© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
Disproportionate enhancement of myocardial contractility by the xanthine oxidase inhibitor oxypurinol in failing rat myocardium
aInstitute of Molecular Cardiobiology, Johns-Hopkins-University, Baltimore, MD, USA
bDepartment of Food Science and Technology, Ohio-State-University, Columbus, OH, USA
cDepartment of Medical Biochemistry, Ohio-State-University, Columbus, OH, USA
hkogler{at}med.uni-goettingen.de
* Corresponding author. Abteilung Kardiologie und Pneumologie Georg-August-Universität Göttingen Robert-Koch-Str. 40 D-37075 Göttingen, Germany. Tel.: +49-551-396-380; fax: +49-551-392-953.
Objective: Xanthine oxidase (XO) inhibitors enhance myofilament Ca2+ responsiveness of normal rat myocardium. We examined whether this inotropic action is preserved or magnified in failing rat myocardium and whether the magnitude of this effect correlates with tissue xanthine-oxidoreductase (XOR) activity. Methods: Hearts of 18–20 month-old SHHF (spontaneous hypertensive/heart failure) rats with end-stage heart failure, as well as of normal control rats, were perfused with the XO inhibitor oxypurinol. Afterwards, [Ca2+]i and tension were measured simultaneously in fura-2-loaded intact isolated right ventricular trabeculae. XOR activity was determined fluorometrically in myocardial homogenates. Results: In failing myocardium, 100 µM oxypurinol significantly increased systolic twitch tension (by 87 and 92% at 1.0 and 1.5 mM extracellular [Ca2+], respectively), without altering [Ca2+]i transient amplitude. Oxypurinol did not alter the midpoint or cooperativity of the steady-state tension-[Ca2+]i relationship, but significantly enhanced maximum Ca2+-activated tension by 75% in failing myocardium. Oxypurinol also exerted a positive inotropic effect in failing myocardium, which was, however, of significantly smaller relative magnitude. Failing rat myocardium exhibited higher XOR activity than nonfailing myocardium, and this activity was largely suppressed in oxypurinol-treated preparations. Conclusions: The magnitude of functional improvement with XOR inhibitors depends on the initial level of XOR activity. Specifically, the inotropic actions of oxypurinol are more pronounced in failing rat myocardium, a tissue that exhibits enhanced XOR activity. Our findings rationalize how XO inhibitors boost cardiac contractility and improve mechanoenergetic coupling, and why the effects might be relatively ‘selective’ for heart failure.
KEYWORDS Heart failure; Contractile function; Calcium; Inotropic agents; Free radicals
1 Present address: CV Therapeutics, Palo Alto, CA, USA.
2 Present address: Myogen, Westminster, CO, USA.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  M. A. Whidden, J. M. McClung, D. J. Falk, M. B. Hudson, A. J. Smuder, W. B. Nelson, and S. K. Powers Xanthine oxidase contributes to mechanical ventilation-induced diaphragmatic oxidative stress and contractile dysfunction J Appl Physiol, February 1, 2009; 106(2): 385 - 394. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Pascual-Figal, J. A. Hurtado-Martinez, B. Redondo, M. J. Antolinos, J. A. Ruiperez, and M. Valdes Hyperuricaemia and long-term outcome after hospital discharge in acute heart failure patients Eur J Heart Fail, May 1, 2007; 9(5): 518 - 524. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Neumann A renaissance of positive inotropic interventions to treat heart failure? Cardiovasc Res, September 1, 2003; 59(3): 534 - 535. [Full Text] [PDF]
|
|