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Serotonin (5-HT) is one of the key vasoconstrictors released in the hemorrhagic blood and an important contributor to the etiology of CVSP. The combination of the ryanodine receptor blocker dantrolene and the Ca2+ channel blocker nimodipine significantly reduces phenylephrine (PHE)-induced vascular contraction in both diabetic and nondiabetic rats, but the effectiveness of this drug combination in reducing 5-HT-induced contraction is unknown. Dose\u2013response curves for the 5-HT-induced contraction (from 0.1\u00a0nM to 100\u00a0\u00b5M) were performed on aortic rings from diabetic and non-diabetic rats after a 30-min incubation period with dantrolene, nimodipine, and both drugs in combination. In diabetic rats, 10\u00a0\u03bcM of dantrolene alone failed to reduce 5-HT-induced maximal contraction (E<jats:sub>max<\/jats:sub>), but 50\u00a0\u03bcM reduced this parameter by 34% (n\u2009=\u20097, p\u2009&lt;\u20090.05). In non-diabetic rats, by contrast, dantrolene did not modify the vascular response to 5-HT. 50\u00a0nM of nimodipine alone, however, reduced this parameter by 57% in diabetic rats (n\u2009=\u200910, p\u2009&lt;\u20090.05), and by 34% in non-diabetic rats (n\u2009=\u200910, p\u2009&lt;\u20090.05). In addition, concomitant administration of dantrolene and nimodipine reduced vascular reactivity to a similar extent in both diabetic (~\u200960% reduction, n\u2009=\u200910, p\u2009&lt;\u20090.05) and non-diabetic rats (~\u200970% reduction, n\u2009=\u200910, p\u2009&lt;\u20090.05). Moreover, the combination of nimodipine with the higher concentration of dantrolene significantly increased the EC<jats:sub>50<\/jats:sub> values for the 5-HT-induced contraction curves in both diabetics (from 10.31\u2009\u00b1\u20091.17\u00a0\u00b5M to 19.26\u2009\u00b1\u20092.82; n\u2009=\u200910, p\u2009&lt;\u20090.05) and non-diabetic rats (5.93\u2009\u00b1\u20090.54\u00a0\u00b5M to 15.80\u2009\u00b1\u20093.24; n\u2009=\u200910, p\u2009&lt;\u20090.05). These results suggest that simultaneous administration of dantrolene and nimodipine has a synergistic effect in reducing 5-HT-induced vascular contraction under both diabetic and non-diabetic conditions. If our findings with rats are applicable to humans, concomitant administration of these drugs may represent a promising alternative for the management of CVSP in both diabetics and non-diabetics.<\/jats:p>","DOI":"10.1038\/s41598-021-89338-6","type":"journal-article","created":{"date-parts":[[2021,5,10]],"date-time":"2021-05-10T10:04:16Z","timestamp":1620641056000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The combination of dantrolene and nimodipine effectively reduces 5-HT-induced vasospasms in diabetic rats"],"prefix":"10.1038","volume":"11","author":[{"given":"Marie","family":"Rom\u00e1n","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Garc\u00eda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myrna","family":"Morales","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7017-7328","authenticated-orcid":false,"given":"Mar\u00eda J.","family":"Crespo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,5,10]]},"reference":[{"key":"89338_CR1","doi-asserted-by":"publisher","unstructured":"Connolly ES Jr, Rabinstein AA, Carhuapoma JR, Derdeyn CP, Dion J, Higashida RT, et al. 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