Opposite Effect of Mast Cell Stabilizers Ketotifen and Tranilast on the Vasoconstrictor Response to Electrical Field Stimulation in Rat Mesenteric Artery

Sastre, Esther; Caracuel, Laura; Xavier, Fabiano E.; Balfagón, Gloria; Blanco-Rivero, Javier

doi:10.1371/journal.pone.0073232

Cited by 10 publications

(19 citation statements)

References 35 publications

(50 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This was confirmed by the fact that NO release, superoxide anion formation and vasodilator response to NO donor DEA-NO were not modified after preincubation with tranilast, similarly to reported in rat aorta [15]. All these results contrast with our previous results in superior mesenteric artery, where we observed decreases in neuronal NO and superoxide anion releases and an increase in the vasodilator response to DEA-NO after tranilast preincubation [14]. In conclusion, the results obtained in the present study confirm the fact that the increased vasodilator response to ACh produced by tranilast is not due to modifications in the NO pathway.…”

Section: Discussionsupporting

confidence: 91%

“…In this study we have located perivascular mast cells around mesenteric resistance vessels, as has been described in superior mesenteric artery [14]. Previously, we have described that tranilast decreases EFS-induced vasoconstriction in superior mesenteric arteries [14]. Since total peripheral resistance mainly depends on resistance vessels, and the role that mesenteric resistance arteries play in this is very relevant, we consider it very important to analyze the possible alterations tranilast may produce in the endothelial function of these vessels.…”

Section: Discussionmentioning

confidence: 88%

“…The concentration of tranilast used and the time of incubation were from previous pilot studies, performed similarly to our previous study [14]. Additionally, vasoconstrictor responses to alpha-adrenergic agonist noradrenaline (10 nmol/L to 0.1 mmol/L) were performed in both control and tranilast-incubated segments.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Tranilast Increases Vasodilator Response to Acetylcholine in Rat Mesenteric Resistance Arteries through Increased EDHF Participation

et al. 2014

Self Cite

View full text Add to dashboard Cite

Background and PurposeTranilast, in addition to its capacity to inhibit mast cell degranulation, has other biological effects, including inhibition of reactive oxygen species, cytokines, leukotrienes and prostaglandin release. In the current study, we analyzed whether tranilast could alter endothelial function in rat mesenteric resistance arteries (MRA).Experimental ApproachAcetylcholine-induced relaxation was analyzed in MRA (untreated and 1-hour tranilast treatment) from 6 month-old Wistar rats. To assess the possible participation of endothelial nitric oxide or prostanoids, acetylcholine-induced relaxation was analyzed in the presence of L-NAME or indomethacin. The participation of endothelium-derived hyperpolarizing factor (EDHF) in acetylcholine-induced response was analyzed by preincubation with TRAM-34 plus apamin or by precontraction with a high K+ solution. Nitric oxide (NO) and superoxide anion levels were measured, as well as vasomotor responses to NO donor DEA-NO and to large conductance calcium-activated potassium channel opener NS1619.Key ResultsAcetylcholine-induced relaxation was greater in tranilast-incubated MRA. Acetylcholine-induced vasodilation was decreased by L-NAME in a similar manner in both experimental groups. Indomethacin did not modify vasodilation. Preincubation with a high K+ solution or TRAM-34 plus apamin reduced the vasodilation to ACh more markedly in tranilast-incubated segments. NO and superoxide anion production, and vasodilator responses to DEA-NO or NS1619 remained unmodified in the presence of tranilast.Conclusions and ImplicationsTranilast increased the endothelium-dependent relaxation to acetylcholine in rat MRA. This effect is independent of the nitric oxide and cyclooxygenase pathways but involves EDHF, and is mediated by an increased role of small conductance calcium-activated K+ channels.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Tranilast Increases Vasodilator Response to Acetylcholine in Rat Mesenteric Resistance Arteries through Increased EDHF Participation

et al. 2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…), mast cell stabilization (Sastre et al. ), and modulation of tryptophan metabolism (Munn et al. ).…”

Section: Discussionmentioning

confidence: 99%

Uricosuric targets of tranilast

Mandal

Mercado

Foster

et al. 2017

Pharmacol Res Perspect

View full text Add to dashboard Cite

Uric acid, generated from the metabolism of purines, has both proven and emerging roles in human disease. Serum uric acid in humans is determined by production and by the net balance of reabsorption and secretion in kidney and intestine. In the human kidney, epithelial reabsorption dominates over secretion, such that in normal subjects there is at least 90% net reabsorption of filtered urate resulting in a fractional excretion of <10%. Tranilast, an anti‐inflammatory drug with pleiotropic effects, has a marked hypouricemic, uricosuric effect in humans. We report here that tranilast is a potent inhibitor of [14C]‐urate transport mediated by the major reabsorptive urate transporters (URAT1, GLUT9, OAT4, and OAT10) in Xenopus oocytes; this provides an unequivocal molecular mechanism for the drug's uricosuric effect. Tranilast was found to inhibit urate transport mediated by URAT1 and GLUT9 in a fully reversible and noncompetitive (mixed) manner. In addition, tranilast inhibits the secretory urate transporters NPT1, OAT1, and OAT3 without affecting the secretory efflux pump ABCG2. Notably, while benzbromarone and probenecid inhibited urate as well as nicotinate transport, tranilast inhibited the urate transport function of URAT1, GLUT9, OAT4, OAT10, and NPT1, without significantly affecting nicotinate transport mediated by SMCT1 (IC 50 ~1.1 mmol/L), SMCT2 (IC 50 ~1.0 mmol/L), and URAT1 (IC 50 ~178 μmol/L). In summary, tranilast causes uricosuria by inhibiting all the major reabsorptive urate transporters, selectively affecting urate over nicotinate transport. These data have implications for the treatment of hyperuricemia and gout, the pharmacology of tranilast, and the structure‐function analysis of urate transport.

show abstract

“…However, later studies using human conjunctival mast cells additionally revealed a mast cell-stabilizing property of ketotifen [7,8], consistent with its higher potency in the treatment of allergic disorders. So far, by measuring the amount of chemokines released from rat peritoneal mast cells, such as histamine and β-hexosaminidase, previous studies have suggested the superiority of ketotifen to tranilast in the properties of mast cell stabilization [9][10][11]. However, due to the limitations of the methods used in molecular biology [12], the effects of these drugs on the exocytotic process of mast cells have not directly been examined.…”

Section: Introductionmentioning

confidence: 99%

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

Baba

Tachi²,

Ejima³

et al. 2016

Cell Physiol Biochem

View full text Add to dashboard Cite

Background: Anti-allergic drugs, such as tranilast and ketotifen, inhibit the release of chemokines from mast cells. However, we know little about their direct effects on the exocytotic process of mast cells. Since exocytosis in mast cells can be monitored electrophysiologically by changes in the whole-cell membrane capacitance (Cm), the absence of such changes by these drugs indicates their mast cell-stabilizing properties. Methods: Employing the standard patch-clamp whole-cell recording technique in rat peritoneal mast cells, we examined the effects of tranilast and ketotifen on the Cm during exocytosis. Using confocal imaging of a water-soluble fluorescent dye, lucifer yellow, we also examined their effects on the deformation of the plasma membrane. Results: Relatively lower concentrations of tranilast (100, 250 µM) and ketotifen (1, 10 µM) did not significantly affect the GTP-γ-S-induced increase in the Cm. However, higher concentrations of tranilast (500 µM, 1 mM) and ketotifen (50, 100 µM) almost totally suppressed the increase in the Cm, and washed out the trapping of the dye on the surface of the mast cells. Compared to tranilast, ketotifen required much lower doses to similarly inhibit the degranulation of mast cells or the increase in the Cm. Conclusions: This study provides electrophysiological evidence for the first time that tranilast and ketotifen dose-dependently inhibit the process of exocytosis, and that ketotifen is more potent than tranilast in stabilizing mast cells. The mast cell-stabilizing properties of these drugs may be attributed to their ability to counteract the plasma membrane deformation in degranulating mast cells.

show abstract

Opposite Effect of Mast Cell Stabilizers Ketotifen and Tranilast on the Vasoconstrictor Response to Electrical Field Stimulation in Rat Mesenteric Artery

Cited by 10 publications

References 35 publications

Tranilast Increases Vasodilator Response to Acetylcholine in Rat Mesenteric Resistance Arteries through Increased EDHF Participation

Tranilast Increases Vasodilator Response to Acetylcholine in Rat Mesenteric Resistance Arteries through Increased EDHF Participation

Uricosuric targets of tranilast

Anti-Allergic Drugs Tranilast and Ketotifen Dose-Dependently Exert Mast Cell-Stabilizing Properties

Contact Info

Product

Resources

About