Novel Myofilament Ca²⁺-Sensitizing Property of Xanthine Oxidase Inhibitors

From the Section of Molecular and Cellular Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Md. The current address for Dr N.G. Pérez is Center for Cardiovascular Investigation, University of La Plata, La Plata, Argentina.

Correspondence to Eduardo Marbán, MD, PhD, Room 844, Ross Building, Johns Hopkins University School of Medicine, 720 Rutland Ave, Baltimore, MD 21205. E-mail marban{at}welchlink.welch.jhu.edu

Abstract—Antioxidants are known to mitigate the cardiac contractile dysfunction that follows brief periods of ischemia ("myocardial stunning"). Stunning decreases contractility at the level of the contractile proteins; therefore, we asked whether antioxidant treatment preserves myofilament Ca²⁺ responsiveness after global ischemia and reflow. Right ventricular trabeculae were dissected from rat hearts subjected either to 20 minutes ischemia and reperfusion in the absence of drugs (stunned group) or to the same protocol in the presence of allopurinol, an inhibitor of xanthine oxidase (XO), and mercaptopropionylglycine (MPG), a hydroxyl radical scavenger (antioxidant group). At 20 minutes of reflow, isovolumic developed pressure recovered completely in the antioxidant group, but in the stunned group it recovered by only 57%. [Ca²⁺]_i and contractile force measurements in trabeculae revealed the expected depression of myofilament function in the stunned group, with no change in Ca²⁺ transients relative to nonischemic controls. In contrast, Ca²⁺ transients were smaller, but force was greater, in the antioxidant group relative to both the stunned group and to nonischemic controls. Steady-state [Ca²⁺]_i-force relationships revealed a striking increase of maximal force and a modest shift of activation to a lower range of [Ca²⁺]_i. The increase in maximal force was reproduced by allopurinol+MPG or by allopurinol alone under nonischemic conditions and also by oxypurinol (100 µmol/L), a potent inhibitor of XO. We conclude that allopurinol and oxypurinol sensitize the cardiac myofilaments to Ca²⁺. This Ca²⁺-sensitizing effect underlies the preservation of contractility observed with an allopurinol+MPG antioxidant cocktail in a model of stunned myocardium. These serendipitous findings identify allopurinol and oxypurinol as the lead compounds of a novel class of inotropic agents.

Key Words: allopurinol • excitation-contraction coupling • ischemia • reperfusion • stunning

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