T1 - Interleukin 1-stimulated prostacyclin synthesis in endothelium

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Age-related decline in prostacyclin synthesis by ..

T1 - Increased prostacyclin synthesis by atherosclerotic arteries from estrogen-treated monkeys

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Heterogeneity in prostacyclin and thromboxane synthesis …

174-176 ()Supernatants from cultures of human monocytes that had been stimulatedwith endotoxin or silica induced the synthesis of prostacyclin inendothelial and smooth muscle cells.

T1 - Synthesis and metabolism of prostaglandins, prostacyclin, and thromboxanes

N2 - We hypothesized that the atheroinhibitory and cardioprotective effects of estrogen may be mediated in part through increased prostacyclin formation by the artery wall. Atherosclerotic abdominal aorta was collected at necropsy from ovariectomized female monkeys fed an atherogenic diet alone or with added Premarin®. Basal and arachidonate-stimulated prostacyclin and thromboxane synthesis by artery segments was measured by radioimmunoassay. In contrast to no observed differences in basal release of prostacyclin by the control and estrogen-treated arteries, there was a marked increase (∼165%) in arachidonate-stimulated formation of prostacyclin by estrogen-treated arteries, and prostacyclin synthesis was inversely correlated with plaque size. No differences were observed in basal or arachidonate-stimulated thromboxane synthesis by the control and estrogen-treated arteries. In light of known antiatherogenic and vasodilatory effects of estrogen, increased prostacyclin synthesis by estrogen-treated arteries may, in part, explain estrogen's beneficial effects on the artery wall.

The Synthesis of Prostacyclin and Its Analogues - …

These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane.

Interleukin-1-induced prostacyclin synthesis represents a new aspect ofthe interaction between the immune system (as well as other tissues) andthe vessel wall and may serve as a basis for the development of newstrategies in antithrombotic therapy.

Prostacyclin controls cardiovascular function via activation of the prostacyclin receptor. Decreased prostacyclin production occurs in several cardiovascular diseases. However, the clinical use of prostacyclin and its analogues is complicated by their chemical and metabolic instability. A medicinal chemistry program searched for novel nonprostanoid prostacyclin receptor agonists not subject to these limitations. A compound with a diphenylpyrazine structural core was synthesized. Metabolic stability and agonist potency were optimized through modification of the linear side chain. Compound 12b (MRE-269, ACT-333679) was identified as a potent and highly selective prostacyclin receptor agonist. Replacement of the terminal carboxyl group with an -acylsulfonamide group yielded parent compound 26a (selexipag, NS-304, ACT-293987), which is orally active and provides sustained plasma exposure of 12b. Compound 26a was developed for the treatment of pulmonary arterial hypertension and shown to reduce the risk of the composite morbidity/mortality end point in a phase 3 event-driven clinical trial.

Hypokalaemia stimulates prostacyclin synthesis in the …

Synthesis of Prostacyclin from Platelet-derived Endoperoxides by Cultured Human Endothelial Cells

This review of prostaglandins (PG) and related compounds discusses in considerable detail their chemical terminology, synthesis, degradation and clinical significance. PGs and related metabolites are easily synthesized by most tissues; at least one-third of all drugs seem to interact at some level of the PG-generating system. Most of the PGs are derived from a 20-carbon, straight chain, fatty acid, arachidonic acid. This acid is obtained directly from the diet or by anabolic transformation from linolenic acid. Indomethacin or a deficiency of essential fatty acids in the diet will ultimately cause PG deficiency. Arachidonic acid is transported free in the plasma bound electrostatically and hydrophobically to albumin. The majority of arachidonic acid is covalently bound and present in the esterified form in phospholipids or bound to cholesterol. The release of free arachidonic acid from its ester seems to be the rate-limiting step in the cascade which leads to the formation of the various PGs. PGs are not stored. The acyl hydroxylase (a lipase) necessary for deesterification of arachidonic acid has been found in many tissues and can be activated by many stimuli including burns, toxins, mechanical stretching and probably also catecholamines, bradykinin and angiotensin II. Arachidonic acid release is inhibited, as far as is known, by only antiinflammatory corticosteroids and anesthetic agents. The arachidonic acid chain is converted to a PG by three routes. The most studied route involves a cyclooxygenase which adds molecular oxygen at C15 followed by the bridging of the gap between C8 and C12 to form a 5 carbon ring (cyclopentane). At the same time, a second molecule of oxygen is added across C9 and C11. This endoperoxide, or PGG, can then be converted to a hydroendoperoxide known as PGH. The subscript numbers found in PG terminology refer to the number of double bonds remaining in the chain after the above-mentioned conversions and depend on the precursor acid; most compounds of clinical importance are derived from arachidonic acid and have a subscript of 2. The cyclic endoperoxides, PGG and PGH, are unstable but give rise to the clinically important PGDs, PGEs, PGIs (or prostacyclins) and the thromboxines (TX). TXs are not considered PGs because the cyclopentane ring has been split open. Clinically, PGE and PGF have found some use in obstetrics as uterine constrictors (although PGE is a potent vasodepressor). Both arachidonic acid and PGF2α will help to maintain patency of the ductus arteriosus in newborns. The inhibition of platelet aggregation by prostacyclin (PGI2), a bicyclic PG formed in vessel walls, and the thrombotic action of the thromboxines, largely derived from platelets, seem to play a major role in blood clotting. Arachidonic acid may be converted by another pathway (5-lipo-oxygenase) to the leukotrienes. Leukotriene C is identical to slow-reacting substance of anaphylaxis and is involved in the bronchoconstriction of asthma and aspirin sensitivity of asthmatics. Catabolism of the PGs is largely by oxidation of the hydroxyl group on carbon 15, and occurs primarily in the lung and, to a lesser degree, in the kidney and liver. Prostacyclin is not inactivated in the lung and follows a different route of inactivation. (Bloodworth Jr. - Madison, Wis.)

AB - We hypothesized that the atheroinhibitory and cardioprotective effects of estrogen may be mediated in part through increased prostacyclin formation by the artery wall. Atherosclerotic abdominal aorta was collected at necropsy from ovariectomized female monkeys fed an atherogenic diet alone or with added Premarin®. Basal and arachidonate-stimulated prostacyclin and thromboxane synthesis by artery segments was measured by radioimmunoassay. In contrast to no observed differences in basal release of prostacyclin by the control and estrogen-treated arteries, there was a marked increase (∼165%) in arachidonate-stimulated formation of prostacyclin by estrogen-treated arteries, and prostacyclin synthesis was inversely correlated with plaque size. No differences were observed in basal or arachidonate-stimulated thromboxane synthesis by the control and estrogen-treated arteries. In light of known antiatherogenic and vasodilatory effects of estrogen, increased prostacyclin synthesis by estrogen-treated arteries may, in part, explain estrogen's beneficial effects on the artery wall.

platelet thromboxane and vascular prostacyclin synthesis is inhibited.
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  • Estrogen Acutely Activates Prostacyclin Synthesis in …

    PROSTAGLANDINS CONTROL OF PROSTACYCLIN SYNTHESIS IN PREGNANCY-INDUCED HYPERTENSION M.J.N.C

  • Prostacyclin synthase - Wikipedia

    The advances in the synthesis of prostacyclin and its analogues are examined. The bibliography includes 114 references.

  • Prostacyclin synthase - an overview | ScienceDirect Topics

    These drugs, therefore, reduce the synthesis of prostaglandins, prostacyclin and thromboxane.

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Synthesis of therapeutically useful ..

AB - Intrapulmonary arteries and veins of 8 near-term fetal lambs (141-145 days gestation and 8 ewes were isolated into segments of >3mm, 1-3 mm, and 3 mm synthesized more prostacyclin than adult arteries of the same size (1.71 ± 0.3 vs 0.45 ± 0.04). However, fetal arteries 3 mm was similar in the fetus and adult (0.49 ± 0.06 vs 0.67 ± 0.08), but in veins

Epoprostenol Accession Number DB01240 ..

We hypothesized that the atheroinhibitory and cardioprotective effects of estrogen may be mediated in part through increased prostacyclin formation by the artery wall. Atherosclerotic abdominal aorta was collected at necropsy from ovariectomized female monkeys fed an atherogenic diet alone or with added Premarin®. Basal and arachidonate-stimulated prostacyclin and thromboxane synthesis by artery segments was measured by radioimmunoassay. In contrast to no observed differences in basal release of prostacyclin by the control and estrogen-treated arteries, there was a marked increase (∼165%) in arachidonate-stimulated formation of prostacyclin by estrogen-treated arteries, and prostacyclin synthesis was inversely correlated with plaque size. No differences were observed in basal or arachidonate-stimulated thromboxane synthesis by the control and estrogen-treated arteries. In light of known antiatherogenic and vasodilatory effects of estrogen, increased prostacyclin synthesis by estrogen-treated arteries may, in part, explain estrogen's beneficial effects on the artery wall.

Practice Questions | Biochemistry for Medics – Lecture Notes

N2 - This review of prostaglandins (PG) and related compounds discusses in considerable detail their chemical terminology, synthesis, degradation and clinical significance. PGs and related metabolites are easily synthesized by most tissues; at least one-third of all drugs seem to interact at some level of the PG-generating system. Most of the PGs are derived from a 20-carbon, straight chain, fatty acid, arachidonic acid. This acid is obtained directly from the diet or by anabolic transformation from linolenic acid. Indomethacin or a deficiency of essential fatty acids in the diet will ultimately cause PG deficiency. Arachidonic acid is transported free in the plasma bound electrostatically and hydrophobically to albumin. The majority of arachidonic acid is covalently bound and present in the esterified form in phospholipids or bound to cholesterol. The release of free arachidonic acid from its ester seems to be the rate-limiting step in the cascade which leads to the formation of the various PGs. PGs are not stored. The acyl hydroxylase (a lipase) necessary for deesterification of arachidonic acid has been found in many tissues and can be activated by many stimuli including burns, toxins, mechanical stretching and probably also catecholamines, bradykinin and angiotensin II. Arachidonic acid release is inhibited, as far as is known, by only antiinflammatory corticosteroids and anesthetic agents. The arachidonic acid chain is converted to a PG by three routes. The most studied route involves a cyclooxygenase which adds molecular oxygen at C15 followed by the bridging of the gap between C8 and C12 to form a 5 carbon ring (cyclopentane). At the same time, a second molecule of oxygen is added across C9 and C11. This endoperoxide, or PGG, can then be converted to a hydroendoperoxide known as PGH. The subscript numbers found in PG terminology refer to the number of double bonds remaining in the chain after the above-mentioned conversions and depend on the precursor acid; most compounds of clinical importance are derived from arachidonic acid and have a subscript of 2. The cyclic endoperoxides, PGG and PGH, are unstable but give rise to the clinically important PGDs, PGEs, PGIs (or prostacyclins) and the thromboxines (TX). TXs are not considered PGs because the cyclopentane ring has been split open. Clinically, PGE and PGF have found some use in obstetrics as uterine constrictors (although PGE is a potent vasodepressor). Both arachidonic acid and PGF2α will help to maintain patency of the ductus arteriosus in newborns. The inhibition of platelet aggregation by prostacyclin (PGI2), a bicyclic PG formed in vessel walls, and the thrombotic action of the thromboxines, largely derived from platelets, seem to play a major role in blood clotting. Arachidonic acid may be converted by another pathway (5-lipo-oxygenase) to the leukotrienes. Leukotriene C is identical to slow-reacting substance of anaphylaxis and is involved in the bronchoconstriction of asthma and aspirin sensitivity of asthmatics. Catabolism of the PGs is largely by oxidation of the hydroxyl group on carbon 15, and occurs primarily in the lung and, to a lesser degree, in the kidney and liver. Prostacyclin is not inactivated in the lung and follows a different route of inactivation. (Bloodworth Jr. - Madison, Wis.)

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