In vitro response of relaxin-treated rat uterus to prostaglandins and oxytocin

Paired segments of rat uterus were treated $\text{in vitro}$ with relaxin (W1164-3, 150 GPU/mg) until the amplitude of contraction was reduced to at least 50% of the pre-treatment amplitude. Test segments then received 100 ng of either PGE₁, PGE₂, PGF_2α or 250 uU of oxytocin. Control segments remained untreated. There was a significant increase in contraction amplitude in response to the spasmogens (P < 0.05) but no increase was seen in controls.     

The effects of prostaglandins, prostaglandin inhibitors, and oxygen on the closure of the ductus arteriosus, pulmonary arteries and umbilical vessels in vitro

Three prostaglandins (PGF₂α and PGE₁, PGE₂) have been found in maternal and fetal circulation during labour. Two of these prostaglandins (PGF₂α and PGE₂) are present in elevated levels in maternal circulation during labour and their presence in fetal vessels has been shown.These three prostaglandins have been tested for their effects on fetal vessels in vitro (umbilical artery and vein, ductus arteriosus, and smaller pulmonary artery). These vessels were selected as being crucial in the conversion from fetal to extra-uterine circulation in mammalian species. Responses of these vessels to the prostaglandins under varying oxygen regimes have been examined as well as their responses to prostaglandin inhibitors. Activity of vessels of varying gestational ages exposed to PGF₂α was also examined. The following results were obtained:

1. All vessels, with the exception of pulmonary arteries, contracted in the presence of oxygen over the range 20–100mmHg pO₂. At a pO₂ of < 20mmHg the ductus arteriosus remained inactive or dilated. Pulmonary arteries dilated at high pO₂.

2. All vessels contracted in response to exogenous PGF₂α with the exception of the pulmonary arteries which dilated. In the presence of PGF₂α, the umbilical veins dilated under low (< 20mmHg) pO₂ and contracted at higher levels. Contraction also occurred at lower levels after a period of time.

3. Although PGF₂α was capable of causing contraction in the ductus arteriosus at near zero pO₂, oxygen, (or possibly the products of oxygenation), appear to be required for continued contraction in the presence of PGF₂α. A synergistic relationship between oxygen and PGF₂α responses was found as oxygen tensions increased. A synergistic response between PGF₂α and oxygen with umbilical arteries which did not increase with increased pO₂ was also found. Oxygen tension appeared to have little effect on the response of other vessels to PGF₂α.

4. PGE₁ caused dilations in all vessels examined. Such dilations appearing to be independent of the oxygen regime prevailing. However, an increase in oxygen during experiments reversed any dilation caused by the prostaglandins.

5. PGE₂ caused contractions in umbilical vessels which were independent of oxygen. PGE₂ caused contraction of pulmonary arteries. However, in the ductus arteriosus, PGE₂ caused an initial contraction followed by a strong dilation. This dilation became weaker as pO₂ increased.

6. Additions of prostaglandin inhibitors (Naproxen and Indomethacin) to the bathing solution in which the ductus arteriosus and umbilical arteries were contracting (in response to PGF₂α, or oxygen alone) caused a decrease in contractions, and sometimes a slight decrease when the vessel had been pretreated with PGF₂α suggesting a possible need for endogenously synthesised prostaglandins for the maintenance of oxygen mediated contractions (in vivo).

7. Vessels responsed to PGF₂α at an early gestational age. A role for prostaglandins and oxygen in the closure of fetal vessels is discussed.

     

Characterisation of the prostanoid receptors mediating contraction of guinea-pig isolated trachea

The receptors mediating prostanoid-induced contraction of guinea-pig isolated trachea have been characterised in terms of a recently proposed general classification of prostanoid receptors. Results obtained on the trachea were compared with those obtained on guinea-pig fundus, which contains a sub-type of PGE₂-sensitive (EP-) receptor termed the EP₁-receptor, and guinea-pig lung strip, which contains a thromboxane-sensitive or TP-receptor. The following agonists were studied, PGE₂, PGF₂α and the thromboxane-like agonists U-46619 and Wy17186. The antagonists studied were SC-19220 which selectivity blocks EP₁-receptors, and AH19437 which selectively blocks TP-receptors. On guinea-pig fundus the rank order of agonist potency was PGE₂ > PGF₂α > Wy17186 U-46619, and responses to all agonists were antagonised by SC-19220 but not by AH19437. On guinea-pig lung strip the rank order of potency was U-46619 > Wy17186 PGF₂α > PGE₂ and responses to all agonists tested were blocked by AH19437 but not by SC-19220. On the trachea, the rank order was PGE₂ = U-46619 > Wy17186 = PGF₂α. SC-19220 antagonised responses to PGE₂ and PGF₂α, but not those to U-46619 or Wy17186. Conversely, AH19437 antagonised responses to U-46619 and Wy17186 but not those to PGE₂ or PGF₂α. It is concluded that prostanoid-induced contractions of guinea-pig trachea can be mediated by both EP₁- and TP-receptors.     

Proinflammatory cytokines interact synergistically with epidermal growth factor to stimulate PGE2 production in amnion-derived cells

Recent evidence has implicated cytokines and growth factors in the initiation of parturition in women. In the present study, the amnion-derived cell line WISH was used to determine whether proinflammatory cytokines (interleukins 1β, 6, and 8, tumor necrosis factor-α, and granulocyte/macrophage colony stimulating factor) could amplify epidermal growth factor-induced prostaglandin E₂ production. WISH cells were preincubated with cytokines (0.0001–10 ng/ml) for 60 min and then challenged with EGF (10 ng/ml) for 4 hrs after which PGE₂ production was measured by radioimmunoassay. EGF, IL-1β and TNF-α alone caused a dose-dependent increase in PGE₂ production, while IL-6, IL-8 and GM-CSF were ineffective over the dose range tested. When cells were preincubated with IL-1β or TNF-α, there was a dose-dependent potentiation of EGF-induced PGE₂ production that was greater than the sum of EGF alone and IL-1β or TNF-α alone. In each case, the minimum dose of IL-1β or TNF-α which amplified EGF-induced PGE₂ production was 0.1 ng/ml (p < 0.05, Student's t-test). These data show that low concentrations of IL-1β or TNF-α may serve to amplify EGF-mediated PGE₂ biosynthesis in amnion-derived cells and suggest that cytokines may modulate EGF function in responsivecells.     

PGE2 attenuates PGF2α-induced increases in free intracellular calcium in ovine large luteal cells

When ovine large luteal cells are placed in culture and exposed to PGF_2α, there is a rapid and sustained increase in the concentration of free intracellular calcium which is believed to play a major role in the luteolytic and cytotoxic effects of PGF_2α. Since administration of exogenous PGE₂ can prevent spontaneous and PGF_2α-induced luteolysis in vivo, and the cytotoxic effects of PGF_2α on large luteal cells in vitro, the objective of this study was to determine if one mechanism by which PGE₂ acts is to attenuate increases in free intracellular calcium induced by PGF_2α. At concentrations of 10 nM or greater, PGF_2α caused a significant and sustained increase in free intracellular calcium in large luteal cells. Similarly, PGE₂ also induced increases in free intracellular calcium but required doses 20-fold greater than PGF_2α. When PGE₂ (1, 10 or 100 nM) was incubated with PGF_2α (100 nM) increases in free intracellular calcium induced by PGF_2α were attenuated (P<0.05) when measured 5 min, but not at 30 min, after initiation of treatment. The observed decrease in the concentration of free intracellular calcium at 5 min in response to PGF_2α was the result of fewer cells responding to PGF_2α. In addition, the concentrations of free intracellular calcium attained in the cells that did respond was reduced 25% compared to cells treated with PGF_2α alone. Thus, part of the luteal protective actions of PGE₂ appears to involve an inhibition of the early (5 min) increase in free intracellular calcium induced by PGF_2α.     

The effects of PGF1α, PGE2 and 16,16 dimethyl PGE2 on gastric emptying and small intestinal transit in rat

Prostaglandins are well known for their ability to stimulate contraction in gastrointestinal smooth muscle, yet very little information is available on how their activity affects propulsion . Thus, studies were undertaken to determine the effect of various prostaglandins on qastric emptying (GE) and small intestinal transit (SIT) in unanesthetized fasted rats. Rats were treated with intravenous, subcutaneous, or oral PGF_2α, PGE₂, or 16,16 dimethyl PGE₂ at various doses, followed 1 (intravenous), 20 (subcutaneous) or 10 (oral) mins later by intragastric ⁵¹Cr oxide in black ink. Forty-five mins later, rats were sacrificed by CO₂ asphyxiation, the pylorus clamped, and the gut excised. SIT was expressed as the percent of intestinal length traveled by the most distal portion of ink. GE was expressed as the percent of the ⁵¹Cr emptied into the intestines. If GE was affected by prostaglandin treatment, the experiments were repeated with rats pre-implanted with duodenal cannula. This preparation allowed the visual transit marker to be deposited directly into the dueodenum, thus avoiding acceleration or delay of SIT caused by fluctuations in GE. The results of these studies show that: (1) intravenous 16,16 dimethyl PGE₂ (5–50 μg/kg), but not PGF_2α or PGE₂, accelerates GE and delays SIT; (2) oral prostaglandin administration increases SIT; (3) oral 16,16 dimethyl PGE₂ delays GE; (4) subcutaneous 16,16 dimethyl PGE₂ accelerates, has no effect upon, or delays GE depending upon dose, but accelerates SIT at all doses tested; and (5) subcutaneous PGE₂ accelerates SIT while PGF_2α does not. Thus, the effect of prostaglandins on GE and SIT depends upon the dosage and route of administration as well as type of prostaglandin used.     

Relationships among mammalian gonadotropin-releasing hormone, prostaglandins, and sex steroids in the brain of the crested newt, Triturus carnifex

The present study was carried out to evaluate the in vitro brain release of prostaglandin F_2α (PGF_2α), prostaglandin E₂ (PGE₂), androgens, and 17β-estradiol in male and female crested newt, Triturus carnifex, during three different periods of the annual sexual cycle; in addition, the effects of mammalian gonadotropin-releasing hormone (mGnRH), PGF_2α, and PGE₂ on prostaglandins and steroids release by the brain were evaluated during the same periods. In brain incubations of both sexes, PGF_2α and estradiol were higher during postreproduction, while PGE₂ and androgens were higher during reproduction. In both sexes, mGnRH increased PGF_2α and estradiol during postreproduction, and PGE₂ during reproduction; PGF_2α increased estradiol secretion during postreproduction. Only in the male, did both mGnRH and PGE₂ increase androgens during reproduction. It could be suggested that in Triturus carnifex, the regulation of the reproductive activity in the central nervous system (CNS) depends on the relationships among mGnRH, prostaglandins and steroids. In particular, PGF_2α and PGE₂ seem to play different roles in the CNS of the newt: PGF_2α is involved in the postreproductive processes, through estradiol secretion, while PGE₂ in the reproductive ones (through androgens secretion?).     

Prostaglandin-induced enhancement of the anamnestic response

The ability of various prostaglandins (PGs) to affect the anamnestic immune response of keyhole limpet hemocyanin (KLH)-primed rabbit popliteal lymph node cells was investigated. Of the four PGs studied (PGA₁, PGE₂ and PGF_2α), PGE₁ was found to have a stimulatory effect, whereas PGA₁, PGE₂ and PGF_2α were ineffective in stimulating or inhibiting the anamnestic response. Under the conditions studied, a 3.5-fold increase in antibody production was obtained in PGE₁-treated, KLH-stimulated cultures. Maximum enhancement was obtained when 0.2 μg of PGE₁ were added at the time of culture initiation and were allowed to remain in contact with the lymph node cells for 24 hours.     

Differential effects of prazosin and rauwolsin on the release of prostaglandins I2 and E2 from the perfused mesenteric arterial bed of the rabbit following nerve stimulation

Sympathetic nerve stimulation of the perfused mesenteric arterial bed of the rabbit, , increase the secretion of prostaglandin (PG)I₂ and PGE₂. Prazosin (4.8 × 10⁻⁶), and α₁ adrenergic receptor antagonist, inhibited this inrease in release of PGI₂ but not of PGE₂ whereas rauwolsin (10⁻⁷ M), an α₂ adrenergic receptor antagonist, inhibited the increase in release of PGE₂ but not of PGI₂. Prazosin (10⁻⁶ M) completely blocked the vasoconstrictor response to nerve stimulation, and to norepinephrine and phenylephrine administration, suggesting there to be little of an α₂ adrenergic receptor component in this response. It is concluded that the increase in PGI₂ release follows the activation of α₁ adrenergic receptors and is therefore post-junctional in origin, whereas the increase in PGE₂ release follows the activation of α₂ adrenergic receptors and may be pre- and/or post-junctional in origin.Indomethacin (2.8 × 10⁻⁷, 5.6 × 10⁻⁷ and 1.12 × 10^{−6 M} did not affect the vasoconstrictor responses to nerve stimulation at 10 Hz, whereas rauwolsin (10⁻⁷ M) in the presence of indomethacin substantially increased them. These results indicate that PGE₂ does not regulate norepinephrine release following nerve stimulation at 10 Hz to rabbit mesenteric arteries, and that the inhibition of norepinephrine release following stimulation of α₂ pre-junctional receptors is independent of PG involvement.     

Sensitivity of ovine myometrial tissue to various eicosanoids in vitro

The sensitivity of sheep myometrial tissue to prostaglandin F_2α (PGF_2α), PGE₂, the thromboxane analog U-44069, and leukotrienes C₄ (LTC₄) and LTD₄ was investigated in a superfusion system. Tissues were obtained from eight oophorectomized ewes, with or without pretreatment with estradiol-17β. After equilibration, spontaneous activity was abolished by adding indomethacin to the superfusion fluid. The dose needed to induce a contraction with a peak level of 50% of the median peak level of spontaneous contractions increased from PGE₂ to PGF_2α, U-44069, LTC₄, and LTD₄. The differences between the doses required were significant for all compounds, except between LTC₄ and LTD₄. Estradiol-17β pretreatment caused an increase in the required dose of PGF_2α. The results of this study do not support the hypothesis that leukotrienes are involved in the regulation of myometrial activity.     

Oviduct response to prostaglandins: Influence of estradiol and progesterone

Oviductal motility was measured in the isthmus of ovariectomized New Zealand rabbits. The effects of estradiol and progesterone on spontaneous motility and on the response of the oviduct to exogenously administered prostaglandin E₁ (PGE₁) and PGF_2α were determined. Estradiol treatment significantly increased both the amplitude (P<0.05) and frequency (P<0.01) of spontaneous contractions. The amplitude of spontaneous activity was less following progesterone treatment than following estradiol treatment (P<0.05). Progesterone treatment increased the duration of oviduct response to PGE₁ (P<0.05). Estradiol treatment had no effect on the response to PGE₁. Increased oviductal activity caused by PGF_2α lasted significantly (P<0.01) longer in ovariectomized, untreated animals than in ovariectomized animals treated with estradiol or progesterone. Progesterone was more effective than estradiol in decreasing the duration of the response to PGF_2α. These effects of steroid hormones on the responsiveness of the oviduct to PGE₁ and PGF_2α could contribute to the physiological control of egg transport. The nadir of ovarian hormone influence, as in the recently ovariectomized animals and as occurs immediately after ovulation, is associated with a high responsiveness of the oviduct to PGF_2α. This could effectively increase isthmic occlusion and prevent the eggs from passing through the oviduct prematurely. The gradual increase in ovarian estradiol and progesterone secretion during the 3 days following coitus could result in decreased responsiveness to PGF_2α and increased responsiveness to PGE₁. These changes might cause relaxation of isthmic tone and allow movement of eggs through the isthmus into the uterus.     

Prostaglandin-induced enhancement of the in vitro anamenstic response

The ability of various prostaglandins (PGs) to affect the in vitro anamnestic immune response of keyhole limpet hemocyanin (KLH)-primed rabbit popliteal lymph node cells was investigated. Of the four PGs studied (PGA₁, PGE₂ and PGF_2α), PGE₁ was found to have a stimulatory effect, whereas PGA₁, PGE₂ and PGF_2α were ineffective in stimulating or inhibiting the in vitro anamnestic response. Under the conditions studied, a 3.5-fold increase in antibody production was obtained in PGE₁-treated, KLH-stimulated cultures. Maximum enhancement was obtained when 0.2 μg of PGE₁ were added at the time of culture initiation and were allowed to remain in contact with the lymph node cells for 24 hours.     

Specific receptors for prostaglandins in airways

The relative bronchomotor activities of prostaglandins (PG) E₁, E₂, F_2α, F_2β and I₂ and of three synthetic E prostaglandin analogues (TR4161, TR4367 and TR4752) were determined on a large number of isolated preparations of guinea-pig trachea and human bronchial muscle. Each prostaglandin was capable of eliciting both contraction and relaxation, the relative incidence of these responses partly depending on concentration. TR4161 was a virtually pure relaxant; TR4367 was virtually devoid of bronchomotor activity; and TR4752 was a potent relaxant, devoid of contractant activity. The results also provided distinct rank orders of approximate potency for contraction and relaxation. Tachyphylaxis to the relaxant activities of PGE₁ and TR4752 confirmed the underlying contractant activity of the two natural E prostaglandins. Antagonism with a high dose of indomethacin of the contractant actions of PGE₁, PGE₂ and PGF_2α confirmed the presence of relaxant activities in each.Inhaled aerosols of the same natural and synthetic prostaglandins were evaluated for irritant activity on the airways, using the cough response of the restrained conscious cat. All of them, except TR4161, elicited severe coughing. The rank order of potencies for irritancy differed from those for tracheobronchial contractant and relaxant activities.These findings suggest that the three responses studied arise from the activation of three distinct PG receptors in the airways. We propose the terms χ (contractant), ψ (relaxant) and ω (irritant) for these putative receptors for prostaglandins or possibly other prostanoids.     

Endogenous synthesis of prostaglandins E2 and I2 in 3T3 fibroblasts transformed by polyoma virus: Effects on adenosine 3′:5′-monophosphate production

Prostaglandins (PG)E₁, E₂ and I₂ were produced by polyoma virus transformed (py) 3T3 fibroblasts. The levels of PGE₁, PGE₂ and 6-keto-PGF_1α (degradation product of PGI₂) were 22.7, 225 and 33.2 ng/ml medium, respectively, 72 h after medium change. The stimulatory potencies of exogenous PGE₁, PGE₂ and PGI₂ on adenosine 3′:5′-monophosphate (cyclic AMP) formation were similar. Therefore, the prostaglandin mediated increase in cyclic AMP levels observed during growth of these cells (Claesson, H.-E., Lindgren, J.Å. and Hammarström, S. (1977) Eur. J. Biochem. , 13) is largely (>80%) mediated by PGE₂ and to lesser extents by PGE₁ and PGI₂.     

Interrelationships among prostaglandins, vasopressin and cAMP in renal papillary collecting tubile cells in culture

To determine the influence of prostaglandins on cAMP metabolism in renal papillary collecting tubule (RPCT) cells, intracellular cAMP levels were measured after incubating cells with prostaglandins (PGs) alone or in combination with arginine vasopressin (AVP). PGE₁, PGE₂ and PGI₂, but not PGD₂ or PGF_2α, increased intracellular cAMP concentrations. At maximal concentrations (10⁻⁵ tthe effects of PGE₂ plus PGI₂ (or PGE₁), but not of PGI₂ plus PGE₁, were additive suggesting that at least two different PG receptors may be present in RPCT cell populations. Bradykinin treatment of RPCT cells caused an accumulation of intracellular cAMP which was blocked by aspirin and was quantitatively similar to that observed with 10⁻⁵ PGE₂. PGs, when tested at concentrations (e.g. 10⁻⁹ ) which had no independent effect on intracellular cAMP levels, did not inhibit the AVP-induced accumulation of intracellular cAMP in RPCT cells. These results indicate that PGs do not block AVP-induced accumulation of intracellular cAMP in RPCT cells at concentrations of PGs which have been shown to inhibit the hydroosmatic effect of AVP on perfused collecting tubule segments. However, at higher concentrations of PGs (e.g. 10⁻⁵ ), the effects of AVP plus PGE₁, PGE₂, PGI₂ or bradykinin on intracellular cAMP levels were not additive. Thus, under certain conditions, there is an interaction between PGs and AVP at the level of cAMP metabolism in RPCT cells.     

Patterns of prostaglandin synthesis and degradation in isolated superficial and proliferative colonic epithelial cells compared to residual colon

Prostaglandin (PG) synthesis and degradation were examined in different regions (epithelial versus non-epithelial structures) of the rat distal colon by both HPLC analysis of [¹⁴C] arachidonate (AA) metabolites and by specific radioimmunoassays. Intact isolated colonic epithelial cells synthesized mainly PGF₂α and TXA₂, as monitored from the formation of its stable degradation product TXB₂ (PGF_2α > TXB₂ > 6-keto-PGF_1α, the stable degradation product of PGI₂=PGD₂=PGE₂=13,14-dihydro-15-keto-PGF_2α). The profile of PG products of isolated surface epithelial cells was identical to that of proliferative epithelial cells. However, generation of PGs by surface epithelium was 2 to 3-fold higher than by proliferative cells both basally and in the presence of a maximal stimulating concentration (0.1 mM) of AA. The latter implied a greater synthetic capacity of surface epithelium, rather than differences due to endogenous AA availability. The major sites of PG synthesis in colon clearly resided in submucosal structures; the residual colon devoid of epithelial cells accounted for at least 99% of the total PGs produced by intact distal colon. The profile of AA metabolites formed by submucosal structures also differed markedly from that of the epithelium. The dominant submucosal product was PGE₂. PGE₂ and its degradation product 13,14-dihydro-15-keto-PGE₂ accounted for 63% of the PG products formed by submucosal structures (PGE₂ PGD₂ > 13,14-dihydro-15-keto-PGE₂ > PGF_2α=TXB₂=6-keto-PGF_1α > 13,14-dihydro- 15-keto-PGF_2α). By contrast, epithelial cells, and particularly surface epithelium, contributed disproportionately to the PG degradative capacity of colon, as assessed from the metabolism of either PGE₂ or PGF_2α. When expressed as a percentage, epithelial cells accounted for 71% of total colonic PGE₂ degradative capacity but only 23% of total colonic protein. Approximately 15% of [³H] PGE₂ added to the serosal side of everted colonic loops crossed to the mucosal side intact. Thus, at least a portion of the PGE₂ formed in the submucosa reaches, and thereby can potentially influence functions of the epithelium.     

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

Hydrocortisone (10 μg/ml) had no effect on the basal outputs and A23187-stimulated outputs of PGF_2α, PGE₂ and 6-keto-PGF_1α from the Day 15 guinea-pig uterus superfused . These findings indicate that the high output of PGF_2α from the guinea-pig uterus during the last one-third of the oestrous cycle is not modulated by the adrenal glucocorticoid hormones. Progesterone (10 gmg/ml) had no effect on the A23187-induced increases in PG output from the Day 15 guinea-pig uterus. However, oestradiol (10 gmg/ml but not 1 μg/ml) significantly reduced the increases in outputs of PGF_2α, PGE₂ and 6-keto-PGF_1α 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 μg/ml). The addition of oestradiol (10 μg/ml) and progesterone together (10 gmg/ml) produced the same effects on the Day 15 guinea-pig uterus as oestradiol alone. Oestradiol (10 μg/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 gmg/ml) reduced the increases in outputs of PGF_2α, PGE₂ and 6-keto-PGF_1α 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.     

Biosynthesis of prostaglandins and thromboxane B2 by fetal lung homogenates

The conversion of arachidonic acid to prostaglandins (PG's) and thromboxane B₂ (TXB₂) was investigated in homogenates from fetal and adult bovine and rabbit lungs. Adult bovine lungs were very active in converting arachidonic acid (100 μg/g tissue) to both PGE₂ (10.7 μg/g tissue) and TXB₂ (6.2 μ/g tissue). Smaller amounts of PGF_2α (0.9 μ/g) and 6-oxoPGF_1α were formed. Homogenates from fetal calf lungs during the third trimester of pregnancy were quite active in converting arachidonic acid to PGE₂, but formed very little TXB₂, PGF_2α or 6-oxoPGF_1α. Homogenates from rabbit lungs converted arachidonic acid (100 μg/g) mainly to PGE₂, both before and after birth. The amount of PGE₂ formed increased during gestation to a maximum of about 6 μg/g tissue at 28 days of gestation. It then decreased to a minimum (1.5 μg/g) which was observed 8 days after birth, followed by an increase to about 4 μg/g in older rabbits.     

Prostaglandins and pacemaker activity in isolated guinea pig SA node

Prostaglandins PGE₂, PGE₁, PGF_2α, and PGA₁ substantially increase automaticity in SA-nodal, right atrial preparations excised from guinea pigs. This natural pacemaker tissue is sensitive to nanomolar doses of PG with, for example, 10⁻⁸ M PGE₂, increasing SA rate by about 20%. If these preparations are pretreated with 2 μM indomethacin, a blocker of endogenous prostaglandin synthesis, then spontaneous rate drops and subsequent rate increases due to PGE₂ administration can be more easily demonstrated. Guinea pig pacemaker tissue differs from similar rabbit tissue not only in that it is directly responsive to PGE₂, but also in that PGE₂ does not depress the absolute response to transmural stimulation (adrenergically mediated rate increase). The positive chronotropic responses to PGE₂ also occur when the guinea pig tissue is pretreated in 0.6 μM propranolol, which causes blockade of beta-adrenergic receptors.The pacemaker myocardium in the guinea pigs thus appears to be directly stimulated by exogenous PGE₂ at very low doses. The observation that 2 μM indomethacin reduces SA-nodal rate suggests the presence of a very sensitive, functionally important, PGE-like system which modulates heart rate in this mammalian species.     

Different responsiveness of a variety of isolated dog arteries to prostaglandin D3

The addition of prostaglandin (PG) D₂ contracted helical strips of dog cerebral, coronary, renal and femoral arteries; the contraction was greatest in cerebral arteries. The contractile response of cerebral arteries was potentiated by aspirin and attenuated by polyphloretin phosphate. In the arterial strips contracted with PGF_2α, PGD₂ elicited a concetration-related relaxation; the relaxation was greatest in mesenteric arteries. In mesenteric arterial strips contracted with norepinephrine, a lesser degree of relaxation was induced, and in the K⁺-contracted arteries, only a contraction was induced. Treatment with PGD₂ attenuated the contractile responses of cerebral and mesentric arteries to PGF_2α or PGE₂; this inhibitory effect was approximately 10 times greater in mesenteric arteries. However, the response to serotonin (for cerebral arteries) or norepinephrine (for mesenteric) was unaffected. It may be concluded that the heterogeneity of response to PGD₂ of a variety of dog arteries is due to different contributions of vasoconstrictor and vasodilator mechanisms. PGD₂ appears top share the mechanism underlying arterial contraction with PGF_2α and PGE₂, and interferes with the effect of these PG's possibly on receptor sites.