The antiarrhythmic action of prostacyclin (PGI2) on aconitine induced arrhythmias in rats.

Prostacyclin (PGI2) produces an antiarrhythmic effect on aconitine induced arrhythmias in rats. The ED50 of PGI2 was 0.7 microgram/kg and the maximum antiarrhythmic effect 54 per cent. The equi-effective doses of PGE2 and PGF2alpha were higher (ED50 of PGF2alpha = 1.2 microgram/kg, ED50 of PGE2 = 2.7 microgram/kg). However, PGF2alpha and PGE2 had a maximum antiarrhythmic effect of 80 per cent in this model.     

The central nervous effect of prostaglandins I2, E2 and F2 alpha on aconitine-induced cardiac arrhythmia in rats.

Intracerebroventricular administration of PGI2 or PGE2 reduced aconitine-induced cardiac arrhythmia in rats. PGF2 alpha had no antiarrhythmic effect under the same conditions. The ED50 values of PGI2 and E2 were 0.25 microgram/kg and 1.1 microgram/kg, respectively. Central mechanisms may participate in the antiarrhythmic effect of these PGs.     

Effects of intracerebroventricular administration of prostaglandins I2, E2, F2 alpha and indomethacin on blood pressure in the rat.

The effects of intraventricularly administered prostaglandins I2 (PGI2), E2 (PGE2), F2alpha (PGF2 alpha) and indomethacin on systemic blood pressure were investigated in conscious rats. PGI2 (1.25--10 micrograms/kg) decreased blood pressure in a dose-related manner, whereas PGE2 (100--1000 mg/kg) dose-dependently increased blood pressure. Both PGF2 alpha (0.31--20 micrograms/kg) and indomethacin (0.625--40 micrograms/kg) had no effects on blood pressure. These results indicate that intraventricular injection of PGI2 or PGE2 can induce significant changes in blood pressure, while endogenous prostaglandins synthesized in the brain seem to play a minor role in direct regulation of systemic blood pressure in the rat.     

The lack of involvement of central nervous system in the antiarrhythmic effects of prostaglandins E2, F2 alpha, and I2 in cat

The role of the central nervous system (CNS) in the antiarrhythmic effects of prostaglandins (PGs) E2, F2 alpha, and I2 was studied by administering each agent into the left lateral cerebral ventricle (i.c.v. administration) of chloralose-anaesthetized cats. The cardiac arrhythmias were produced by intravenous (i.v.) infusion of ouabain (1 microgram/kg/min). The PGs E2, F2 alpha and I2 on i.c.v. administration in the dose range of 1 ng to 10 micrograms failed to inhibit ouabain-induced cardiac arrhythmias. However, when infused i.v., PGE2 (1 microgram/kg/min), PGF2 alpha (5 micrograms/kg/min), and PGI2 (2 micrograms/kg/min) effectively suppressed these arrhythmias. The standard antiarrhythmic drug propranolol (0.5-8.0 mg) on i.c.v. administration also significantly reduced the ouabain-induced cardiac arrhythmias. It is suggested that the CNS is not the site of action of PGs E2, F2 alpha, and I2 in antagonising the ouabain-induced cardiotoxicity in cats.     

Characterization of prostaglandin (PG)-binding sites expressed on human basophils. Evidence for a prostaglandin E1, I2, and a D2 receptor.

Recent data suggest that prostaglandins (PGs) are involved in the regulation of basophil activation. The aim of this study was to characterize the basophil PG-binding sites by means of radioreceptor assays using 3H-labeled PGs. Scatchard analysis for pure (greater than 95%) chronic myeloid leukemia (CML) basophils revealed two classes of PGE1-binding sites differing in their affinity for the natural ligand (Bmax1 = 217 +/- 65 fmol/10(8) cells; Kd1 = 0.5 +/- 0.2 nM; Bmax2 = 2462 +/- 381 fmol/10(8) cells; Kd2 = 47 +/- 20 nM; IC50 = PGE1 less than PGI2 less than PGD2 less than PGE2 less than PGF2 alpha) as well as two classes of PGI2 (iloprost)-binding sites (Bmax1 = 324 +/- 145 fmol/10(8) cells; Kd1 = 0.5 +/- 0.3 nM; Bmax2 = 2541 +/- 381; Kd2 = 27 +/- 6 nM; IC50 = PGI2 less than PGE1 less than PGD2 less than PGE2 less than PGF2 alpha. In addition, CML basophils exhibited a single class of PGD2-binding sites (Bmax = 378 +/- 98 fmol/10(8) cells; Kd = 13 +/- 4 nM; IC50: PGD2 less than PGI2 less than PGE1 less than PGE2 less than PGF2 alpha). In contrast, we were unable to detect specific saturable PGE2-binding sites. Primary and immortalized (KU812) CML basophils revealed an identical pattern of PG receptor expression. Basophils (KU812) expressed significantly (p less than 0.001) lower number of PGE1 (PGI2)-binding sites (Bmax1: 9% (20%) of control; Bmax2: 36% (50%) of control) when cultured with recombinant interleukin 3 (rhIL-3), a basophil-activating cytokine, whereas rhIL-2 had no effect on PG receptor expression. Functional significance of binding of PGs to basophils was provided by the demonstration of a dose-dependent increase in cellular cAMP upon agonist activation, with PGE1 (ED50 = 1.7 +/- 1.1 nM) and PGI2 (ED50 = 2.8 +/- 2.3 nM) being the most potent compounds. These findings suggest that human basophils express specific receptors for PGE1, PGI2 as well as for PGD2.     

Prostaglandin F2 alpha as the luteolysin in swine: VI. Hormonal regulation of the movement of exogenous PGF2 alpha from the uterine lumen into the vasculature

To test the endocrine-exocrine theory of maternal recognition of pregnancy in the pig 16 gilts were assigned randomly to a 2 X 2 factorial involving pretreatment with sesame oil (SO) or estradiol valerate (5 mg; EV) injected on Days 11 through 14 of the estrous cycle and an intrauterine injection of saline (5 ml; SA) or prostaglandin F2 alpha (50 micrograms; PGF) on Day 14. Peripheral blood samples were collected for 120 min postinjection and analyzed for 15-keto-13,14-dihydro-PGF2 alpha (PGFM). PGFM concentrations were lower in EV than SO gilts (438 vs. 844 pg/ml; p less than 0.05). There was heterogeneity of regression between EV and SO gilts (p less than 0.01), with EV gilts having a slower release of PGF from the uterine lumen into the vasculature. Prostaglandin F2 alpha did not increase mean PGFM concentrations (p greater than 0.10), but resulted in an altered temporal pattern of PGFM (p less than 0.05) compared to SA gilts. There was an interaction between the two treatments over time, with EV-PGF gilts demonstrating a slower, more gradual release of PGFM than SO-PGF gilts. To test whether prostaglandins of the E series were involved in this mechanism, gilts were assigned to two 4 X 4 latin squares balanced for residual effects and treated with saline or flunixen meglumine (Banamine). Each gilt was treated with four PGE:PGF infusion sequences (SEQ) in each uterine horn: phosphate-buffered saline (PBS; PBS-SEQ), PGE1 (50 micrograms), PGE2 (50 micrograms), and PGE1 (25 micrograms) + PGE2 (25 micrograms) (PGE-SEQ), with each infusion followed 15 min later by PGF (25 micrograms).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of prostaglandin E2 and F2 alpha on peri-implantation development of mouse embryos in vitro.

The effects of exogenous prostaglandin (PG) E2 and F2 alpha on the morphology and lactate dehydrogenase (LDH) activities of pre-implantation mouse embryos in vitro were studied. A 24-hour exposure from 0.01 to 10 micrograms/ml of PGE2 at the 4-cell or morula stages had no effect on the morphology of embryos during the 144 hours in culture. Exposure to 10 micrograms/ml PGE2 at the blastocyst stage accelerated and enhanced spreading of the trophoblast in vitro. Embryos treated at 0.01 to 10 micrograms/ml PGE2 at various stages all showed a more rapid decline in LDH activity from morula to blastocysts. Treatment with 50 or 100 micrograms/ml PGE2 led to abnormal morphology of embryos in vitro. In contrast, continuous treatment with 0.01 to 100 micrograms/ml PGF2 alpha from 4-cell to early post-implantation (day 8) had no effect on the morphology of embryos, although breakdown of LDH was again accelerated. These results suggest that the peak of PGE2 secretion on day 4 of pregnancy in mice may enhance trophoblastic outgrowth, and the lower levels of PGE2 and PGF2 alpha secreted earlier in pregnancy modulate the development of pre-implantation mouse embryos.     

The vagal involvement in the antiarrhythmic and arrhythmogenic effects of prostaglandin F2 alpha on ouabain-induced cardiac arrhythmias in cats

The effects of prostaglandin F2 alpha (PGF2 alpha) on ouabain-induced cardiac arrhythmias were investigated in chloralose-anaesthetized cats. Bilateral vagotomy and atropine intervention were employed to elucidate the involvement of vagal neural influences. PGF2 alpha (2-16 micrograms/kg i.v. bolus) predominantly suppressed the ouabain-induced ventricular and supraventricular arrhythmias and less commonly aggravated them in vagi-intact cats. The antiarrhythmic effect of PGF2 alpha was considerably, but not statistically significantly, decreased while its arrhythmogenic effect was significantly (p less than 0.05) increased in atropine-pretreated group. In vagotomised group PGF2 alpha failed to abolish the arrhythmias but it aggravated them to a degree comparable to that observed in vagi-intact group. It is concluded that the PGF2 alpha exhibits both antiarrhythmic and arrhythmogenic properties and these are largely due to elicitation of two opposing neural reflexes - one being protective and another being deleterious to ouabain-induced arrhythmias.     

Novel effects of PGF2 alpha on airway function in asthmatic subjects

The effects of inhaled prostaglandin F2 alpha (PGF2 alpha) have been examined in eight subjects with asthma. Incremental PGF2 alpha aerosol concentrations, ranging from 1 to 5,000 micrograms/ml, were administered at 15-min intervals. Plethysmographic specific airway conductance (sGaw), forced expiratory volume at 1 s (FEV1), and maximum expiratory flow at 50% vital capacity breathing air (Vmax50% air) and 80% He-20% O2 (Vmax50% He-O2) were measured after each dose and compared with saline control values. We observed unexpected triphasic dose-response characteristics, i.e., an initial decline in physiological variables at low concentrations (1-100 micrograms/ml), followed by improvement at intermediate concentrations (100-1,000 micrograms/ml) and a subsequent steep decline at high concentrations (1,000-5,000 micrograms/ml). Improvement in FEV1 and Vmax50% air between 100 and 1,000 micrograms/ml was associated with sGaw increases above control levels in six subjects and a significant fall in density-dependent index (Vmax50% He-O2/Vmax50% air) when compared with values before challenge and at low concentrations. Inhaled atropine (5 mg) improved prechallenge lung function but had no effect on PGF2 alpha dose-response characteristics. Intermediate PGF2 alpha concentrations given as a single dose consistently induced greater FEV1 reductions than the same concentration during graded dose challenges. Our findings are consistent with the demonstration of in vivo airway tachyphylaxis and indicate that airway effects of PGF2 alpha are far more complex than previously reported. Moreover, these novel effects suggest that, in addition to its well-known bronchoconstrictor effects, PGF2 alpha directly or indirectly causes airway relaxation, predominantly in large airways.     

Effects of hydrocortisone, oestradiol and progesterone on A23187-stimulated prostaglandin output from the guinea-pig uterus superfused in vitro

Hydrocortisone (10 micrograms/ml) had no effect on the basal outputs and A23187-stimulated outputs of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha from the Day 15 guinea-pig uterus superfused in vitro. These findings indicate that the high output of PGF2 alpha from the guinea-pig uterus during the last one-third of the oestrous cycle is not modulated by the adrenal glucocorticoid hormones. Progesterone (10 micrograms/ml) had no effect on the A23187-induced increases in PG output from the Day 15 guinea-pig uterus. However, oestradiol (10 micrograms/ml but not 1 microgram/ml) significantly reduced the increases in outputs of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha induced by A23187 from the Day 15 guinea-pig uterus, without affecting basal PG outputs. The increase in uterine tone induced by A23187 in the Day 15 guinea-pig uterus was reduced by 20-50% by oestradiol (10 micrograms/ml). The addition of oestradiol (10 micrograms/ml) and progesterone together (10 micrograms/ml) produced the same effects on the Day 15 guinea-pig uterus as oestradiol alone. Oestradiol (10 micrograms/ml) also reduced the A23187-induced increases in PG output from the Day 7 guinea-pig uterus, but did not reduce the increase in uterine tone. Oestradiol (10 micrograms/ml) reduced the increases in outputs of PGF2 alpha, PGE2 and 6-keto-PGF1 alpha induced by exogenous arachidonic acid from the Day 7 and Day 15 guinea-pig uterus. Previous studies have shown that oestradiol is not a cyclo-oxygenase inhibitor. The present findings suggest that oestradiol, at a relatively high concentration, may interfere with the access of arachidonic acid to the cyclo-oxygenase enzyme. This action of oestradiol may explain its anti-luteolytic action when administered to guinea-pigs in large doses after Day 9 of the cycle.     

Increase in uterine prostaglandin E2, F2 alpha, prostacyclin and stability in thromboxane A2 production during late pregnancy in streptozotocin-induced diabetic rats

This experiment was conducted to determine the effect of diabetes on uterine prostanoids production in near-term rats. The incidence of an insulin therapy was also studied. On the 21st day of pregnancy, uterine PGE2, PGF2 alpha and PGI2 levels showed a significant increase (respectively p less than 0.05, p less than 0.01 and p less than 0.05) in diabetic rats compared to controls whereas TxA2 production remained unchanged. The insulin therapy restored PGE2 levels, the most potent stimulatory factor of the myometrial fiber at control values, whereas it enhanced significantly PGI2 concentrations (p less than 0.05) and had no effect on PGF2 alpha production; TxA2 levels remaining always unchanged. It is suggested that the increase in uterine protanolds production during diabetes could induce a myometrial hypertonicity and play a role in the disturbances of the fetal development. The maintenance of PGE2 levels to control values by the insulin therapy might contribute to a normal delivery.     

Effects of prostaglandin E2 and F2 alpha on cytoplasmic pH in a clonal osteoblast-like cell line, MOB 3-4.

Prostaglandin E2 (PGE2, 5 ng/ml to 5 micrograms/ml) induced a dose-dependent increase in cAMP accumulation, inositol phosphates (IPs) accumulation, and cytoplasmic free Ca2+ ([Ca2+]i) in a clonal osteoblast-like cell line, MOB 3-4. In contrast, prostaglandin F2 alpha (PGF2 alpha, 5 ng/ml to 5 micrograms/ml) stimulated increases in IPs accumulation and [Ca2+]i without stimulating an increase in cAMP accumulation. Both PGE2 (greater than 0.5 micrograms/ml) and PGF2 alpha (greater than or equal to 5 micrograms/ml) increased cytoplasmic pH (pHi) from approximately 7.15 to 7.35 in BCECF-loaded cells. A tumor promotor, phorbol 12-myristate 13-acetate (PMA, 0.1-100 nM) also increased pHi without effect on phosphoinositide hydrolysis. Both PGE2-(5 micrograms/ml) and PMA- (100 nM) induced cytoplasmic alkalinization was inhibited by removal of extracellular Na+, or by pretreatment of the cells with amiloride (0.5 mM), an inhibitor of Na+/H+ exchange, or H-7 (100 microM), a nonspecific inhibitor of protein kinase C. Thus, MOB 3-4 cells appeared to possess PGE2 receptors and PGF2 alpha receptors: the former are coupled to adenylate cyclase and phospholipase C, and the latter are predominantly coupled to phospholipase C. Also the cells appeared to possess an amiloride-sensitive Na+/H+ exchange activity, which increases pHi in response to PGE2 and PGF2 alpha, as well as to PMA. Long-term (48 hr) exposure of the cells to PGE2 at a high concentration (5 micrograms/ml), but not to PGF2 alpha and PMA, decreased DNA synthesis in the serum-deficient medium. Thus, cytoplasmic alkalinization appeared insufficient for cell replication. At least in MOB 3-4 cells, the inhibitory effect of PGE2 on DNA synthesis may be due to the cAMP messenger system.     

The effects of certain vasodilating prostaglandins on the coronary and hindlimb vascular beds of the conscious sheep

Vasodilating prostaglandins were injected, in bolus doses, into the lower abdominal aorta or left circumflex coronary artery (LCCA) of conscious sheep. Local blood flow, mean arterial pressure (MAP), heart rate (HR) and ECG were monitored continuously. 6-Keto PGF1 alpha had no effect on either vascular bed in doses up to 100 micrograms. PGE2 was more potent than PGI2 in dilating hindlimb vasculature and PGE2 induced a more persistent hyperaemia whereas PGD2 elicited a biphasic response (constriction-dilation). PGE1, PGE2, PGD2 and PGI2 all produced dose-dependent vasodilation, the order of potency being PGD2 greater than PGI2 greater than PGE1 greater than or equal to PGE2. The effect of PGI2 was more transient and PGE1 and PGD2 caused small but consistent decreases in MAP and HR, respectively.     

The action of 15-fluorine derivatives of prostaglandins E2 and F2 alpha on isolated smooth muscles

The effect of exchange of 15-hydroxyl for fluor on biological activity of PGF2 alpha and PGE2 on isolated smooth muscles of different organs has been studied. The exchange leads to significant increase in contractile (100-fold) and relaxation (1000-fold) activity of PGF2 alpha on smooth respiratory muscles. At the same time, the effect of 15-fluor-15-deoxyprostaglandin F2 alpha on smooth muscles of intestinal and vascular tracts did not differ from that of PGF2 alpha. Similar modification of PGE2 led to the decrease (10-fold) both in contractile and relaxation activity on all studied types of smooth muscles. The data obtained have been discussed within the boundaries of prostanoid receptor classification (Kennedy, 1982). Fluor derivative of PGF2 alpha may be used for pharmacological differentiation of EP-receptors.     

Effects of prostaglandins on cyclic AMP levels in isolated cells from developing chick limbs

Effects of prostaglandins (PGs) on accumulation of cyclic AMP (cAMP) in the presence of a phosphodiesterase inhibitor were investigated in cells isolated from avian limb buds at various stages of development. Cells were responsive to PGE2 at the earliest stage investigated (stage 20-21) which was well in advance of specific cytodifferentiation of limb tissues. At three later stages (24-25; 26-28; 30-32), the responsiveness of cells isolated from the developing skeletal anlagen of the limb progressively increased coincident with the differentiation and maturation of the cartilage phenotype. Cells isolated from stage 26-28 cartilage rods were responsive also to prostacyclin (PGI2); however, the response produced was only about 50% of the response to an equivalent concentration of PGE2. Cells were not responsive to either PGF2 alpha or 6-keto PGF1 alpha, at concentrations of 30-33 micrograms/ml demonstrating a degree of specificity for PGE2 and PGI2. In the absence of the phosphodiesterase inhibitor, PGE2 increased cAMP accumulation two-fold over the controls and produced a concentration-dependent response between 0.3-30 micrograms/ml. The results demonstrate that PGs are capable of modulating cAMP levels of undifferentiated limb mesenchymal cells as well as embryonic cartilage cells and suggest a role for these compounds in limb chondrogenesis.     

The actions of prostaglandins I2 and E2 on arrhythmias produced by coronary occlusion in the rat and dog.

Prostaglandins E2 and I2 were compared with known antiarrhythmics for their actions against arrhythmias produced by occlusion of the left anterior descending coronary artery in the anaesthetised rat while PGI2 was also examined in the dog. PGI2 in the dog suppressed early arrhythmias produced during occlusion but did not influence those produced by occlusion-release or those occurring 24 hours after a permanent occlusion; none of the A,B,C or D series prostaglandins tested markedly reduced 24 hour arrhythmias. In the rat PGE2 was antiarrhythmic against early occlusion arrhythmias (30 minutes occlusion) in a dose related manner (infusions of 1-4 microgram/kg/min) whereas PGI2 infusions potentiated the arrhythmogenic effect of occlusion. PGE2 was as effective an antiarrhythmic as 10mg/kg Org. 6001 which was more effective in this test situtation than dl-propranolol. No obvious mechanisms for the actions of PGE2 or PGI2 were apparent although both agents lowered blood pressure and reduced the size of the occluded zone produced by ligation.     

PGE2 is a more potent vasodilator of the lamb ductus arteriosus than is either PGI2 or 6 keto PGF1alpha.

It has been shown in vitro that the lamb ductus arteriosus forms prostaglandins PGE2, PGF2alpha, 6 keto PGF1alpha (and its unstable precursor PGI2). In this study the relative potencies of these endogenous prostaglandins were investigated on isolated lamb ductus arteriosus preparations contracted by exposure to elevated PO2 and indomethacin. All the prostaglandins (except PGF2alpha) relaxed the vessel. This is consistent with the hypothesis that endogenous prostaglandins inhibit the tendency of the vessel to contract in response to oxygen. Only PGE2, however, relaxed the vessel at concentrations below 10(-8)M. PGI2 and 6 keto PGF1alpha had approximately 0.001 and 0.0001 times the activity of PGE2. Although PGE2 has been observed to be a minor product of prostaglandin production in the lamb ductus arteriosus, the tissue's marked sensitivity to PGE2 might make it the most significant prostaglandin in regulating the patency of the vessel.     

Effect of PGF2 alpha and 15(S)-15-methyl PGE2 methyl ester on feline generalized penicillin epilepsy.

The effect of PGF2alpha and 15(S)-15-methyl PGE2 methyl ester on transient generalized epilepsy in the cat induced by penicillin was examined. Epileptic activity before and after administration of the prostaglandins by several routes was determined from continuous EEG recordings and expressed in epileptic bursts per min. The PGE2 analogue given in single non-toxic doses (1.6-3 mug/kg) by intramuscular or intravenous routes at the peak of epileptic activity significantly reduced epileptic activity for up to four hours. Subcutaneous administration was less effective. PG2alpha given by the intramuscular route (0.3 mg/kg) also markedly reduced the number of epileptic bursts. Increasing the dosage 4-fold almost completely suppressed epileptic activity. Intracarotid infusion of PGF2alpha for one hour (10 mug/min) almost abolished all epileptic activity. Neither prostaglandin given in non-toxic doses induced EEG abnormalities in non-epileptic cats. Toxic doses of the E2 analogue (greater than 16 mug/kg) caused bilaterally synchronous high voltage slow wave activity. It is concluded that these prostaglandins reduce penicillin epilepsy in the cat. The findings are consistent with either a direct excitatory action on neurones of the medial reticular formation or anatagonism of the depressant action of norepinephrine on Purkinje cells.     

Pertussis toxin abolishes the inhibitory effects of prostaglandins E1, E2, I2 and F2 alpha on hormone-induced cAMP accumulation in cultured hepatocytes

Several prostaglandins inhibit the cAMP response to glucagon and beta-adrenergic stimulation in hepatocytes. To probe the mechanism of this inhibition, we have examined in primary hepatocyte cultures how pretreatment with pertussis toxin (islet-activating protein) influences the ability of the cells to respond to hormones and prostaglandins. Pertussis toxin augmented the effects of glucagon, epinephrine and isoproterenol, and also markedly enhanced the cAMP response to prostaglandin E1 (PGE1). Furthermore, whereas PGE1, PGE2, PGI2 and PGF2 alpha attenuated the cAMP responses to glucagon in control cultures, this inhibition was abolished in cells pretreated with pertussis toxin. A more detailed comparison was made of the effects of PGE1 and PGF2 alpha. In cells not treated with pertussis toxin, both these prostaglandins at high concentrations reduced the cAMP response to glucagon and isoproterenol by approximately 50%, but dose-effect curves showed that PGE1 was about 100-fold more potent as an inhibitor than PGF2 alpha. Pertussis toxin abolished the inhibitory effects of PGE1 and PGF2 alpha with almost identical time and dose requirements. The results obtained with PGE1, PGE2, PGI2 and PGF2 alpha suggest that prostaglandins of different series attenuate hormone-activable adenylate cyclase in hepatocytes through a common mechanism, dependent on the inhibitory GTP-binding protein.     

Physiological involvement of placental endothelin-1 and prostaglandin F2alpha in uteroplacental circulatory disturbance in pregnant rats exposed to heat stress

Several studies suggest that heat stress affects placental functions including uteroplacental circulation, subsequently leading to pregnancy failure and birth weight reduction. To clarify the involvement of endothelin and placental prostaglandin (PG) systems in the uteroplacental circulation during heat stress, we examined the effects of i.v. administration of the endothelin receptor antagonist bosentan and the cyclooxygenase inhibitor indomethacin on uteroplacental blood flow and on placental PGE2 and PGF2alpha levels and their 13,14-dyhydro-15-keto-metabolites (PGEM and PGFM, respectively) in heat-exposed or non-heat-exposed pregnant rats. The administration of bosentan or indomethacin did not change uteroplacental blood flow in non-heat-exposed pregnant rats. In contrast, heat reduced uteroplacental blood flow in pregnant rats, but the reduction was reversed by the administration of bosentan or indomethacin before heat exposure. Heat did not change placental PGE2 or PGEM levels, but in pregnant rats it increased placental PGF2alpha and PGFM levels, which were reversed by bosentan or indomethacin. Our results suggest that the activation of placental endothelin receptor and PGF2alpha systems are involved in the uteroplacental circulatory disturbances produced by heat. PGF2alpha systems activated by heat may be involved in the vasoconstricting effects of endothelin-A and -B receptors during heat exposure.