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However, there are concerns that combined midazolam and allopregnanolone increases risk of adverse cardiovascular events. To address this, we used telemetry devices to record cardiovascular responses in adult male Sprague\u2013Dawley rats acutely intoxicated with diisopropylfluorophosphate (DFP). Animals were administered DFP (4\u00a0mg\/kg, sc), followed immediately by atropine (2\u00a0mg\/kg, i.m.) and 2-PAM (25\u00a0mg\/kg, i.m.). At 40\u00a0min post-exposure, a subset of animals received midazolam (0.65\u00a0mg\/kg, im); at 50\u00a0min, these rats received a second dose of midazolam or allopregnanolone (12\u00a0mg\/kg, im). DFP significantly increased blood pressure by\u2009~\u200980\u00a0mmHg and pulse pressure by\u2009~\u200934\u00a0mmHg that peaked within 12\u00a0min. DFP also increased core temperature by\u2009~\u20093.5\u00a0\u00b0C and heart rate by\u2009~\u2009250\u00a0bpm that peaked at\u2009~\u20092\u00a0h. Heart rate variability (HRV), an index of autonomic function, was reduced by\u2009~\u200980%. All acute (within 15\u00a0min of exposure) and two-thirds of delayed (hours after exposure) mortalities were associated with non-ventricular cardiac events within 10\u00a0min of cardiovascular collapse, suggesting that non-ventricular events should be closely monitored in OP-poisoned patients. Compared to rats that survived DFP intoxication without treatment, midazolam significantly improved recovery of cardiovascular parameters and HRV, an effect enhanced by allopregnanolone. These data demonstrate that midazolam improved recovery of cardiovascular and autonomic function and that the combination of midazolam and allopregnanolone may be a better therapeutic strategy than midazolam alone.<\/jats:p>","DOI":"10.1007\/s00204-023-03679-x","type":"journal-article","created":{"date-parts":[[2024,2,2]],"date-time":"2024-02-02T16:02:24Z","timestamp":1706889744000},"page":"1177-1189","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Cardiovascular responses of adult male Sprague\u2013Dawley rats following acute organophosphate intoxication and post-exposure treatment with midazolam with or without allopregnanolone"],"prefix":"10.1007","volume":"98","author":[{"given":"Shiyue","family":"Pan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald A.","family":"Bruun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"Lein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3001-7543","authenticated-orcid":false,"given":"Chao-Yin","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,2]]},"reference":[{"issue":"6","key":"3679_CR1","first-page":"1247","volume":"26","author":"A Aghabiklooei","year":"2013","unstructured":"Aghabiklooei A, Mostafazadeh B, Farzaneh E, Morteza A (2013) Does organophosphate poisoning cause cardiac injury? 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