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Some clinical and theoretical aspects on prostaglandins in obstetrics and gynecology.

The present article discusses two aspects on prostaglandins, both related to the control of uterine contractility. One concerns a clinical problem, induction of abortion, and argues in favor of systemic instead of intrauterine administration of prostaglandins and the choice of E instead of F analogues. The other relates to the stimulatory effect on the myometrium of some recently detected endogenous prostaglandins. The discussion regarding the endogenous control of myometrial contractility has so far exclusively been focused upon the classical prostaglandins. It is, however, felt that substances like PGH2, PGI2 and thromboxane A2 may play a significant role in the regulation of uterine activity.

Abortion, Induced↗

Vasoconstrictor actions of isoprostanes via tyrosine kinase and Rho kinase in human and canine pulmonary vascular smooth muscles.

1. We examined the effects of several E-ring and F-ring isoprostanes on mechanical activity in pulmonary artery and vein. 2. 8-iso PGE(2) and 8-iso PGF(2 alpha) were powerful spasmogens in human vasculature and in canine pulmonary vein. 8-iso PGE(1) and 8-iso PGF(2 beta) also exhibited moderate spasmogenic activity in canine pulmonary vein; 8-iso PGF(1 alpha), 8-iso PGF(1beta), and 8-iso PGF(3 alpha) were generally ineffective. Canine pulmonary arteries did not exhibit excitatory responses to any of the isoprostanes. 3. The spasmogenic effects of 8-iso PGE(2) were markedly attenuated by the TP-receptor blocker ICI 192605 and by the EP-receptor blocker AH 6809 (-log K(B)=8.4 and 5.7, respectively). PGE(2) was a very weak agonist ( approximately 100 fold less so than 8-iso PGE(2)). 4. In the presence of ICI 192605 (10(-6) M), 8-iso PGE(1) evoked modest dose-dependent relaxations in human and canine pulmonary vein, and in canine pulmonary artery, but not in the human pulmonary artery. The other isoprostanes were generally ineffective as vasodilators in the pulmonary vasculature of both species. 5. The spasmogenic effects of 8-iso PGE(2) and 8-iso PGF(2 alpha) did not involve elevation of [Ca(2+)](i). 6. 8-iso PGE(2)-evoked contractions were blocked by inhibitors of tyrosine kinase (genistein) and Rho kinase (Y 27632 and HA 1077), but not by inhibitors of protein kinase C (calphostin C or chelerythrine), mitogen-activated protein kinase kinase (PD 98059) or p38-kinase (SB 203580). 7. The actions of 8-isoprostanes in the lungs are compound-, species- and tissue-dependent. Several isoprostanes evoke vasoconstriction: in the case of 8-iso PGE(2), this involves activation of TP-receptors, tyrosine kinases and Rho kinases. 8-iso PGE(1) is also able to cause vasodilation.

Animals↗

Prostaglandins and erythropoiesis: structure/action relationships and identification of the prostaglandin responsive cells.

Ten prostaglandin derivatives have been investigated for their ability to stimulate heme synthesis in serum-free cultures of fetal mouse liver cells in an attempt to define the structural requirements of the prostaglandin molecule necessary for erythrostimulation. In descending order of potency, only PGE2, PGF2 alpha and PGB1 produced at least 50% stimulation of endogenous heme synthesis. Seven of the ten prostaglandin derivatives tested were inhibitory at high concentrations. The PGE2 effect was pharmacologically distinct from that of Ep and could be antagonized by 15 epi PGF2 alpha. Unit gravity cell sedimentation studies demonstrated that PGE2 stimulated only the larger cells within the erythropoietin responsive cell population.

Animals↗

Activation of guinea pig pulmonary adenylate cyclase by prostacyclin.

Prostacyclin activates adenylate cyclase of guinea pig lung homogenates. The concentration for half-maximum activation was 20 nM. Kinetic analysis of the increase in enzyme activity suggested a non-cooperative, bimolecular interaction between prostacyclin and a single receptor population. Comparison of the activity of prostacyclin with that of other prostaglandins revealed a rank order of potency: prostacyclin > prostaglandin E1 > prostaglandin E2 > prostaglandin F1 alpha. 6-Oxo-prostaglandin F1 alpha, the stable hydrolysis product of prostacyclin, produced no increase in adenylate cyclase activity. Lungs were dissected before homogenisation, and prostacyclin-sensitive adenylate cyclase was identified at high concentrations in peripheral lung tissue containing small airways, blood vessels and parenchyma. The precise cellular location of these receptors remains obscure, but the probability that they are in the pulmonary vascular bed rather than airway smooth muscle is discussed.

Adenylyl Cyclases↗

The role of various prostaglandins on the correlation between permeability to albumin and cAMP levels in the isolated mesentery.

Prostaglandins (PG) have been shown to raise the level of cyclic AMP (cAMP) in various tissues, and to increase permeability. Whether both events are linked, is at present a matter of speculation. We have investigated the effects of PGE1, E2, A1, A2, F1alpha and F2alpha on an isolated rat mesentery placed in a diffusion cell (surface area : 2 sq.cm). The PGs (5 microgram/ml) increased the passage of (I 125) - Albumin across the mesentery. In other experiments, diks of rat mesentery (surface area : 2 sq.cm) have been incubated in assay tubes, and cAMP levels measured by a binding protein assay. We have observed an excellent correlation between increases in permeability and cAMP levels (r=0.961). In order of increasing potency on both parameters, the PGs may be classified as follows : PGF, PGA and PGE. In the rat mesentery, under the influence of prostaglandins, increases in permeability and in cAMP levels are apparently connected.

Albumins↗

The effects of synthetic prostaglandin analogs on canine hepatic bile flow.

The synthetic prostaglandin analogs 16, 16-dimethyl PGF2 alpha and 16, 16-dimethyl PGE2 were administered to dogs with chronic biliary and gastric fistulas. The effects of 16, 16 diMePGF2 alpha and 16, 16 diMePGE2 were evaluated on bile flow and composition and bile adenosine 3', 5' monophosphate (cyclic AMP) secretion. 16, 16 diMePGF2 alpha in doses of 0.125 and 0.25 microgram-kg-min significantly increased hepatic bile flow. The choleresis was characterized by increased chloride and bicarbonate secretion. Measurement by radioimmunoassay of bile cyclic AMP concentration demonstrated no evident increase in bile cyclic AMP secretion associated with the choleresis produced by 16, 16 diMePGF2 alpha. The administration of 16, 16 diMePGE2 in a dose range 0.01 to 1.0 microgram-kg-min did not significantly alter bile flow rates or composition. Bile erythritol-14C clearance, a measure of canalicular bile flow, was significantly increased by PGF2 alpha but not by 16, 16-dimethyl PGF2 alpha, suggesting that the mechanism of action of PGF2 alpha in stimulating hepatic bile flow may be different from that involved in 16, 16-dimethyl PGF2 alpha choleresis. The results of this study indicate that the synthetic PGF2 alpha analog produces a choleretic response not mediated by adenylate cyclase and associated with increased chloride and bicarbonate secretion.

16,16-Dimethylprostaglandin E2↗

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.

Animals↗

Actions of prostaglandins on isolated perfused cat coronary arteries.

Effects of prostaglandins on coronary arterial smooth muscle were studied in isolated perfused cat coronary arteries. This preparation was shown to be responsive to known vasoactive agents, including angiotensin II, adenosine, and norepinephrine. Prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha) produced dose-dependent coronary arterial constriction at concentrations of 3 times 10(-9) M or greater. PGE1 produced a biphasic dose-response curve with constriction at low concentrations greater than 10(-7) M.PGI2 dilated coronary arteries at concentrations greater than 10(-8) M. Inhibition of endogenous prostaglandin synthesis with meclofenamate potentiated responses to prostaglandins. The endoperoxide, PGH2, slightly constricted cat coronary arteries. However, in the presence of human platelet microsomes, PGH2 was converted to thromboxane A2(TxA2), which was the most potent coronary artery constrictor among the naturally occurring compounds studied. Analysis of coronary artery perfusate for TxB2 confirmed the thromboxane generation, which was markedly lower in the presence of imidazole. Two synthetic endoperoxide analogs produced potent coronary arterial constriction. Induction of hypoxia to a PO2 of 50 mmHg or increasing basal tome with 30 mM KCl did not diminish coronary artery response to prostaglandins, suggesting that prostaglandins released from ischemic myocardial tissue may influence coronary arterial tone.

Animals↗

Prostaglandins and the contractility of the guinea pig biliary system.

The effects of exogenously applied prostaglandins on the contractile responses of the gallbladder and sphincter of Oddi isolated from guinea pigs were examined in normal and indomethacin-treated preparations. Indomethacin reduced the tone and the contractile responses to transmural stimulation and to exogenously applied ACh of the gallbladder, while the tone and contractile responses of the sphincter of Oddi were little affected by indomethacin. Prostaglandins E1, E2 and F2 alpha potentiated the contractile responses of the gallbladder to transmural stimulation and ACh, and furthermore, treatment with indomethacin enhanced the potentiating effects of prostaglandins E1 and E2 but not the effect of PGF2 alpha. The reduced tone and contractility of the gallbladder were restored to the control level by addition of PGE1 and PGE2 but not by PGF2 alpha. These results suggest that endogenous PGE1 and PGE2 may play an important role in neurogenic control of contractility of the gallbladder, but not of the sphincter of Oddi.

Acetylcholine↗

Effects of some prostaglandins on the main phosphorylating, electron transporting and peroxidative systems of the erythrocyte membrane.

Investigations regarding the main biochemical systems of the erythrocyte membrane were performed on rat erythrocyte ghosts after treating the animals with PGA1, PGE1 and PGF2alpha. These investigations have shown that the prostaglandins which were found to induce changes in the erythrocyte flexibility (PGE1 and PGF2ALPHA) also induce significant changes in the concentrations of lipid peroxides, SH groups, proteins and nicotinamide adenine nucleotides, as well as in the activity of some electron transportors belonging to the nicotinamide proteins, in the erythrocyte membrane.

Adenine Nucleotides↗

Clinical applications of prostaglandins in Obstetrics and Gynaecology.

Although a number of potential practical uses of prostaglandins have been identified, these compounds have so far found clinical applications mainly in Obstetrics and Gynaecology. It is almost 15 years since a prostaglandin was first used for the induction of term labour and prostaglandin E2 is now commercially available for this purpose in many countries. For the termination of second trimester pregnancy, prostaglandins have almost completely replaced other methods previously in use. Other areas where prostaglandins are routinely used or where their uses are being developed, include menstrual induction, preevacuation dilatation of the cervix in the first trimester, termination of pregnancy in cases of missed abortion, intrauterine fetal death and other types of abnormal pregnancies, control of post-partum haemorrhage, treatment of post-partum or post surgical urine retention and ripening of the cervix prior to induction of labour at term. In early studies, prostaglandins E2 and F2 alpha were used for all the applications listed above. In order to increase efficacy and reduce side effects, a number of synthetic analogues were later evaluated for application in selected areas. Those with modification in the 15 and 16 positions of PGE2 and PGF2 alpha molecules have undergone extensive clinical trials and some of these analogues are now in routine use. The current status of the practical applications of prostaglandins in Obstetrics and Gynaecology is reviewed.

Abortifacient Agents↗