Contractile activities of leukotrienes C4 and D4 on vascular strips from rabbits
Abstract
Leukotrienes C4 (LTC4) and D4 (LTD4), major components of slow-reacting substances of anaphylaxis (SRS-A), caused dose-dependent contractions of rabbit coronary arteries in concentrations of 10−9 to 10−7 M and 10−10 to 10−7 M, respectively. The potency of LTC4 and LTD4, when compared with the concentration that elicits half of the contraction induced by 25 mM KCl, was 17 and 76 times, respectively, greater than that of histamine. In contrast, other blood vessels from rabbits were either unresponsive (renal artery and vein, mesenteric artery and thoracic aorta) or only weakly responsive (pulmonary artery and vein and portal vein) to both leukotrienes even at 10−7 M. The LTD4-induced coronary contraction was inhibited by FPL 55712 (10−7 and 10−6 M), a selective SRS-A inhibitor, in a dose-dependent manner, but not by diphenhydramine (10−7 M), a histamine H1-receptor blocker or by indomethacin (10−5 M), a prostaglandin synthetase inhibitor, suggesting that LTD4 has a direct effect on the coronary arteries. These results indicate that the leukotrienes may act as potent, selective coronary vasoconstrictors and that SRS-A responsive receptors exist in the rabbit coronary artery.
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Cited by (27)
Synthesis of Leukotrienes by Freshly Harvested Endothelial Cells
1993, Journal of Molecular and Cellular CardiologyEndothelial cells produce endothelin, a powerful vasoconstrictor. We report the release of additional vasoconstrictor material in conditional filtrate from freshly harvested cells, which we identified as leukotrienes by radioimmunoassay (RIA) and by high pressure liquid chromotography (HPLC). The material was collected in cell free filtrates by superfusion of freshly harvested bovine endothelial cells attached to cytodex-3 microcarrier beads. Cells and beads form a dense network on filter paper permitting collection of cell free filtrate. The amount of leukotrienes in conditioned filtrate was 158 ± 21 picograms/million cells. The calcium ionophore A23187 stimulated the release of leukotrienes (392.0 ± 47.6). The peak of leukotriene production occurred within an hour after incubation of cells slowly declining thereafter. Conditioned filtrate to which indomethacian had been added caused coronary vasoconstriction in the perfused rat heart preparation, as did synthetic leukotrienes C+, D+ and E+. It was found by RIA and HPLC that some of the constrictor effect of conditioned filtrate derived from leukotrienes.
The production of coronary vasoconstrictor substances by freshly harvested endothelial cells
1993, International Journal of CardiologyThe effects of cell free superfusates from freshly harvested bovine endothelial cells attached to microcarrier beads on the isolated rabbit and rat heart and on superfused rabbit jugular veins were observed. Cell free conditioned filtrates from freshly harvested cells caused marked diminution in coronary flow and cardiac output in the isolated rabbit heart; in the perfused rat heart an increase in coronary perfusion pressure and a decline in left ventricular systolic tension and maximal left ventricular contractility () were recorded. Marked differences were found between changes induced by conditioned filtrate as compared to synthetic endothelin. Endothelin as present in conditioned filtrate could not account for the pronounced effect on coronary perfusion pressure, and cardiac output induced by conditioned filtrate; more than one hundred times that of synthetic endothelin was needed to achieve comparable cardiodynamic effects. This suggested that additional non-prostanoid vasoconstrictor substance or substances are produced by freshly harvested endothelial cells. This conclusion was supported by the observation that BQ-123, a specific inhibitor of endothelin A (ETA) receptor significantly prevented contractions by endothelin, while failing to inhibit those induced by freshly harvested endothelial cells. These constrictor substances may be leukotrienes.
U19052 (ICIAm): A novel leukotriene analog which antagonizes LTC<inf>4</inf>, LTD<inf>4</inf>, and LTE<inf>4</inf>
1988, ProstaglandinsChemically stable analogs of peptide leukotrienes (LT) have been developed in our laboratories by replacement of the natural triene backbone with a C7H15 substituted aromatic moiety (1). These analogs are potent agonists of airway smooth muscle. Substitution in the peptide region resulted in U19052, an LT receptor antagonist. U19052 antagonized LT-induced contractions of guinea-pig tracheal spirals in a concentration-related manner. The pA2 values versus LTD4 and LTE4 were 6.0 and 5.7, respectively, with slopes which were not significantly different from unity. LTC4-induced contractions were antagonized by U19052 with a pKB of 5.6 obtained either in the absence of presence of L-serine borate. In contrast, carbachol and histamine concentration-response curves were not altered by U19052. LTD4 or LTE4 contractions of isolated guinea-pig ileum were antagonized by U19052 with pKB values of 7.2. The results indicate that potent selective LT antagonists can be developed from stable analogs of leukotrienes. U19052, an example of this series, appears to be as effective in antagonizing LTC4- as well as LTD4- and LTE4-induced contractions in guinea-pig tracheal spirals.
Effects of leukotrienes B<inf>4</inf>, C<inf>4</inf>, and D<inf>4</inf> on rat mesenteric microcirculation
1987, Journal of Surgical ResearchArachidonic acid is metabolized to leukotriene (LT) B4, C4, D4, and E4 by lipooxygenase. LTB4 is a chemotactic agent while LTC4 and LTD4 stimulate smooth muscle fibers to contract. Mesenteric vessels have the capacity to release leukotrienes. The possibility that leukotrienes might be responsible for or contribute to mesenteric ischemia during mesenteric low flow, embolism, and thrombosis prompted us to investigate their action on mesenteric vessels. LTB4, C4, and D4 were applied topically on small bowel mesentery of 22 Sprague-Dawley rats in sequentially increasing concentrations. Mesenteric arterioles with diameters of 8–20μm were observed through a microscope and vessel diameters were measured using a video shear monitor. LTB4 had no effect on diameter, but doses as low as 3 × 10−8M induced white blood cell adherence to venular endothelium, reflecting the potent chemotactic properties of this compound. LTC4 and D4 had no effect on systemic blood pressure or white blood cell adherence. Applications of 6.4 × 10−9, 3.2 × 10−8, and 6.4 × 10−8M LTC4 decreased mesenteric arteriolar diameter to 85.3∗ ± 4.7% (mean ± SD), 75.7∗ ± 7.5%, and 66.8∗ ± 6.1% of baseline, and 4 × 10−9, 2 × 10−8, and 4 × 10−8M LTD4 decreased diameter to 84.9∗ ± 6.1%, 75.1∗ ± 4.2%, and 64.1∗ ± 5% of baseline, respectively (). In five rats, in which erythrocyte velocity was measured simultaneously with vessel diameter, calculated flow decreased to 64.3∗ ± 16.2%, 57.2∗ ± 5.7%, and 48.1∗ ± 10.0% of baseline following 6.4 × 10−9, 3.2 × 10−8, and 6.4 × 10−8M LTC4, respectively, (), LTC4- and D4-induced diameter reductions were not inhibited by ibuprofen, a cyclooxygenase blocker. LY 171883, a leukotriene receptor antagonist, blocked the vasoconstriction induced by LTC4. LTC4 and D4 are potent mesenteric artery vasoconstrictors and may play a role in mesenteric ischemia.
Actions of some prostaglandins and leukotrienes on rat cerebral and mesenteric arteries
1987, General Pharmacology- 1.
1. The effects of some prostaglandins (PG's) and leukotrienes (LT's) on rat middle cerebral, basilar and mesenteric arteries were evaluated in vitro.
- 2.
2. The order of potency of some prostanoids with respect to their contractile effects in basilar arteries was: U44069 > PGF2α > PGI2 ≈ PGE2 > 6-keto-PGE1 > 6-keto-PGF1α, whereas 6,15-diketo-PGF1α was inactive.
- 3.
3. Middle cerebral and basilar arteries were 3–5 times more sensitive than mesenteric arteries to PGF2α. LTD4 and LTC4 were inactive in all three vessel types.
- 4.
4. PGI2 produced a concentration-related relaxation of similar potency in all three arteries contracted by PGF2α. Arteries preactivated by other agents (K+, noradrenaline, 5-hydroxytryptamine) either failed to relax or inconsistently relaxed after PGI2 application.
- 5.
5. Among the PGI2 metabolites (6-keto-PGF1α, 16,15-diketo-PGF1α, 6-keto-PGE1), only 6-keto-PGE1 elicited relaxation in the PGF2α-contracted basilar artery. However, the drug potency was significantly smaller than that of PGI2.
- 6.
6. Nifedipine inhibited the PGF2α-induced contraction by 68% in middle cerebral arteries and by 80% in mesenteric arteries.
- 7.
7. Exposure to Ca2+-free medium for a time period which almost competely abolished the contractile response to K+ (< 5% left), reduced the PGF2α-induced contraction by 54, 61 and 85% in middle cerebral, basilar and mesenteric arteries, respectively.
- 8.
8. The PGF2α-induced contraction of cerebral arteries in Ca2+-free medium was usually composed of a rapidly developing first phase, which levelled off after 1–2 min, and a second slowly developing tonic phase.
- 9.
9. The second phase was absent in mesenteric arteries. Nifedipine and exposure to EGTA concentrations above 10−5 M abolished the second phase. The first phase was not influenced by these procedures in either vessel type.
- 10.
10. It is suggested that PGF2α elicits contraction in rat basilar arteries by causing activation of a thromboxane A2-sensitive receptor.
- 11.
11. Whereas influx of Ca2+ from two extracellular pools appears to contribute to the PGF2α-induced contraction in cerebral arteries, extracellular free Ca2+ seems to be the major source in mesenteric arteries.
- 12.
12. Mechanisms independent of the presence of extracellular Ca2+ also seem to be involved in the reponse to PGF2α in either vessel type.
- 1.
Pharmacology of peptide leukotrienes on ferret isolated airway smooth muscle
1986, ProstaglandinsThe contractile activities of peptide leukotrienes (LT) on isolated spiral strips of ferret trachea were chracterized pharmacologically. LTC4 and LTD4 contracted ferret tracheal strips in a concentration-related manner and were 3- to 8-fold more potent than carbachol. In contrast, high concentrations of LTE4 evoked either weak contraction or none at all, whereas LTC4 and D4 were partial agonists compared to carbachol. In tissues which were unresponsive to LTE4, this compound antagonized contractile responses to LTC4 and D4 in an apparently competitive manner: Carbachol-induced contractions were not altered by LTE4. The cyclooxygenase inhibitor, indomethacin (5 μM), LT antagonists, FPL55712 (10 μM), atropine (1 μM), phenoxybenzamine (10 μM), and LTB4 (10 μM) failed to alter LTC4 and D4 concentration-response curves. The results in dicate that ferret trachea is sensitive to the contractile activity of LTC4 and LTD4 but not LTE4. The LT-induced contractions appear to be mediated by a direct action of the LT rather than indirectly through release of secondary mediators such as thromboxane, prostaglandin, or acetylcholine. LT receptors in ferret trachea are insensitive to FPL55712 but are antagonized by LTE4.