Disproportionate enhancement of myocardial contractility by the xanthine oxidase inhibitor oxypurinol in failing rat myocardium.
OBJECTIVE
Xanthine oxidase (XO) inhibitors enhance myofilament Ca(2+) 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, [Ca(2+)](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 microM oxypurinol significantly increased systolic twitch tension (by 87 and 92% at 1.0 and 1.5 mM extracellular [Ca(2+)], respectively), without altering [Ca(2+)](i) transient amplitude. Oxypurinol did not alter the midpoint or cooperativity of the steady-state tension-[Ca(2+)](i) relationship, but significantly enhanced maximum Ca(2+)-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.
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000503:physiopathology*; D006973:Hypertension / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D010117:Oxypurinol / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D011918:Rats, Inbred SHR; D011920:Rats, Inbred WF; D011956:Receptors, Cell Surface / Q000235:genetics; D054411:Receptors, Leptin; D013268:Stimulation, Chemical; D014969:Xanthine Oxidase / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000378:metabolism
D004791:Enzyme Inhibitors; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D014969:Xanthine Oxidase; D010117:Oxypurinol