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Quinidine, but not eicosanoid antagonists or dexamethasone, protect the gut from platelet activating factor-induced vasoconstriction, edema and paralysis.

Lautenschläger I, Frerichs I, Dombrowsky H, Sarau J, Goldmann T, Zitta K, Albrecht M, Weiler N, Uhlig S - PLoS ONE (2015)

Bottom Line: The COX and LOX inhibitors ASA and AA861 (500 μM, 10 μM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 μM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen.Quinidine (100 μM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph.We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Division of Barrier Integrity, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.

ABSTRACT
Intestinal circulatory disturbances, atony, edema and swelling are of great clinical relevance, but the related mechanisms and possible therapeutic options are poorly characterized, in part because of the difficulties to comprehensively analyze these conditions. To overcome these limitations we have developed a model of the isolated perfused rat small intestine where all of these symptoms can be studied simultaneously. Here we used this model to study the role of eicosanoids, steroids and quinidine in platelet-activating factor (PAF)-induced intestinal disorders. A vascular bolus of PAF (0.5 nmol) triggered release of thromboxane and peptidoleukotrienes into the vascular bed (peak concentration 35 nM and 0.8 nM) and reproduced all symptoms of intestinal failure: mesenteric vasoconstriction, translocation of fluid and macromolecules from the vasculature to the lumen and lymphatics, intestinal edema formation, loss of intestinal peristalsis and decreased galactose uptake. All effects of PAF were abolished by the PAF-receptor antagonist ABT491 (2.5 μM). The COX and LOX inhibitors ASA and AA861 (500 μM, 10 μM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 μM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen. The steroid dexamethasone (10 μM) showed no barrier-protective properties and failed to prevent edema formation. Quinidine (100 μM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph. While quinidine by itself reduced peristalsis, it also obviated paralysis, preserved intestinal functions and prevented edema formation. We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine. The therapeutic use of quinidine for intestinal ailments deserves further study.

No MeSH data available.


Related in: MedlinePlus

PAF-induced eicosanoid liberation to the vascular compartment.A. Concentration of thromboxane in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4); B. Concentration of cysteinyl leukotrienes in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4).
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pone.0120802.g001: PAF-induced eicosanoid liberation to the vascular compartment.A. Concentration of thromboxane in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4); B. Concentration of cysteinyl leukotrienes in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4).

Mentions: Administration of a 0.5 nmol PAF bolus into the mesenteric artery liberated thromboxane and leukotriene from the intestine into the vascular compartment (Fig. 1). It caused a rapid and strong vasoconstriction (Fig. 2A and 2B) and a remarkable shift of fluid with a dramatic loss of vascular volume equivalent to about 13% of the total vascular fluid flow (Fig. 2C). In addition there was a transfer of FITC-labeled dextran from the vascular compartment to the lumen and the lymphatics (Fig. 2D), behaving similar as FITC-labeled albumin [3]. In the experiments in which the acute effects of PAF were analyzed, we observed intestinal edema located at the villus tips (Fig. 3B, 3D and Fig. 4A) and in the circular and longitudinal muscular layers (Fig. 3F and Fig. 4C). In these experiments, edema formation was also documented by a significant increase in the wet-to-dry weight ratio in the PAF group (4.02±0.19 to 4.79±0.17, p<0.05; paired t-test; n = 4), while, in the control group, there was just a slight change in the wet-to-dry weight ratio (4.05±0.26 to 4.31±0.24, p>0.05; paired t-test; n = 4). Of note, the histological stability scores of the intestines were not altered three minutes after the administration of PAF in comparison to controls (0.94±0.02 vs 0.97±0.01, p>0.05; unpaired t-test; n = 4), implying that the rapid effects of PAF depend on specific effects rather than on tissue damage. In addition, intestinal function, as monitored by the uptake of galactose derived from luminal lactose to the portal vein, was impaired within 15 minutes after the PAF administration and recovered thereafter (Fig. 5A). PAF reduced peristalsis within seconds (33±6 seconds) up to a period of complete atony (after 49±4 seconds, duration 97±50 seconds, Fig. 5C) with total recovery.


Quinidine, but not eicosanoid antagonists or dexamethasone, protect the gut from platelet activating factor-induced vasoconstriction, edema and paralysis.

Lautenschläger I, Frerichs I, Dombrowsky H, Sarau J, Goldmann T, Zitta K, Albrecht M, Weiler N, Uhlig S - PLoS ONE (2015)

PAF-induced eicosanoid liberation to the vascular compartment.A. Concentration of thromboxane in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4); B. Concentration of cysteinyl leukotrienes in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4368623&req=5

pone.0120802.g001: PAF-induced eicosanoid liberation to the vascular compartment.A. Concentration of thromboxane in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4); B. Concentration of cysteinyl leukotrienes in the venous compartment of PAF-stimulated intestines (PAF, n = 3) and untreated intestines (SOL, n = 4).
Mentions: Administration of a 0.5 nmol PAF bolus into the mesenteric artery liberated thromboxane and leukotriene from the intestine into the vascular compartment (Fig. 1). It caused a rapid and strong vasoconstriction (Fig. 2A and 2B) and a remarkable shift of fluid with a dramatic loss of vascular volume equivalent to about 13% of the total vascular fluid flow (Fig. 2C). In addition there was a transfer of FITC-labeled dextran from the vascular compartment to the lumen and the lymphatics (Fig. 2D), behaving similar as FITC-labeled albumin [3]. In the experiments in which the acute effects of PAF were analyzed, we observed intestinal edema located at the villus tips (Fig. 3B, 3D and Fig. 4A) and in the circular and longitudinal muscular layers (Fig. 3F and Fig. 4C). In these experiments, edema formation was also documented by a significant increase in the wet-to-dry weight ratio in the PAF group (4.02±0.19 to 4.79±0.17, p<0.05; paired t-test; n = 4), while, in the control group, there was just a slight change in the wet-to-dry weight ratio (4.05±0.26 to 4.31±0.24, p>0.05; paired t-test; n = 4). Of note, the histological stability scores of the intestines were not altered three minutes after the administration of PAF in comparison to controls (0.94±0.02 vs 0.97±0.01, p>0.05; unpaired t-test; n = 4), implying that the rapid effects of PAF depend on specific effects rather than on tissue damage. In addition, intestinal function, as monitored by the uptake of galactose derived from luminal lactose to the portal vein, was impaired within 15 minutes after the PAF administration and recovered thereafter (Fig. 5A). PAF reduced peristalsis within seconds (33±6 seconds) up to a period of complete atony (after 49±4 seconds, duration 97±50 seconds, Fig. 5C) with total recovery.

Bottom Line: The COX and LOX inhibitors ASA and AA861 (500 μM, 10 μM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 μM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen.Quinidine (100 μM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph.We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine.

View Article: PubMed Central - PubMed

Affiliation: Department of Anesthesiology and Intensive Care Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany; Division of Barrier Integrity, Research Center Borstel, Leibniz-Center for Medicine and Biosciences, Borstel, Germany.

ABSTRACT
Intestinal circulatory disturbances, atony, edema and swelling are of great clinical relevance, but the related mechanisms and possible therapeutic options are poorly characterized, in part because of the difficulties to comprehensively analyze these conditions. To overcome these limitations we have developed a model of the isolated perfused rat small intestine where all of these symptoms can be studied simultaneously. Here we used this model to study the role of eicosanoids, steroids and quinidine in platelet-activating factor (PAF)-induced intestinal disorders. A vascular bolus of PAF (0.5 nmol) triggered release of thromboxane and peptidoleukotrienes into the vascular bed (peak concentration 35 nM and 0.8 nM) and reproduced all symptoms of intestinal failure: mesenteric vasoconstriction, translocation of fluid and macromolecules from the vasculature to the lumen and lymphatics, intestinal edema formation, loss of intestinal peristalsis and decreased galactose uptake. All effects of PAF were abolished by the PAF-receptor antagonist ABT491 (2.5 μM). The COX and LOX inhibitors ASA and AA861 (500 μM, 10 μM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 μM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen. The steroid dexamethasone (10 μM) showed no barrier-protective properties and failed to prevent edema formation. Quinidine (100 μM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph. While quinidine by itself reduced peristalsis, it also obviated paralysis, preserved intestinal functions and prevented edema formation. We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine. The therapeutic use of quinidine for intestinal ailments deserves further study.

No MeSH data available.


Related in: MedlinePlus