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The drugs share the unwanted side\u2010effect of evoking hypertension that is associated with reduced endothelial function and nitric oxide production. The underlying mechanisms are not understood. FKBP may regulate IP<jats:sub>3<\/jats:sub> receptors (IP<jats:sub>3<\/jats:sub>R) and ryanodine receptors (RyR) to alter Ca<jats:sup>2+<\/jats:sup> signalling in endothelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We investigated the effects of FK506 and rapamycin on Ca<jats:sup>2+<\/jats:sup> release via IP<jats:sub>3<\/jats:sub>R and RyR in hundreds of endothelial cells, using the indicator Cal\u2010520, in intact mesenteric arteries from male Sprague\u2010Dawley rats. IP<jats:sub>3<\/jats:sub>Rs were activated by acetylcholine or localised photo\u2010uncaging of IP<jats:sub>3<\/jats:sub>, and RyR by caffeine.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>While FKBPs were present, FKBP modulation with rapamycin did not alter IP<jats:sub>3<\/jats:sub>\u2010evoked Ca<jats:sup>2+<\/jats:sup> release. Conversely, FK506, which modulates FKBP and blocks calcineurin, increased IP<jats:sub>3<\/jats:sub>\u2010evoked Ca<jats:sup>2+<\/jats:sup> release. Inhibition of calcineurin (okadiac acid or cypermethrin) also increased IP<jats:sub>3<\/jats:sub>\u2010evoked Ca<jats:sup>2+<\/jats:sup> release and blocked FK506 effects. When calcineurin was inhibited, FK506 reduced IP<jats:sub>3<\/jats:sub>\u2010evoked Ca<jats:sup>2+<\/jats:sup> release. These findings suggest that IP<jats:sub>3<\/jats:sub>\u2010evoked Ca<jats:sup>2+<\/jats:sup> release is not modulated by FKBP, but by FK506\u2010mediated calcineurin inhibition. The RyR modulators caffeine and ryanodine failed to alter Ca<jats:sup>2+<\/jats:sup> signalling suggesting that RyR is not functional in native endothelium.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>The hypertensive effects of the immunosuppressant drugs FK506 and rapamycin, while mediated by endothelial cells, do not appear to be exerted at the documented cellular targets of Ca<jats:sup>2+<\/jats:sup> release and altered FKBP binding to IP<jats:sub>3<\/jats:sub> and RyR.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14905","type":"journal-article","created":{"date-parts":[[2019,11,9]],"date-time":"2019-11-09T04:04:53Z","timestamp":1573272293000},"page":"1131-1149","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["FK506 regulates Ca<sup>2+<\/sup> release evoked by inositol 1,4,5\u2010trisphosphate independently of FK\u2010binding protein in endothelial 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