Prostaglandin Endoperoxide Analogue Research Articles

The influence of secretin, glucagon and other peptides, of amino acids, prostaglandin endoperoxide analogues and diazepam on the level of adenosine 3',5'-cyclic monophosphate in neuroblastoma x glioma hybrid cells.

Abstract— Neuroblastoma glioma hybrid cells display many properties of neurons. A series of compounds, among them a number of amino acids, peptides and peptide hormones were tested for their ability to influence the level of adenosine 3′,5′‐cyclic monophosphate (cyclic AMP) in the hybrid cells. Two prostaglandin endoperoxide analogues exhibit a weak stimulatory action, if applied in at least micromolar concentrations. At nanomolar concentrations, only the gastrointestinal hormones secretin and glucagon stimulate the formation of cyclic AMP, as detected in the presence of a phosphodiesterase inhibitor. The effect of secretin but not that of glucagon is antagonized by secretin‐(5–27), suggesting that secretin and glucagon act on the cells via different receptors. These results appear to be noteworthy since (a) an effect of secretin or glucagon on a cell with neuronal characteristics has not yet been described, and (b) many peptide hormones have been detected both in the gastrointestinal tract and the nervous system.

9,11-Iminoepoxyprosta-5,13-dienoic acid is a selective thromboxane A 2 synthetase inhibitor

9,11-Iminoepoxyprosta-5,13-dienoic acid inhibits the thromboxane A 2 synthetase in platelet and lung microsomal enzyme preparations and in intact platelets. It does not inhibit the prostaglandin I 2 synthetase in aorta or lung microsomes and intact Balb 3T3 fibroblasts. In lung microsomes, which contain both enzymes, 9,11-iminoepoxyprosta-5,13-dienoic acid inhibits only thromboxane A 2 formation and augments prostaglandin I 2 formation. This inhibitor is more selective than other reported prostaglandin endoperoxide analogs which inhibit the platelet thromboxane synthetase.

Synthesis of a new prostaglandin endoperoxide (PGH 2) analog and its function as an inhibitor of the biosynthesis of thromboxane A 2 (TBXA 2)

Synthesis of a new prostaglandin endoperoxide (PGH 2) analog and its function as an inhibitor of the biosynthesis of thromboxane A 2 (TBXA 2)

Effect of prostaglandin endoperoxide analogue on canine renal function, hemodynamics and renin release

We studied the effect of a stable, cyclic ether analogue of prostaglandin endoperoxide (EPA) on canine renal function, hemodynamics, and renin release. Infusion of EPA into one renal artery decreased renal blood flow in a dose dependent manner. At a dose of 10 −7 g/kg/min the renal blood flow decreased from a baseline of 384 to 267 ml/min/100 g. This flow decrease was unaltered by phentolamine and saralasin, but was potentiated by prior treatment with indomethacin. Urine flow, glomerular filtration rate, sodium, and potassium excretion all decreased in a dose dependent manner; however, neither fractional excretion of sodium nor free water clearance showed any significant change, making direct tubular effects of EPA unlikely. EPA caused a significant increase in renin release that was completely blocked by prior treatment with indomethacin. We conclude that EPA is a potent renal vasoconstriction and that this vasoconstrictor is responsible for the renal functional changes observed. Renin release is not a direct effect of EPA but probably is secondary to an endogenously generated prostaglandin. Since EPA mimics the effects of natural prostaglandin endoperoxides on smooth muscle in vitro, it is possible that prostaglandin endoperoxide-induced vasoconstriction in vivo modulates the effects of their vasodilatory products, prostaglandin E 2 and I 2.

Mode of action of dipyridamole on human platelets

The effects of dipyridamole were investigated on platelet aggregation, ( 14C)-5 hydroxytryptamine release, cyclic nucleotide metabolism and malonyldialdehyde and thromboxane B2 production. Pre-incubation of platelet-rich plasma with dipyridamole inhibited platelet aggregation in response to ADP, epinephrine, an epoxymethano prostaglandin endoperoxide analogue and collagen, and potentiated the inhibitory effect of prostacyclin on platelet aggregation. A small inhibition of 5-hydroxytryptamine release was also found. Dipyridamole potentiated the stimulation of platelet cyclic AMP accumulation by prostacyclin, and also potentiated the stimulatory effect of both arachidonic acid and dihomo-γ-linoleic acid on cyclic GMP accumulation. An inhibitory effect of the drug was observed on both cyclic AMP and cyclic GNP phosphodiesterase activities, particularly at high substrate concentrations. In addition, a slight stimulation of platelet membrane adenylate cyclase activity was found. The inhibition of platelet aggregation induced by collagen and arachidonic acid by the drug was accompanied by a reduction in the thromboxane B 2 production. The inhibition of thromboxane B 2 formation was also apparent in human platelet-rich plasma containing EDTA and in an isolated bovine platelet microsome preparation indicating that dipyridamole has a dose-dependent inhibitory effect on thromboxane synthesis which was independent of aggregation. Dipyridamole also inhibited malonyldialdehyde production in response to both thrombin and arachidonic acid. Thus dipyridamole may inhibit platelet function not only by increasing platelet cyclic AMP but may also exert a minor effect on platelet thromboxane biosynthesis.

A Convenient Synthesis of π-Allylpalladium Compounds from Monosubstituted Terminal Olefins

Abstract There has been considerable recent interest in new applications of π-allylpalladium compounds in organic synthesis.2,3 In our own work on the synthesis of prostaglandin endoperoxide analogs, we had need of π-allylpalladium compounds of the following type where X is a functional group. W e had originally hoped to prepare these compounds directly from the corresponding terminal olefins. Unfortunately however, the most widely used methods for the direct conversion of olefins to π-allylpalladium compounds apparently are not applicable to monosubstituted terminal olef ins,4–8 and those which appeared applicable either gave very low yields, mixtures of π-allylpalladium compounds,11 or no product at a11.12 An equally important route to π-allylpalladium compounds employs allylic chlorides and palladium(I1) salts.13–15 Unfortunately, allylic chlorides are difficult compounds to handle and one would prefer to avoid isolating these compounds if at all possible.

Studies on the thromboxane synthesizing system in human platelet microsomes

The thromboxane synthesizing system from human platelets has been characterized by using arachidonic acid and prostaglandin endoperoxide as indirect and direct substrates. The synthesis of thromboxanes from either substrates catalyzed by the microsomal fraction was monitored by measuring the formation of thromboxane B 2 immunoreactivity. Both hemoglobin and phenolic compounds were required for the maximal synthesis of thromboxane B 2 from arachidonic acid but not from prostaglandin endoperoxide. Studies on the kinetics of the formation of thromboxane B 2 from either substrates indicated that the synthesis of prostaglandin endoperoxide intermediate is the rate-limiting step in the overall production of thromboxanes from arachidonic acid. Effect of the microsomal protein concentrations on the rate of formation of thromboxane B 2 showed concave upward relationship suggesting the possible involvement of endogenous stimulator(s) in thromboxane synthetase catalyzed reaction. A variety of compounds including sulfhydryl inhibitors, prostaglandin endoperoxide analog, prostaglandin antagonist, N-0164, and N-substituted imidazoles could directly inhibit the thromboxane synthetase, while nonsteroidal antiinflammatory drugs apparently affected the prostaglandin endoperoxide synthetase which catalyzes the synthesis of the immediate precursor of thromboxanes.

Effects of prostaglandin E2, analogs, fatty acids, and indomethacin on fibrinogen level

Dose-response relations in rabbits for 3-h intravenous infusion of prostaglandin E2 (PGE2) and (15S)-15-methyl-1-prostaglandin E2 methyl ester (MePGE2) on plasma fibrinogen and systolic blood pressure were determined and described by regression equations. MePGE2 was 20 times more active than PGE2. Fibrinogen synthetic rate responses to PGE2 and MePGE2 were estimated. Infusion of the PGE2 precursor, arachidonic acid, elevated plasma fibrinogen, but fibrinogen response to 0.5-9 mg/kg arachidonic acid was unrelated to dose and half that given by 3 mg/kg PGE2. Slow infusion of several other fatty acids raised plasma fibrinogen as effectively as arachidonic acid, but prostaglandins D2 and F2alpha had only a slight effect. Infusion of 30 times the indomethacin dose that blocks platelet prostaglandin synthetase did not alter the plasma fibrinogen response to arachidonic acid. Indomethacin did not inhibit plasma fibrinogen elevations following ACTH or endotoxin infusion, or subcutaneous turpentine injection. Intravenous infusion of two cyclic ether prostaglandin endoperoxide analogs, (15S)-hydroxy-9alpha, 11alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid, and (15S)-hydroxy-11alpha, 9alpha(epoxymethano) prosta-5Z, 13E-dienoic acid, failed to increase plasma fibrinogen.

EFFECTS OF PROSTAGLANDIN E2 AND A PROSTAGLANDIN ENDOPEROXIDE ANALOGUE ON NEUROEFFECTOR TRANSMISSION IN THE RAT ANOCOCCYGEUS MUSCLE

1 Investigations were made into the effects of prostaglandin E(2) (PGE(2)) and a prostaglandin endoperoxide analogue (Upjohn compound U-46619) on the responses of the rat anococcygeus muscle to field stimulation of the intrinsic sympathetic nerves, and to exogenous noradrenaline. The effects of PGE(2) on responses to stimulation of intrinsic inhibitory nerves were also studied.2 PGE(2) (5.6 x 10(-8) or 2.8 x 10(-6) mol/l) decreased motor (sympathetic) responses to field stimulation at all frequencies tested (2 to 24 Hz). The prostaglandin also reduced the inhibitory responses to field stimulation, seen when the tone of the preparation had been raised and its sympathetic innervation had been blocked by guanethidine. However, these inhibitory responses were also reduced by other spasmogens (carbachol and 5-hydroxytryptamine) which, like PGE(2), further increased the tone of guanethidine-treated preparations.3 At a concentration of 5.6 x 10(-8) mol/l, PGE(2) had no effect on responses to noradrenaline, whereas at a fifty-fold higher concentration the prostaglandin potentiated these.4 Unlike PGE(2), U-46619 (5.6 x 10(-8) mol/l) greatly potentiated motor responses to field stimulation, at frequencies from 0.75 to 24 Hz. This effect did not represent a specific facilitation of sympathetic neurotransmission, as responses to carbachol and 5-hydroxytryptamine, as well as to noradrenaline, were also potentiated.5 The results are discussed in relation to the effects of prostaglandins and prostaglandin endoperoxides on neuroeffector transmission in other sympathetically innervated tissues. It is concluded that PGE(2) inhibits sympathetic neurotransmission in the rat anococcygenus muscle by a prejunctional action, whereas the predominant effect of U-46619 is direct excitation of the muscle. The effect of PGE(2) on inhibitory responses to field stimulation may represent an interference with inhibitory neuroeffector transmission in this tissue, or may simply be a consequence of the spasmogenic action of the prostaglandin.

Synthesis and biological properties of prostaglandin endoperoxides, thromboxanes and prostacyclins.

AbstractProstaglandins continue to be a major and fast‐developing area of research in the chemical and biological sciences. Increasing evidence has recently prompted some researchers to suggest that the important physiological actions of these hormones are exerted by their unstable arachidonic acid pathway intermediates, the endoperoxides, thromboxanes, and prostacyclin. The importance of these substances in physiology and medicine and the challenge they pose to synthetic chemistry place them in the forefront of chemical and biochemical investigation. Current biological research has greatly benefited by synthetic advances which have made available large quantities of some of these naturally occurring intermediates and several analogs with increased stabilities. Following a brief review of the primary prostaglandins, the present article describes recent biosynthetic developments, partial and total syntheses of prostaglandin endoperoxide analogs, thromboxane B2, and prostacyclins, and the biological properties of these molecules.

Contractile action of a stable prostaglandin endoperoxide analogue on the human umbilical artery.

Contractile action of a stable prostaglandin endoperoxide analogue on the human umbilical artery.

Stimulation of afferent vagal endings in the intrapulmonary airways by prostaglandin endoperoxide analogues

Two cyclic ether (CE) analogues of the prostaglandin endoperoxide PGH 2, CE I and CE II, have been found to exert powerful stimulant effects on lung ‘irritant’ receptors and bronchial C-fiber endings after intravascular or aerosol administration in open-chest dogs under Dial-pentobarbital anesthesia. ‘Irritant’ receptors responded to a dose as small as 0.1 μg/kg CE II, injected into the right atrium. CE II was twice as effective as CE I and 10–20 times more potent than PGF 2α. As an aerosol, it exceeded histamine in potency by more than 800 times. ‘Irritant’ receptor stimulation was always associated with decrease in lung compliance and increase in lung resistance. Isoproterenol which reduced the latter effects also diminished the response of ‘irritant’ receptors. Left atrial injection of GE S had only weak and delayed effects. CE-induced ‘irritant’ receptor firing declined or ceased during ventilatory arrest in expiration and following hyperinflation of the lungs. In contrast to ‘irritant’ receptors, C-fibers responded more effectively and more rapidly, and in the absence of mechanical changes, when the drugs were injected into the left atrium as compared to right atrial injection. These findings suggest that CE-induced ‘irritant’ receptor stimulation is secondary to changes in lung mechanics, whereas C-fiber stimulation is a direct effect upon the nerve ending.

Rat osteogenic sarcoma cells: Effects of some prostaglandins, their metabolites and analogues on cyclic AMP production

Cyclic AMP production by freshly isolated cells, from a 32P-induced transplantable rat osteogenic sarcoma, was stimulated by PGE 1, PGE 2 and to a less extent by PGF 2α and PGA 2. In the case of PGE 2, the cyclic AMP content of cells was miximal within 5 min. The 13, 14-dihydro derivatives of PGE 1, PGE 2 and PGF 2α had approximately 40% of the activity of the parent prostaglandin whilst, in every case, the metabolites (15-keto and 13,14-dihydro-15-keto) had very little activity. Two prostaglandin endoperoxide analogues (U44069 and U46619) had only 10% of the activity of an equimolar dose of PGE 2. The data presented in this paper demonstrates similarities between the responses of these cells and cells derived from bony tissue in terms of the ability of prostaglandins to stimulate bone resorption in tissue culture.

Effects of prostaglandin endoperoxide analogs on contractile elements in lung and gastrointestinal tract

Prostaglandin endoperoxides are formed in the lung as intermediate compounds in the biosynthesis of prostaglandins and thromboxanes. The effects of different doses of two analogs of prostaglandin endoperoxide PGH 2 were compared with those of PGF 2α and PGE 2 on superfused preparations of isolated trachea, bronchiole, peripheral lung, pulmonary artery and gastrointestinal smooth-muscle tissues. Endoperoxide analogs induced contraction of all smooth-muscle structures in the lung and airways. Compared to PGF 2α, analog I was approximately 71 times as potent on guinea-pig trachea, 214 times as potent on guinea-pig lung, and 57 times as potent on guinea-pig polmunary artery. Analog II was moderately less potent on all tissues than analog I. On gastrointestinal smooth-muscle organs, the PGH 2 analogs were generally closer in activity to PGF 2α and PGE 2, or even weaker. The findings show that PG endoperoxide vessels, and suggest that the naturally occurring compounds may participate in the mediation of bronchoconstriction and pulmonary vasoconstriction in disease states.

Influence of a prostaglandin endoperoxide analogue on the canine pulmonary vascular bed.

We evaluated the effects of an analogue of the prostaglandin endoperoxide, PGH2, in the canine pulmonary vascular bed. The analogue increased pulmonary arterial pressure whereas cardiac output and left atrial pressure were unchanged. Although pulmonary vascular resistance was increased markedly, only small increases in systemic vascular resistance were observed. In experiments in which blood flow to a lobe was maintained constant, the analogue produced dose-related increases in lobar arterial and small vein pressure but little change in left atrial pressure. These data suggest that the analogue increased resistance to flow by constricting intrapulmonary veins and upstream vessels presumed to be small arteries. The increase in resistance was similar when the lung was perfused with dextran or with blood. In addition, the analogue increased inflation pressure; however, similar increments in vascular resistance were obtained in ventilated and nonventilated lung lobes. Indomethacin, in doses which abolished responses to arachidonic acid, did not attenuate the response to the analogue. These results suggest that interaction with formed elements, increases in airway tone, or stimulation of prostaglandin synthesis contribute little if anything to the pressor response to the analogue. These data show that the analogue is far more potent than the bisenoic prostaglandins in the pulmonary vascular bed and suggest that endoperoxides may represent an active form of the prostaglandins in the lung.

Angiotensin II-induced contractions of rabbit splenic capsular strips and release of prostaglandins. Use of radioimmunoassays for prostaglandins E1 and E2.

Rabbit splenic capsular strips contract in response to angiotensin II and simultaneously release prostaglandins E and F into the bath fluid. Contractions, though not sustained, and prostaglandin release are dependent on the concentrations of angiotensin II. Addition of indometacin to the bath fluid inhibits prostaglandin release and potentiates the angiotensin II-induced contractions. Similarly, 5,8,11,14-eicosatetraynoic acid, another blocker of prostaglandin synthesis, potentiates contractions elicited by angiotensin II. Exogenous prostaglandin E1 (300 ng/ml) tends to decrease angiotensin II-induced contractions, while prostaglandin E2 (300 ng/ml) as well as prostaglandin F2alpha (300 ng/ml) significantly increase the contractions produced by angiotensin II. The prostaglandin endoperoxide analogues (15S)-hydroxy-9alpha,11alpha-(epoxymethano)prosta-5Z,13 E-dienoic acid and (15S)-hydroxy-11alpha,9alpha-(epoxymethano)-prosta-5Z,13 E-dienoic acid in concentrations of 300 ng/ml are either without effect or weak smooth muscle stimulants of their own, but do not influence the effect of angiotensin II. By the simultaneous use of sensitive and specific radioimmunoassays for prostaglandins E1 and E2 the prostaglandin E-like substance released by the rabbit splenic capsular strips was found to resemble serologically much more the dienoic prostaglandin E2 than prostaglandin E1. The potentation of the effect of angiotensin II by indometacin and 5,8,11,14-eicosatetraynoic acid might be caused by inhibition of synthesis of prostaglandins or related compounds in the splenic tissue. However, an undefined sensitizing effect of indometacin and 5,8,11,14-eicosatetraynoic acid, not related to their effect on prostaglandin synthetase, on the smooth muscle preparation cannot be excluded.

Stimulation of renin release from rabbit renal cortex by arachidonic acid and prostaglandin endoperoxides.

The mechanism by which renal prostaglandins stimulate renin secretion in vivo is unknown. In this in vitro study we measured the effects of activation of the prostaglandin (PG) system on renin release from slices of rabbit renal cortex. The PG precursor arachidonic acid (C20:4), a natural PG endoperoxide (PGG2), two stable synthetic PG endoperoxide analogues (EPA I and II), PGE2, PGF2alpha, and two different PG synthesis inhibitors [indomethacin and 5,8,11,14-eicosatetraynoic acid (ETA)] were used to evaluate the possibility of a direct action of the cortical PG system on renin secretion. Renin release increased significantly with time after addition of C20:4, PGG2, EPA I, and EPA II to the incubation medium. Stimulation of renin release was se-related for C20:4 in concentrations of 0.6 to 4.5 X 10(-6) M, for EPA I in concentrations of 0.7 to 2.8 X 10(-6) M, and for EPA II in concentrations of 1.4 to 14.0 X 10(-6) M. Indomethacin (10(-4) M) and ETA (10(-4) M) significantly decreased basal renin release as well as the renin release stimulated by C20:4 and EPA I. PGE2(10(-12) to 10(-6) M) had no effect on renin release, whereas PGF2alpha (10(-12) to 10(-6) M) decreased renin release in a dose-dependent manner. These data raise the possibility of a direct action of the renal cortical PG system on renin secretion. The results further indicate that stimulation of renin release by C20:4 may depend more specifically on the action of PG endoperoxides than on the primary prostaglandins.

Cardiovascular responses to three prostaglandin endoperoxide analogs in the dog.

SummaryThree stable analogs of prosta-glandin endoperoxides have been studied in limited quantities for their effects on the canine cardiovascular system. They are potent systemic pressor agents and powerful pulmonary vasoconstrictors. They directly increase myocardial contractile force. These responses are not altered by indomethacin. In their blood pressure and myocardial effects they are considerably more potent than arachidonic acid and may be estimated to be more potent than the primary bisenoic PGs, PGE2 and PGF20. The cyclic ether endo-peroxide analogs of Bundy are approximately twice as potent in their effects on these parameters as the azo analog of Corey et al.

Prostaglandin endoperoxide analogues and prostaglandin D 2 as substrates of human placental 15-hydroxy prostaglandin dehydrogenase

Prostaglandin endoperoxide analogues and prostaglandin D 2 as substrates of human placental 15-hydroxy prostaglandin dehydrogenase

Further studies on prostaglandin E 2 (PGE 2)-induced gonadotropin release: Comparison with the effect of 15-methyl PGE 2, PGAs, PGBs and prostaglandin endoperoxide analogs

It is known that PGE 2 is a potent stimulus of LH release. To determine if the effect of PGE 2 could be enhanced and/or prolonged by retarding its metabolic degradation, a derivative, 15-methyl PGE 2 (15-E 2) which is more slowly degraded than the natural compound was injected intravenously (i.v.) at various dose levels or into the third ventricle (3rd V) of ether-anesthetized, ovariectomized, estrogen (OVX, Eb)-treated rats and its effect on gonadotropin release was compared with that of PGE 2. Both PGs injected i.v. were equally effective in increasing plasma LH and maintaining the elevated levels, although 15-E 2 induced a larger and more sustained increase in plasma FSH than PGE 2. By contrast, 3rd V PGE 2 was clearly more effective than 3rd V 15-E 2 in releasing LH and to a lesser extent, FSH. The effect of 15-E 2 on LH was similar to that produced by 3rd V PGE 1 injected at a similar dose. However, its effect on FSH was greater than that of PGE 1. To evaluate the effect(s) of prostaglandins of the A and B series on gonadotropin release, PGA 1, PGA 2, PGB 1 or PGB 2 were injected intraventricularly in OVX, Eb-treated rats. PGBs were injected into conscious, free-moving rats. PGA 2 or PGB 2 increased plasma LH concnetrations although much less effectively than PGE 2. Third V PGA 1 or PGB 1 were ineffective. The 3rd V injection of two cyclic esters (U-44069 and U-46619), stable analogs of the PG endoperoxide PGG 2 and PGH 2, induced a small, transient increase in LH levels and did not alter plasma FSH in conscious, free-moving animals. PGE 2 injected intraventricularly at a similar dose was demonstrated to be much more potent than the analogs in stimulating LH and FSH release. The results indicate that: 1) 15-E 2, in spite of its described long-lasting activity, does not appear to be more potent than the natural compound in releasing LH, although when injected i.v., it appeared to induce a more sustained increase in plasma FSH; 2) although PGA 2 and PGB 2 can also act centrally to stimulate LH release, their low potency suggests that this is a pharmacological effect; and 3) the two analogs of PG endoperoxides tested proved to be poor stimuli for gonadotropin release. The significance of these findings is discussed.