The vasodilatory action of PGE1 is reflected by an increase in vessel diameter, and PGE1 may have a role in reversing vascular spasm after microsurgery, enhancing the survival rate of replanted extremities.

Guanine nucleotide-independent inhibition of adenylate cyclase by a stimulatory hormone.

Stimulation of basal adenylate cyclase activity in membranes of neuroblastoma x glioma hybrid cells by prostaglandin E1 (PGE1) is half-maximal and maximal (about 8-fold) at 0.1 and 10 microM respectively. This hormonal effect requires GTP, being maximally effective at 10 microM. However, at the same concentrations that stimulate adenylate cyclase in the presence of GTP, PGE1 inhibited basal adenylate cyclase activity when studied in the absence of GTP, by maximally 60%. A similar dual action of PGE1 was observed with the forskolin-stimulated adenylate cyclase, although the potency of PGE1 in both stimulating and inhibiting adenylate cyclase was increased and the extent of stimulation and inhibition of the enzyme by PGE1 was decreased by the presence of forskolin. The inhibition of forskolin-stimulated adenylate cyclase by PGE1 occurred without apparent lag phase and was reversed by GTP and its analogue guanosine 5'-[gamma-thio]triphosphate at low concentrations. Treatment of neuroblastoma x glioma hybrid cells or membranes with agents known to eliminate the function of the inhibitory GTP-binding protein were without effect on PGE1-induced inhibition of adenylate cyclase. The data suggest that stimulatory hormone agonist, apparently by activating one receptor type, can cause both stimulation and inhibition of adenylate cyclase, and that the final result depends only on the activity state of the stimulatory GTP-binding protein, Gs. Possible mechanisms responsible for the observed adenylate cyclase inhibition by the stimulatory hormone PGE1 are discussed.

Mechanisms of action of PGE1 in hemorrhagic shock in rats.

We studied the effects of prostaglandin E1 (PGE1) in a severe model of hemorrhagic shock in rats. PGE1 was administered as a continuous IV infusion of either 0.1 microgram/kg/min or 1.0 microgram/kg/min starting 30 minutes after the onset of bleeding and continuing until one hour after reinfusion. Hemorrhaged rats treated with PGE1 (1 microgram/kg/min) maintained post-reinfusion mean arterial blood pressure (MABP) at significantly higher values than rats receiving only the vehicle (ie, 0.9% NaCl) (final MABP 84 +/- 3 vs 57 +/- 4 mm Hg, P less than .01). PGE1 at 1 microgram/kg/min also attenuated the increase in plasma activities of cathepsin D (P less than .01), and at both doses blunted the plasma accumulation of free amino-nitrogen compounds (P less than .02 at 0.1 microgram/kg/min and P less than .01 at 1.0 microgram/kg/min). Furthermore, the plasma activity of a myocardial depressant factor (MDF) was significantly lower in rats treated with PGE1 (1 microgram/kg/min) than in rats receiving the vehicle (35 +/- 4 U/mL vs 74 +/- 12 U/mL, P less than .01). Rats receiving PGE1 (1.0 microgram/kg/min) also exhibited a significantly increased survival rate (P less than .01) and post-reinfusion survival time (P less than .01) compared with rats receiving only the vehicle. Our data suggest that antiproteolytic and membrane-stabilizing actions of PGE1 are important and may contribute to its beneficial effects in hemorrhagic shock. Other mechanisms (eg, inhibition of platelet aggregation and vasodilation) may also be involved.

Platelet alpha 2-adrenoceptor and adenylate cyclase in patients with anorexia nervosa and bulimia.

Platelets alpha 2-adrenoceptors were studied in 24 patients with anorexia nervosa shortly after admission to the hospital and after 10% weight gain. Twenty patients with bulimia and 24 healthy age- and sex-matched normal subjects also were studied. Receptor number was significantly increased in patients with bulimia and anorexia nervosa. After 10% weight gain, the receptor number almost normalized in anorexia nervosa patients. Kd values were increased in all patients groups at all times of study. In patients with bulimia or anorexia nervosa, both initially and after weight gain, the maximal effect of prostaglandin E1 (PGE1) on platelet cAMP production was greatly increased, while the half-maximally effective dose was unchanged. Also, the maximal inhibitory effects of epinephrine and clonidine on PGE1-stimulated platelet cAMP production were greater, while the half-maximal dose of both alpha 2-agonists was unchanged. Metabolic and endocrine indicators of starvation were present in both bulimic and anorexia nervosa patients initially. Blood beta-hydroxybutyric acid was elevated, and plasma T3 values and the orthostatic response of plasma norepinephrine (delta NA) were reduced, while cortisol was elevated (only in anorexia nervosa patients). Among these parameters, only delta NA significantly correlated with the actions of PGE1 and epinephrine on cAMP production. In conclusion, the activity of the sympathetic nervous system was reduced in patients with anorexia nervosa and bulimia. This reduction was accompanied by an increased capacity and a decreased affinity of platelet alpha 2-receptors and an increased PGE1 stimulatory and epinephrine inhibitory effects on cAMP production.

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). Similar injections of PGE1, E2 and F2 alpha, all failed to antagonize apomorphine-induced stereotyped behaviour, or to induce catalepsy. PGE, (0.01-0.5 fig) and PGE2 (0.002-1 pg), but not PGF2 alpha, caused asymmetry following unilateral injection into the striatum and peripheral challenge with apomorphine. 5 It is concluded that the major effect in the striatum of the prostaglandins of the E series is to antagonize dyskinetic biting; this action is not shared by other prostaglandins tested, and does not reflect a generalised ability to antagonize striatal dopamine function. It is suggested that the actions of the prostaglandins to modify differentially dopamine-dependent behaviours from the striatum may reflect activity at a site subsequent to the dopamine receptor.

Effects of prostaglandin E1 and isosorbide dinitrate on acute hypoxic pulmonary vasoconstriction in conscious sheep.

The pulmonary vascular effects of prostaglandin E1 (PGE1) and isosorbide dinitrate (ISD) on acute hypoxic pulmonary vasoconstriction in conscious sheep were studied. While the animals inhaled room air or hypoxic gas (O2:N2 = 1:9), PGE1 (0.5 microgram/kg/min) and ISD (10 microgram/kg/min) were administered intravenously for 20 min, using an infusion pump. The changes of pulmonary arterial pressure (PPA) or pulmonary vascular resistance (PVR) in room air due to PGE1 were not significant, but in the hypoxic condition, PGE1 decreased PPA by 14.7% (p less than 0.05) and PVR by 14.5% (p less than 0.05). The effect of PGE1 in room air on systemic arterial pressure (PSA) remained nearly constant, whereas slight decreases in systemic vascular resistance (SVR) were noticed. In hypoxic condition, PSA levels were slightly decreased by PGE1, but SVR indicated a slight degree of delayed rise. When ISD in room air was administered, the values of PPA, PVR, PSA and SVR decreased by 9% (p less than 0.05), 10.4% (p less than 0.05), 17.7% (p less than 0.05) and 21.8% (p less than 0.05), respectively. In hypoxic condition, ISD decreased the values of PPA, PVR, PSA and SVR by 14.7% (p less than 0.05), 15.8% (p less than 0.05), 10.2% (p less than 0.05) and 6.7% (p less than 0.05), respectively. In summary in hypoxic condition both PGE1 and ISD cause similar decreases of PPA and PVR. Furthermore, there was a very little decrease in PSA during PGE1 infusion in the hypoxic condition.(ABSTRACT TRUNCATED AT 250 WORDS)

Haemorrheological effects of prostaglandin E1 infusion in Raynaud's syndrome.

Eighteen patients with severe Raynaud's syndrome had impaired deformability of erythrocytes, as measured by filtration through 5 micron diameter pores, compared with 19 healthy controls. The patients were given prostaglandin E1 (PGE1) or placebo by intravenous infusion for 72 h to assess the haemorrheological action of PGE1. Contrary to a previous report, PGE1 did not improve erythrocyte filterability. Infusion of PGE1 did, however, evoke an acute phase response with hyperproteinaemia and a leucocytosis and is a potentially important mediator of this stress response in patients with vascular disease.

Ca2+ as messenger of 5HT2-receptor stimulation in human blood platelets.

In blood platelets of man, both 5-hydroxytryptamine (5HT) and 80 nM of the Ca2+-ionophore A23187 led to rapid shape change reactions which were inhibited by prostaglandin E1 (PGE1), forskolin, 2-methyl-6-methoxy-8-nitroquinoline ( quin2 ) and chlortetracycline. The IC50-values of the inhibitors were similar in the 5HT- and the A23187-experiments. Higher amounts of A23187 abolished the inhibitory actions of PGE1 and forskolin. Furthermore, 5HT and A23187 enhanced adrenaline-induced platelet aggregation their effects showing similar time dependence. Ketanserin, an antagonist of 5HT2 -receptors, and 8-(N,N-diethyl-amino)octyl-3,4,5-trimethoxybenzoate (TMB-8), an intracellular Ca2+-antagonist, counteracted the effects of 5HT much more than those of A23187, whereas acetylsalicylate and indomethacin did not influence the actions of either 5HT or A23187. In addition, 5HT caused a concentration-dependent rise of intracellular free Ca2+ in platelets which was counteracted by ketanserin. PGE1 and forskolin reduced the resting Ca2+-levels. 5HT did not affect either the basal or the PGE1-stimulated activity of adenylate cyclase, whereas the Ca2+-ionophore A23187 slightly raised the basal activity of the enzyme. In conclusion, the functional effects of 5HT2 -receptor stimulation in human blood platelets (shape change reaction and enhancement of adrenaline aggregation) seem to be mediated by a rise of intracellular free Ca2+.

Effect of prostaglandin E1 and its biosynthesis inhibitor indomethacin on drinking in the rat.

In the rat, injection of prostaglandin E1 (PGE1) 0.5, 1.0 or 2.0 microgram into the 3rd brain ventricle (3rd b.v.) inhibited the water deprivation-induced water intake in a dose-related fashion. The 1.0 microgram dose of PGE1 also inhibited the intake of 1.8% sodium chloride in rats depleted of body sodium by intraperitoneal dialysis, and of food in food deprived rats during a 60 min test period. Prostaglandin E1 (1 microgram) depressed the dipsogenic effect of angiotensin II (AII) or carbachol injected through the same cannula. Water-deprived rats pretreated with the PG synthetase inhibitor indomethacin, in two different doses, showed enhanced water intake. The pretreatment with indomethacin also enhanced the dipsogenic effect of various doses of AII injected into the 3rd b.v. The antagonistic action of PGE1 on water-deprivation, or AII-induced water intake, and the enhancement of water intake after blocking PGs synthesis, suggests the involvement of PG in the regulation of thirst.

Pulmonary and systemic vascular responses of perinatal goats to prostaglandins E1 and E2

Effects of prostaglandins of the E series and their metabolites on pulmonary and systemic circulations of newborn and exteriorized fetal goats (anesthetized with chloralose) were evaluated in situ using an isolated perfused left lung lobe preparation. Prostaglandin E1 (PGE1) and, to a lesser extent, prostaglandin E2 (PGE2) infusions resulted in decreases of pulmonary vascular resistance (PVR) of fetal and neonatal goats. Infusions of PGE1 or PGE2 (less than 2 microgram.kg-1.min-1 for 1 min) directly into left pulmonary arterial blood did not affect systemic arterial pressure (SAP). Infusions of PGEs (greater than 2 microgram.kg-1.min-1 for 1 min) resulted in decreases in SAP and heart rate. The dose-response characteristics of the pulmonary circulation in response to PGE1 and PGE2 were not different in fetal and newborn goats. Fetal asphyxia did not alter the dose-response characteristics of pulmonary circulation in response to PGE1. Metabolites (15-keto) of PGE1 and PGE2 had no effect upon PVR or SAP of perinatal goats. These results demonstrate in perinatal mammals 1) vasodilator action of PGE1 and PGE2 on the pulmonary and systemic circulations, and 2) catabolism by the lungs of these prostaglandins.

Effects of prostaglandin E1 and indomethacin on ACTH, prolactin, GH and LH from rat pituitary in vitro.

The effects of prostaglandin E1 (PGE1) and indomethacin (IDM) on the release of several pituitary hormones from the rat pituitary were investigated in vitro. An addition of 2 microng/ml of PGE1 to the medium elicited the release of growth hormone (GH) and prolactin, but not of adrenocorticotropin (ACTH) and luteinizing hormone (LH). Although the addition of 1 microng/ml of IDM alone resulted in no effect on the basal release of these hormones, IDM diminished the release of ACTH induced by crude rat hypothalamic extracts (HE) or lysine-8-vasopressin (LVP), and LH induced by HE or luteinizing hormone-releasing hormone (LH-RH). These findings implicate that a part of PGE1 action might be a direct one on the pituitary gland and PGE1 might release GH and prolactin, whereas IDM might have a direct action on the pituitary gland, and that blunt the release of these pituitary hormones induced by several stimuli.