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Intrinsic Prostaglandin Biosynthesis in Blood Vessels

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Abstract

The sections in this article are:

1 Prostaglandin Synthesis and General Properties
1.1 Biosynthesis of Prostaglandins
1.2 Effects of Exogenous Prostaglandins on Vascular Smooth Muscle
1.3 Summary
2 Prostaglandins and the Mesenteric and Celiac Arteries
2.1 Intrinsic Vascular Synthesis of Prostaglandins
2.2 Influence of Local Vascular Prostaglandins on Neuronal Activity and Blood Vessel Tone
2.3 Differential PG Synthesis in Arteries and Veins
3 Prostaglandin Biosynthesis in the Ductus Arteriosus
4 Human Umbilical Artery
4.1 Intrinsic Prostaglandin Biosynthesis
4.2 Prostaglandin Synthesis in Blood Vessel Tissue Culture
5 Coronary Arteries
5.1 Contribution of Intrinsic Prostaglandins to Coronary Tone
5.2 Paradoxical Endogenous Synthesis of a Coronary Dilating Substance from Arachidonate
5.3 Effect of Prostaglandin Endoperoxides on Bovine Coronary Arteries
5.4 Novel Metabolic Arachidonate Pathway that Generates a Potent Endogenous Vasodilator
6 Prostacyclin
6.1 Arterial Synthesis of a Novel Prostaglandin that Inhibits Platelet Aggregation
6.2 Inhibition of the Vascular Synthesis of the Novel Prostaglandin
6.3 Intrinsic Vascular Synthesis of a Prostaglandin Vasodilator in Mesenteric, Celiac, and Coronary Arteries
6.4 Chemical Identification of Prostacyclin
6.5 Prostacyclin and Thromboxane A2 Characterization Criteria
7 Pathophysiological Significance of Vascular Prostacyclin Synthesis and its Pharmacological Modification
Figure 1. Figure 1.

Schematic pathway and structures for the liberation and oxidation of arachidonic acid.

Figure 2. Figure 2.

Schematic pathway for the conversion of endoperoxides to various prostaglandin products. Side chains are deleted from some of the products of the endoperoxide for the sake of illustration. PG, prostaglandin; TA2, thromboxane A2; TB2, thromboxane B2.

Figure 3. Figure 3.

Responses of strips of vascular smooth muscle from various sources to several concentrations of the prostaglandins. Responses are expressed as a percentage of the contractile response to 50 mM KCl. Aortic and coronary arterial strips are contracted by the prostaglandins. But smooth muscle cells from small muscular, mesenteric, and renal arteries show a biphasic dose‐response relationship with the prostaglandins: the cells relax when exposed to low concentrations and contract when exposed to higher concentrations.

From Strong and Bohr 127
Figure 4. Figure 4.

Differential bioassay of aorta‐contracting substances in rabbit. PGG2 (200 ng) was added to 500 μl of TRIS buffer (50 mM, pH 7.8) at 0°C, and a 50 μl sample (equivalent to 20 ng) was tested. Immediately after testing, horse platelet microsomes were added to the PGG2 solution, and 50 μl of the solution was tested 2 min later.

From Needleman et al. 105
Figure 5. Figure 5.

Comparative potency of prostaglandin endoperoxides and thromboxanes. Values represent the mean ± SE, and number in parentheses represents number of aorta strips tested. Thromboxanes (i.e., thromboxane A2 = PGH2 + platelets, and thromboxane A3 = PGH3 + platelets) were generated by incubating the endoperoxides with 15 μl of human platelet microsomes before being tested on the aortic strip for 2 min at 0°C.

From Needleman et al. 104. Copyright 1976 by the American Association for the Advancement of Science
Figure 6. Figure 6.

A: response of assay organs and perfused rabbit mesentery to angiotensin II (AII) and bradykinin (BK). B: the influence of Sar1, Ile8AII and indomethacin. Two assay organs selected for their sensitivity to prostaglandins were recorded simultaneously. Injections of substances in amounts indicated (all ng) were made directly (DIR) into Kreb's solution that was supervising assay organs or into fluid just before it entered mesentery (TM). AII applied directly to the assay organs had no effect on the isolated chick rectum but contracted the rat stomach strip. The specific antagonist Sar1, Ile8‐AII was infused across the assay tissues, and it blocked the direct effect of AII on the rat stomach strip, enhancing the strip's specificity for prostaglandinlike substances.

Prom Blumberg, Needleman, et al. 14
Figure 7. Figure 7.

Schematic representation of hormonal interactions in blood vessels. AI, angiotensin I; AII, angiotensin II; BK, bradykinin; PG, prostaglandin; Sar1, Ile8AII, a receptor blocker; SQ‐20881, a nonapeptide that inhibits the conversion of AI to AII and that blocks the destruction of bradykinin.

Figure 8. Figure 8.

Actions and interactions of prostaglandin synthesis inhibitors on bovine coronary arterial strips. A: strip exposed to aspirin (ASA) (1 × 10−5 g/ml) and to indomethacin (INDO) (1 × 10−5 g/ml). B: strip exposed to indomethacin followed by aspirin. C: strip treated with 5,8,11,14‐eicosatetraynoic acid (ETA) (1 × 10−5 g/ml) for 15 min, and the muscle chamber washed at arrow, followed by aspirin and indomethacin.

From Kalsner 72
Figure 9. Figure 9.

Responses of bovine coronary arterial strips to decreased oxygen and to sodium nitrite. Upper curve for strip under the standard PO2 of 515 mmHg exposed to a PO2 of 53 mmHg (dot) and subsequently returned to the standard 515 mmHg (dot), followed by NaNO2 (NO2) (1 × 10−3 g/ml). Lower curve for strip (taken from the same vessel as in upper curve) pretreated with aspirin (1 × 10−5 g/ml) under the standard PO2 of 515 mmHg and then treated as the strip in upper curve.

From Kalsner 73
Figure 10. Figure 10.

Effect of arachidonate (AA) on the bovine coronary artery. Arrows at the bottom indicate addition of the drugs to the media. A: strip was partially contracted with PGE2 (1 μg/ml) and a steady‐state contractile response was reached. Dose‐dependent relaxation responses were obtained by cumulative additions of arachidonate. Addition of 10 μg/ml indomethacin (INDO) caused contraction. B: same strip was washed for 11/2 h and indomethacin (10 μg/ml) was re‐added to the media. Strip was contracted by PGE2, (1 μg/ml) and arachidonate added at this point was without effect.

From Kulkarni, Roberts, and Needleman 76
Figure 11. Figure 11.

Representative tracings showing the pattern of tension changes in pig coronary arteries (blocked against 5‐hydroxytryptamine) in response to the addition of four substances. A: washed platelets stimulated with thrombin for 30 s; B: 225 nM PGE2; C: 255 nM PGH2; and D: platelet particles plus 225 nM PGH2 (i.e., thromboxane A2). All tracings have the same tension scale.

From Ellis et al. 31. Copyright 1976 by the American Association for the Advancement of Science
Figure 12. Figure 12.

Comparative arterial vascular responsiveness to the endoperoxide PGH2. In experiments designed to simultaneously compare the endoperoxide response in blood vessels removed from various species, a superfusion cascade was used. Spirals of blood vessels were continuously perfused (10 ml/min) with Krebs‐Henseleit solution (95% O2 + 5% CO2) that contained a mixture of antagonists that rendered the tissues insensitive to catecholamines, histamine, acetylcholine, and serotonin.

From Needleman et al. 101. Copyright 1977 by the American Association for the Advancement of Science
Figure 13. Figure 13.

Dose‐dependent and species‐dependent contraction or relaxation of coronary arterial strips to exogenous prostaglandin endoperoxides and to the primary PGEs (series 1, 2, and 3).

From Needleman et al. 101
Figure 14. Figure 14.

Coronary relaxant effect of PGH2. Upper panel illustrates a typical recording of the coronary relaxation produced either by direct PGH2 addition to a superfused (10 ml/min of Krebs‐Henseleit medium) bovine coronary arterial strip or by addition of the reaction mixture with the same amount of PGH2 incubated with bovine coronary arterial microsomes (2 min at 22°C). Microsomes themselves have no direct effect. Lower panel presents a dose‐response curve comparing the potency of PGH2 alone versus the so‐called activated product produced by the coronary microsomes.

From Raz, Needleman, et al. 119
Figure 15. Figure 15.

Comparison of inhibition of aggregation by PGX and PGE1. PGX in concentrations (per ml) of 0.5 or 0.25 ng incubated for 1 min in platelet‐rich plasma before the addition of arachidonic acid (AA) (0.9 mM) resulted in dose‐dependent inhibition of the resulting aggregation. PGE1 (20 or 10 ng/ml) also inhibited aggregation but was about 40 times less potent than PGX.

From Moncada et al. 94
Figure 16. Figure 16.

Effect of 15‐hydroperoxy arachidonic acid (15‐HPAA) at 1 μg/ml on the responses of strips of rabbit aorta and rabbit celiac and mesenteric arteries to PGG2 and PGX (prostacyclin). PGG2 (100 ng) contracted the rabbit aorta and caused a small contraction followed by a longer lasting relaxation of the celiac and mesenteric arteries. PGX, formed by incubating PGG2 (100 ng) with 250 μg pig aortic microsomes (AM), did not contract rabbit aorta but relaxed the celiac and mesenteric arteries, because PGX is more potent than the parent endoperoxide. A 5‐min infusion of 15‐HPAA (1 μg/ml) caused contraction of all tissues (not shown). PGG2 (100 ng) gave a much greater contraction of rabbit aorta 1 h later, and also contracted celiac and mesenteric arteries. Activity of PGX was not significantly altered after the 15‐HPAA infusion.

From Bunting et al. 18
Figure 17. Figure 17.

Schematic representation of the pathways of prostaglandin metabolism. Primary substrates and products are indicated in the boxes; enzymes are presented in slanted lower case type; and the enzymatic inhibitors and their currently known site of action are indicated by X.

Figure 18. Figure 18.

Interaction of platelets with normal vascular wall. Platelets, attempting to stick, generate endoperoxides that are then converted by the vessel enzyme into prostacyclin (PGX).

From Moncada and Vane 97
Figure 19. Figure 19.

Vascular damage uncovers proaggregating material from the vessel wall. Platelets interact with this proaggregating material and release thromboxane A2 (TXA2).

From Moncada and Vane 97


Figure 1.

Schematic pathway and structures for the liberation and oxidation of arachidonic acid.



Figure 2.

Schematic pathway for the conversion of endoperoxides to various prostaglandin products. Side chains are deleted from some of the products of the endoperoxide for the sake of illustration. PG, prostaglandin; TA2, thromboxane A2; TB2, thromboxane B2.



Figure 3.

Responses of strips of vascular smooth muscle from various sources to several concentrations of the prostaglandins. Responses are expressed as a percentage of the contractile response to 50 mM KCl. Aortic and coronary arterial strips are contracted by the prostaglandins. But smooth muscle cells from small muscular, mesenteric, and renal arteries show a biphasic dose‐response relationship with the prostaglandins: the cells relax when exposed to low concentrations and contract when exposed to higher concentrations.

From Strong and Bohr 127


Figure 4.

Differential bioassay of aorta‐contracting substances in rabbit. PGG2 (200 ng) was added to 500 μl of TRIS buffer (50 mM, pH 7.8) at 0°C, and a 50 μl sample (equivalent to 20 ng) was tested. Immediately after testing, horse platelet microsomes were added to the PGG2 solution, and 50 μl of the solution was tested 2 min later.

From Needleman et al. 105


Figure 5.

Comparative potency of prostaglandin endoperoxides and thromboxanes. Values represent the mean ± SE, and number in parentheses represents number of aorta strips tested. Thromboxanes (i.e., thromboxane A2 = PGH2 + platelets, and thromboxane A3 = PGH3 + platelets) were generated by incubating the endoperoxides with 15 μl of human platelet microsomes before being tested on the aortic strip for 2 min at 0°C.

From Needleman et al. 104. Copyright 1976 by the American Association for the Advancement of Science


Figure 6.

A: response of assay organs and perfused rabbit mesentery to angiotensin II (AII) and bradykinin (BK). B: the influence of Sar1, Ile8AII and indomethacin. Two assay organs selected for their sensitivity to prostaglandins were recorded simultaneously. Injections of substances in amounts indicated (all ng) were made directly (DIR) into Kreb's solution that was supervising assay organs or into fluid just before it entered mesentery (TM). AII applied directly to the assay organs had no effect on the isolated chick rectum but contracted the rat stomach strip. The specific antagonist Sar1, Ile8‐AII was infused across the assay tissues, and it blocked the direct effect of AII on the rat stomach strip, enhancing the strip's specificity for prostaglandinlike substances.

Prom Blumberg, Needleman, et al. 14


Figure 7.

Schematic representation of hormonal interactions in blood vessels. AI, angiotensin I; AII, angiotensin II; BK, bradykinin; PG, prostaglandin; Sar1, Ile8AII, a receptor blocker; SQ‐20881, a nonapeptide that inhibits the conversion of AI to AII and that blocks the destruction of bradykinin.



Figure 8.

Actions and interactions of prostaglandin synthesis inhibitors on bovine coronary arterial strips. A: strip exposed to aspirin (ASA) (1 × 10−5 g/ml) and to indomethacin (INDO) (1 × 10−5 g/ml). B: strip exposed to indomethacin followed by aspirin. C: strip treated with 5,8,11,14‐eicosatetraynoic acid (ETA) (1 × 10−5 g/ml) for 15 min, and the muscle chamber washed at arrow, followed by aspirin and indomethacin.

From Kalsner 72


Figure 9.

Responses of bovine coronary arterial strips to decreased oxygen and to sodium nitrite. Upper curve for strip under the standard PO2 of 515 mmHg exposed to a PO2 of 53 mmHg (dot) and subsequently returned to the standard 515 mmHg (dot), followed by NaNO2 (NO2) (1 × 10−3 g/ml). Lower curve for strip (taken from the same vessel as in upper curve) pretreated with aspirin (1 × 10−5 g/ml) under the standard PO2 of 515 mmHg and then treated as the strip in upper curve.

From Kalsner 73


Figure 10.

Effect of arachidonate (AA) on the bovine coronary artery. Arrows at the bottom indicate addition of the drugs to the media. A: strip was partially contracted with PGE2 (1 μg/ml) and a steady‐state contractile response was reached. Dose‐dependent relaxation responses were obtained by cumulative additions of arachidonate. Addition of 10 μg/ml indomethacin (INDO) caused contraction. B: same strip was washed for 11/2 h and indomethacin (10 μg/ml) was re‐added to the media. Strip was contracted by PGE2, (1 μg/ml) and arachidonate added at this point was without effect.

From Kulkarni, Roberts, and Needleman 76


Figure 11.

Representative tracings showing the pattern of tension changes in pig coronary arteries (blocked against 5‐hydroxytryptamine) in response to the addition of four substances. A: washed platelets stimulated with thrombin for 30 s; B: 225 nM PGE2; C: 255 nM PGH2; and D: platelet particles plus 225 nM PGH2 (i.e., thromboxane A2). All tracings have the same tension scale.

From Ellis et al. 31. Copyright 1976 by the American Association for the Advancement of Science


Figure 12.

Comparative arterial vascular responsiveness to the endoperoxide PGH2. In experiments designed to simultaneously compare the endoperoxide response in blood vessels removed from various species, a superfusion cascade was used. Spirals of blood vessels were continuously perfused (10 ml/min) with Krebs‐Henseleit solution (95% O2 + 5% CO2) that contained a mixture of antagonists that rendered the tissues insensitive to catecholamines, histamine, acetylcholine, and serotonin.

From Needleman et al. 101. Copyright 1977 by the American Association for the Advancement of Science


Figure 13.

Dose‐dependent and species‐dependent contraction or relaxation of coronary arterial strips to exogenous prostaglandin endoperoxides and to the primary PGEs (series 1, 2, and 3).

From Needleman et al. 101


Figure 14.

Coronary relaxant effect of PGH2. Upper panel illustrates a typical recording of the coronary relaxation produced either by direct PGH2 addition to a superfused (10 ml/min of Krebs‐Henseleit medium) bovine coronary arterial strip or by addition of the reaction mixture with the same amount of PGH2 incubated with bovine coronary arterial microsomes (2 min at 22°C). Microsomes themselves have no direct effect. Lower panel presents a dose‐response curve comparing the potency of PGH2 alone versus the so‐called activated product produced by the coronary microsomes.

From Raz, Needleman, et al. 119


Figure 15.

Comparison of inhibition of aggregation by PGX and PGE1. PGX in concentrations (per ml) of 0.5 or 0.25 ng incubated for 1 min in platelet‐rich plasma before the addition of arachidonic acid (AA) (0.9 mM) resulted in dose‐dependent inhibition of the resulting aggregation. PGE1 (20 or 10 ng/ml) also inhibited aggregation but was about 40 times less potent than PGX.

From Moncada et al. 94


Figure 16.

Effect of 15‐hydroperoxy arachidonic acid (15‐HPAA) at 1 μg/ml on the responses of strips of rabbit aorta and rabbit celiac and mesenteric arteries to PGG2 and PGX (prostacyclin). PGG2 (100 ng) contracted the rabbit aorta and caused a small contraction followed by a longer lasting relaxation of the celiac and mesenteric arteries. PGX, formed by incubating PGG2 (100 ng) with 250 μg pig aortic microsomes (AM), did not contract rabbit aorta but relaxed the celiac and mesenteric arteries, because PGX is more potent than the parent endoperoxide. A 5‐min infusion of 15‐HPAA (1 μg/ml) caused contraction of all tissues (not shown). PGG2 (100 ng) gave a much greater contraction of rabbit aorta 1 h later, and also contracted celiac and mesenteric arteries. Activity of PGX was not significantly altered after the 15‐HPAA infusion.

From Bunting et al. 18


Figure 17.

Schematic representation of the pathways of prostaglandin metabolism. Primary substrates and products are indicated in the boxes; enzymes are presented in slanted lower case type; and the enzymatic inhibitors and their currently known site of action are indicated by X.



Figure 18.

Interaction of platelets with normal vascular wall. Platelets, attempting to stick, generate endoperoxides that are then converted by the vessel enzyme into prostacyclin (PGX).

From Moncada and Vane 97


Figure 19.

Vascular damage uncovers proaggregating material from the vessel wall. Platelets interact with this proaggregating material and release thromboxane A2 (TXA2).

From Moncada and Vane 97
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Philip Needleman, Peter C. Isakson. Intrinsic Prostaglandin Biosynthesis in Blood Vessels. Compr Physiol 2011, Supplement 7: Handbook of Physiology, The Cardiovascular System, Vascular Smooth Muscle: 613-633. First published in print 1980. doi: 10.1002/cphy.cp020220