d-Propranolol protects against oxidative stress and progressive cardiac dysfunction in iron overloaded rats.
d-Propranolol (d-Pro: 2-8 mg·(kg body mass)(-1)·day(-1)) protected against cardiac dysfunction and oxidative stress during 3-5 weeks of iron overload (2 mg Fe-dextran·(g body mass)(-1)·week(-1)) in Sprague-Dawley rats. At 3 weeks, hearts were perfused in working mode to obtain baseline function; red blood cell glutathione, plasma 8-isoprostane, neutrophil basal superoxide production, lysosomal-derived plasma N-acetyl-β-galactosaminidase (NAGA) activity, ventricular iron content, and cardiac iron deposition were assessed. Hearts from the Fe-treated group of rats exhibited lower cardiac work (26%) and output (CO, 24%); end-diastolic pressure rose 1.8-fold. Further, glutathione levels increased 2-fold, isoprostane levels increased 2.5-fold, neutrophil superoxide increased 3-fold, NAGA increased 4-fold, ventricular Fe increased 4.9-fold; and substantial atrial and ventricular Fe-deposition occurred. d-Pro (8 mg) restored heart function to the control levels, protected against oxidative stress, and decreased cardiac Fe levels. After 5 weeks of Fe treatment, echocardiography revealed that the following were depressed: percent fractional shortening (%FS, 31% lower); left ventricular (LV) ejection fraction (LVEF, 17%), CO (25%); and aortic pressure maximum (P(max), 24%). Mitral valve E/A declined by 18%, indicating diastolic dysfunction. Cardiac CD11b+ infiltrates were elevated. Low d-Pro (2 mg) provided modest protection, whereas 4-8 mg greatly improved LVEF (54%-75%), %FS (51%-81%), CO (43%-78%), P(max) (56%-100%), and E/A >100%; 8 mg decreased cardiac inflammation. Since d-Pro is an antioxidant and reduces cardiac Fe uptake as well as inflammation, these properties may preserve cardiac function during Fe overload.
Biochemistry & Molecular Biology, Division of Experimental Medicine, The George Washington University Medical Center, Washington, DC 20037, USA. phyjhk@gwu.edu
Jay H
JH
Kramer
Christopher F
CF
Spurney
Micaela
M
Iantorno
Constantine
C
Tziros
Joanna J
JJ
Chmielinska
I Tong
IT
Mak
William B
WB
Weglicki
D000118:Acetylglucosaminidase / Q000097:blood; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004452:Echocardiography; D004912:Erythrocytes / Q000187:drug effects / Q000378:metabolism; D005978:Glutathione; D006331:Heart Diseases / Q000097:blood / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D019190:Iron Overload / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D018384:Oxidative Stress / Q000187:drug effects*; D010477:Perfusion; D011433:Propranolol / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013482:Superoxide Dismutase / Q000378:metabolism; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D011433:Propranolol; D013482:Superoxide Dismutase; D000118:Acetylglucosaminidase; D005978:Glutathione