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ORIGINAL RESEARCH ARTICLE

Antioxidant and Lysosomotropic Properties of Acute D-Propranolol Underlies Its Cardioprotection of Postischemic Hearts from Moderate Iron-Overloaded Rats

Jay H. Kramer^*,,1, Sarah B. Murthi^,2, Robert M. Wise, I-Tong Mak^*, and William B. Weglicki^*,

^* Departments of Biochemistry and Molecular Biology, Division of Experimental Medicine; Surgery; and Medicine, The George Washington University Medical Center, Washington, District of Columbia 20037

To whom requests for reprints should be addressed at ¹ Department of Biochemistry and Molecular Biology, Division of Experimental Medicine, The George Washington University Medical Center, 435 Ross Hall, 2300 Eye Street, N.W., Washington, DC 20037. E-mail: phyjhk{at}gwumc.edu

The benefits of acute D-propranolol (D-Pro, non–ß-adrenergic receptor blocker) pretreatment against enhanced ischemia/reperfusion (I/R) injury of hearts from moderate iron–overloaded rats were examined. Perfused hearts from iron-dextran–treated rats (450 mg/kg/week for 3 weeks, intraperitoneal administration) exhibited normal control function, despite iron treatment that elevated plasma iron and conjugated diene levels by 8.1-and 2.5-fold, respectively. However, these hearts were more susceptible to 25 mins of global I/R stress compared with nonloaded hearts; the coronary flow rate, aortic output, cardiac work, left ventricular systolic pressure, positive differential left ventricular pressure (dP/dt), and left ventricular developed pressure displayed 38%, 60%, 55%, 13%, 41%, and 15% lower recoveries, respectively, and a 6.5-fold increase in left ventricular end-diastolic pressure. Postischemic hearts from iron-loaded rats also exhibited 5.6-, 3.48-, 2.43-, and 3.45-fold increases in total effluent iron content, conjugated diene levels, lactate dehydrogenase (LDH) activity, and lysosomal N-acetyl-ß-glucosaminidase (NAGA) activity, respectively, compared with similarly stressed nonloaded hearts. A comparison of detection time profiles during reperfusion suggests that most of the oxidative injury (conjugated diene) in hearts from iron-loaded rats occurred at later times of reperfusion (8.5–15 mins), and this corresponded with heightened tissue iron and NAGA release. D-Pro (2 µM infused for 30 mins) pretreatment before ischemia protected all parameters compared with the untreated iron-loaded group; pressure indices improved 1.2- to 1.6-fold, flow parameters improved 1.70- to 2.96-fold, cardiac work improved 2.87-fold, and end-diastolic pressure was reduced 56%. D-Pro lowered total release of tissue iron, conjugated diene content, LDH activity, and NAGA activity 4.59-, 2.55-, 3.04-, and 4.14-fold, respectively, in the effluent of I/R hearts from the iron-loaded group. These findings suggest that the enhanced postischemic dysfunction and tissue injury of hearts from iron-loaded rats was caused by excessive iron-catalyzed free radical stress, and that the membrane antioxidant properties of D-Pro and its stabilization of sequestered lysosomal iron by D-Pro may contribute to the cardioprotective actions of D-Pro.

Key Words: iron overload • rat heart • ischemia/reperfusion • D-propranolol • hemodynamic recovery • oxidative tissue injury