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In view of increasing evidence that platelet\u2010based defects may occur in CAS patients, we investigated platelet reactivity in CAS patients and whether symptomatic crises reflect activation of platelet\u2013endothelial interactions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>CAS patients were evaluated during acute and\/or chronic symptomatic phases and compared with healthy control subjects. Inhibition of ADP\u2010induced platelet aggregation by the NO donor sodium nitroprusside (SNP) and plasma concentrations of syndecan 1 (glycocalyx shedding marker), tryptase (mast cell activation marker) and platelet microparticles were measured.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Inhibition of platelet aggregation by SNP was diminished in chronic CAS, with further (non\u2010significant) deterioration during symptomatic crises, whereas plasma concentrations of syndecan 1, tryptase and platelet microparticles increased. Treatment of patients with high\u2010dose <jats:italic>N<\/jats:italic>\u2010acetylcysteine (NAC) plus glyceryl trinitrate rapidly increased platelet responsiveness to SNP and decreased plasma syndecan 1 concentrations. The effect of NAC on platelet responsiveness to SNP was <jats:italic>confirmed in vitro<\/jats:italic> and mimicked by the H<jats:sub>2<\/jats:sub>S donor NaHS. Conversely, inhibition of enzymatic production of H<jats:sub>2<\/jats:sub>S attenuated NAC effect.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>CAS is associated with substantial impairment of platelet NO signalling. During acute symptomatic exacerbations, platelet resistance to NO is aggravated, together with mast cell activation and damage to both vasculature and platelets. NAC, via release of H<jats:sub>2<\/jats:sub>S, reverses platelet resistance to NO and terminates glycocalyx shedding during symptomatic crises: This suggests that H<jats:sub>2<\/jats:sub>S donors may correct the pathophysiological anomalies underlying CAS.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.15388","type":"journal-article","created":{"date-parts":[[2021,1,24]],"date-time":"2021-01-24T12:51:30Z","timestamp":1611492690000},"page":"1639-1650","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Impairment of platelet NO signalling in coronary artery spasm: role of hydrogen sulphide"],"prefix":"10.1111","volume":"178","author":[{"given":"Hasan","family":"Imam","sequence":"first","affiliation":[{"name":"Cardiology Research Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital The University of Adelaide  Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanh H.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Cardiology Research Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital The University of Adelaide  Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Stafford","sequence":"additional","affiliation":[{"name":"Cardiology Research Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital The University of Adelaide  Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saifei","family":"Liu","sequence":"additional","affiliation":[{"name":"Cardiology Research Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital The University of Adelaide  Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tamila","family":"Heresztyn","sequence":"additional","affiliation":[{"name":"Cardiology Research Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital The University of Adelaide  Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuliy Y.","family":"Chirkov","sequence":"additional","affiliation":[{"name":"Cardiology Research Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital The University of Adelaide  Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Horowitz","sequence":"additional","affiliation":[{"name":"Cardiology Research Laboratory, Basil Hetzel Institute, The Queen Elizabeth Hospital The University of Adelaide  Adelaide Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,2,23]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"S247","article-title":"The Concise Guide To Pharmacology 2019\/20: Catalytic receptors","volume":"176","author":"Alexander S. 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