title: The timing of administration of a clinically relevant dose of losartan influences the healing process after contusion induced muscle injury.
abstract: Losartan (Los) is a Food and Drug Administration-approved antihypertensive medication that has a well-tolerated side effect profile. We have demonstrated that treatment with Los immediately after injury was effective at promoting muscle healing and inducing an antifibrotic effect in a murine model of skeletal muscle injury. We initially investigated the minimum effective dose of Los administration immediately after injury and subsequently determined whether the timing of administering a clinically relevant dose of Los would influence its effectiveness at improving muscle healing after muscle injury. In the first part of this study, mice were administered 3, 10, 30, or 300 mg·kg(-1)·day(-1) of Los immediately after injury, and the healing process was evaluated histologically and physiologically 4 wk after injury. In the second study, the clinically relevant dose of 10 mg·kg(-1)·day(-1) was administered immediately or started at 3 or 7 days postinjury. The administration of 300 mg·kg(-1)·day(-1) immediately following injury led to a significant increase in muscle regeneration, a significant decrease in fibrosis, and an improvement in muscle function. Moreover, we observed a significant decrease in fibrosis and a significant increase in muscle regeneration at 4 wk postinjury, when the clinically relevant dose of 10 mg·kg(-1)·day(-1) was administered at 3 or 7 days postinjury. Functional evaluation also demonstrated a significant improvement compared with the injured untreated control when Los treatment was initiated 3 days after injury. Our study revealed accelerated muscle healing when the 300 mg·kg(-1)·day(-1) of Los was administered immediately after injury and a clinically relevant dose of 10 mg·kg(-1)·day(-1) of Los was administered at 3 or 7 days postinjury.
authors.affiliation: Stem Cell Research Center, Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kobayashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Uehara
authors.forename: Shusuke
authors.initials: S
authors.lastname: Ota
authors.forename: Kimimasa
authors.initials: K
authors.lastname: Tobita
authors.forename: Fabrisia
authors.initials: F
authors.lastname: Ambrosio
authors.forename: James H
authors.initials: JH
authors.lastname: Cummins
authors.forename: Satoshi
authors.initials: S
authors.lastname: Terada
authors.forename: Freddie H
authors.initials: FH
authors.lastname: Fu
authors.forename: Johnny
authors.initials: J
authors.lastname: Huard
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D002460:Cell Line; D003288:Contusions / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D038681:Follistatin / Q000378:metabolism; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000293:injuries* / Q000378:metabolism / Q000503:physiopathology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D055435:Myostatin / Q000378:metabolism; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D000959:Antihypertensive Agents; D038681:Follistatin; D055435:Myostatin; D019808:Losartan