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Few reports investigating the effect of chloroquine on vascular responsiveness of coronary arteries have been made. In this study, we examined how chloroquine affected endothelium\u2010dependent relaxation in coronary arteries under normal and diabetic conditions.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>We isolated coronary arteries from mice and examined endothelium\u2010dependent relaxation (EDR). Human coronary endothelial cells and mouse coronary endothelial cells isolated from control and diabetic mouse (TALLYHO\/Jng [TH] mice, a spontaneous type 2 diabetic mouse model) were used for the molecular biological or cytosolic NO and Ca<jats:sup>2+<\/jats:sup> measurements.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>Chloroquine inhibited endothelium\u2010derived NO\u2010dependent relaxation but had negligible effect on endothelium\u2010derived hyperpolarization (EDH)\u2010dependent relaxation in coronary arteries of control mice. Chloroquine significantly decreased NO production in control human coronary endothelial cells partly by phosphorylating eNOS<jats:sup>Thr495<\/jats:sup> (an inhibitory phosphorylation site of eNOS) and attenuating the rise of cytosolic Ca<jats:sup>2+<\/jats:sup> concentration after stimulation. EDR was significantly inhibited in diabetic mice in comparison to control mice. Interestingly, chloroquine enhanced EDR in diabetic coronary arteries by, specifically, increasing EDH\u2010dependent relaxation due partly to its augmenting effect on gap junction activity in diabetic mouse coronary endothelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>These data indicate that chloroquine affects vascular relaxation differently under normal and diabetic conditions. Therefore, the patients' health condition such as coronary macrovascular or microvascular disease, with or without diabetes, must be taken account into the consideration when selecting chloroquine for the treatment of malaria.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.14864","type":"journal-article","created":{"date-parts":[[2019,9,10]],"date-time":"2019-09-10T14:09:21Z","timestamp":1568124561000},"page":"314-327","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Chloroquine differentially modulates coronary vasodilation in control and diabetic mice"],"prefix":"10.1111","volume":"177","author":[{"given":"Qian","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medicine University of California  San Diego, La Jolla California"},{"name":"Department of Physiology The University of Arizona  Tucson Arizona"},{"name":"State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory 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