Mast cell degranulation – a mechanism for the anti‐arrhythmic effect of endothelin‐1?

Walsh, SK; Kane, Kathleen A.; Wainwright, Cherry L.

doi:10.1111/j.1476-5381.2009.00222.x

Cited by 10 publications

(7 citation statements)

References 40 publications

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“…ET-1 and Ang-II can also induce the expression of fibrogenic factors such as transforming growth factor-b1 (Leask, 2010) and MMP-9 (Rouet-Benzineb et al, 2000;Ergul et al, 2003), which are themselves enzymatically activated by chymase (Takai et al, 2010). ET-1 can itself induce mast cell degranulation, thereby releasing chymase in the interstitium in a positive feedback loop (Walsh et al, 2009). Hence, chymase inhibition could have a tremendous effect on the ET-1 and Ang-II systems and their activities.…”

Section: Discussionmentioning

confidence: 99%

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Houde

Jamain

Labonté

et al. 2013

J Pharmacol Exp Ther

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The serine protease chymase has been reported to generate intracardiac angiotensin-II (Ang-II) from Ang-I as well as an intermediate precursor of endothelin-1 (ET-1), ET-1 (1-31) from Big-ET-1. Although humans possess only one chymase, several murine isoforms are documented, each with its own specific catalytic activity. Among these, mouse mast cell protease 4 (mMCP-4) is the isoform most similar to the human chymase for its activity. The aim of this study was to characterize the capacity of mMCP-4 to convert Big-ET-1 into its bioactive metabolite, ET-1, in vitro and in vivo in the mouse model. Basal mean arterial pressure did not differ between wild-type (WT) and mMCP-4(2/2) mice. Systemic administration of Big-ET-1 triggered pressor responses and increased blood levels of immunoreactive (IR) ET-1 (1-31) and ET-1 that were reduced by more than 50% in mMCP-4 knockout (2/2) mice compared with WT controls.Residual responses to Big-ET-1 in mMCP-4(2/2) mice were insensitive to the enkephalinase/neutral endopeptidase inhibitor thiorphan and the specific chymase inhibitor TY-51469 {2-[4-(5-fluoro-3-methylbenzo[b]thiophen-2-yl)sulfonamido-3-methanesulfonylphenyl]thiazole-4-carboxylic acid}. Soluble fractions from the lungs, left cardiac ventricle, aorta, and kidneys of WT but not mMCP-4(2/2) mice generated ET-1 (1-31) from exogenous Big-ET-1 in a TY-51469-sensitive fashion as detected by high-performance liquid chromatography/ matrix-assisted laser desorption/ionization-mass spectrometry. Finally, pulmonary endogenous levels of IR-ET-1 were reduced by more than 40% in tissues derived from mMCP-4(2/2) mice compared with WT mice. Our results show that mMCP-4 plays a pivotal role in the dynamic conversion of systemic Big-ET-1 to ET-1 in the mouse model.

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Section: Discussionmentioning

confidence: 99%

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Houde

Jamain

Labonté

et al. 2013

J Pharmacol Exp Ther

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“…The primary aim of this study was therefore to determine the effects of a single acute dose of CBD, both immediately prior to ischaemia onset and at the time of reperfusion, on cardiac arrhythmias and infarct size in a rat model of I/R. Because platelet activation (Flores et al ., 1994) and mast cell degranulation (Walsh et al ., 2009a,b) are two major contributors to arrhythmogenesis, and there have been reports of CBD affecting both these processes, the second aim was to explore whether or not any cardioprotective effects were accompanied by effects on platelet function and I/R‐induced mast cell degranulation.…”

Section: Introductionmentioning

confidence: 99%

Acute administration of cannabidiol in vivo suppresses ischaemia‐induced cardiac arrhythmias and reduces infarct size when given at reperfusion

Walsh

Hepburn

Kane

et al. 2010

British J Pharmacology

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Background and purpose: Cannabidiol (CBD) is a phytocannabinoid, with anti-apoptotic, anti-inflammatory and antioxidant effects and has recently been shown to exert a tissue sparing effect during chronic myocardial ischaemia and reperfusion (I/R). However, it is not known whether CBD is cardioprotective in the acute phase of I/R injury and the present studies tested this hypothesis. Experimental approach: Male Sprague-Dawley rats received either vehicle or CBD (10 or 50 mg·kg -1 i.v.) 10 min before 30 min coronary artery occlusion or CBD (50 mg·kg -1 i.v.) 10 min before reperfusion (2 h). The appearance of ventricular arrhythmias during the ischaemic and immediate post-reperfusion periods were recorded and the hearts excised for infarct size determination and assessment of mast cell degranulation. Arterial blood was withdrawn at the end of the reperfusion period to assess platelet aggregation in response to collagen. Key results: CBD reduced both the total number of ischaemia-induced arrhythmias and infarct size when administered prior to ischaemia, an effect that was dose-dependent. Infarct size was also reduced when CBD was given prior to reperfusion. CBD (50 mg·kg -1 i.v.) given prior to ischaemia, but not at reperfusion, attenuated collagen-induced platelet aggregation compared with control, but had no effect on ischaemia-induced mast cell degranulation. Conclusions and implications:This study demonstrates that CBD is cardioprotective in the acute phase of I/R by both reducing ventricular arrhythmias and attenuating infarct size. The anti-arrhythmic effect, but not the tissue sparing effect, may be mediated through an inhibitory effect on platelet activation. British Journal of Pharmacology

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“…Counting was performed by the pathologist blinded to the histological section’s group of origin, with each number expressed with “mean ± SE”. MCs degranulation was determined as a loss of MC membrane integrity with extrusion of intracellular granules to the extracellular space or MCs completely lacking in intracellular granules as described previously [13]. …”

Section: Methodsmentioning

confidence: 99%

Alterations of Mast Cells in the Esophageal Mucosa of the Patients With Non-Erosive Reflux Disease

Ding

Wang

et al. 2011

Gastroenterol Res

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BackgroundMast cells (MCs) are widely distributed in the gastrointestinal tract, which could be involved in visceral hypersensitivity and gut dysmotility. Whether esophageal MCs play a role in non-erosive reflux disease (NERD) has yet to be determined. The aim of this study was to characterize esophageal MCs distribution, degranulation, and ultrastructure.MethodsThe esophageal mucosa at 5 cm above the end of esophagus was obtained from 26 NERD and 14 healthy volunteers (control) by gastroscopy. Immunohistochemistry was performed and average MC counts per high-power field (HPF) and the percentage of degranulated MCs were obtained. The ultrastructure of MCs was observed by transmission electron microscope (TEM).ResultsMore MCs were observed in NERD (7.23 ± 2.41 cells/HPF) as compared with controls (3.79 ± 1.67 cells/HPF) (P < 0.01) and the percentage of degranulated MCs in NERD was also significantly higher than controls (26.85 ± 8.79% vs 11.5 ± 4.18%, P < 0.01). Under TEM, more Golgi apparatus, mitochondria and endoplasmic reticulum were found in MCs in patients with NERD. Special secreting particles were also found in cytoplasm, more vacuoles were left after MCs degranulation in patients with NERD.ConclusionsOur results indicate that increased numbers of MCs and MCs activation may be involved in the pathogenesis of NERD.

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Mast cell degranulation – a mechanism for the anti‐arrhythmic effect of endothelin‐1?

Abstract: These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation.

Cited by 10 publications

References 40 publications

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Pivotal Role of Mouse Mast Cell Protease 4 in the Conversion and Pressor Properties of Big-Endothelin-1

Acute administration of cannabidiol in vivo suppresses ischaemia‐induced cardiac arrhythmias and reduces infarct size when given at reperfusion

Alterations of Mast Cells in the Esophageal Mucosa of the Patients With Non-Erosive Reflux Disease

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