title: Carvedilol reduces ischaemic skeletal muscle necrosis.
abstract: Carvedilol is an alpha1 and nonselective beta-adrenergic receptor antagonist with antioxidative properties known to protect against reperfusion injury in the heart, brain, and kidneys. The aim of this study was to test the hypothesis that carvedilol improves postischaemic reperfusion and tissue survival in skeletal muscle. Sixteen Wistar rats underwent tourniquet ischaemia of the left hindlimb for 3 hours and 15 minutes at 27 degrees C. Single-fiber laser Doppler probes were inserted in the left and right anterior tibial muscles, and microvascular perfusion was measured until 2 hours after removal of the tourniquet. Perfusion indices for each 15-minute interval were calculated for the left hindlimb (tourniquet ischaemia) by dividing the postischaemic by the pre-ischaemic laser Doppler flowmetry values, and the geometrical areas under the curves representing a plot of perfusion index relative to time, measured in arbitrary units, were compared. Laser Doppler flowmetry values for the right anterior tibial muscle were compared. Tissue damage was measured by histomorphometry of necrotic areas and no-reflow zones in cross sections from the anterior tibial muscle 72 hours after ischaemia. Neutrophils were counted in the same sections. The treatment group received 1 mg carvedilol/kg body weight before ischaemia and 1 mg/kg immediately before removal of the tourniquets. The areas under the curves representing the plot of perfusion index relative to time were larger for the rats treated with carvedilol: 9.5 compared with 3.0 arbitrary units (p = 0.0003). Treatment did not change the laser Doppler flowmetry values for the right hindlimbs. The histomorphometric areas of necrosis in cross sections from the muscles were reduced from 88% (38-96%) in the control animals to 41% (7-85%) in those treated with carvedilol (p = 0.01), and the area of no-reflow was reduced from 20% (2-52%) to 0% (0-7%) (p = 0.006). The number of neutrophils did not differ between groups. The study supports the hypothesis that carvedilol improves early reperfusion and protects skeletal muscle subjected to 3 hours and 15 minutes of ischaemia.
authors.affiliation: Institute for Surgical Research, National Hospital, Orthopaedic Department, Ullevaal Hospital, University of Oslo, Norway. kjetil.hvaal@rh.uio.no
authors.forename: K
authors.initials: K
authors.lastname: Hvaal
authors.forename: S R
authors.initials: SR
authors.lastname: Mathisen
authors.forename: A
authors.initials: A
authors.lastname: Svindland
authors.forename: O J
authors.initials: OJ
authors.lastname: Kirkeby
authors.forename: S
authors.initials: S
authors.lastname: Skjeldal
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D019540:Area Under Curve; D001794:Blood Pressure; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D006614:Hindlimb / Q000098:blood supply; D017078:Laser-Doppler Flowmetry; D008297:Male; D018482:Muscle, Skeletal / Q000098:blood supply* / Q000473:pathology*; D009336:Necrosis; D011412:Propanolamines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol