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Cardiovascular Research 2003 59(3):534-535; doi:10.1016/S0008-6363(03)00557-1
© 2003 by European Society of Cardiology
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Copyright © 2003, European Society of Cardiology

A renaissance of positive inotropic interventions to treat heart failure?

Joachim Neumann*

Institut für Pharmakologie und Toxikologie, Universitätsklinikum Münster, Domagkstr. 12, D-48129 Münster, Germany

neumannjoachim{at}hotmail.com

* Tel.: +49-251-835-502; fax: +49-251-835-5501.

See article by Kögler et al. [1] (pages 582–592) in this issue.

Heart failure has a high and increasing prevalence due to the aging population and the better survival rates in other heart diseases (e.g. acute myocardial infarction) in the Western world. Myocardial oxidative stress due to increased production of reactive oxygen free radicals may play an important role in the development and progression of heart failure.

In this issue of Cardiovascular Research, Kögler et al. [1] report on a positive inotropic effect of oxypurinol in a rat model of heart failure. Oxypurinol (plasma half life about 14 h) is the active metabolite of allopurinol (plasma half life about 40 min); both are xanthine oxidase (XO) inhibitors. XO forms free oxygen radicals as it catalyzes the degradation of purines like hypoxanthine and xanthine to uric acid. Increased plasma levels of uric acid lead to gout. Inhibition of XO activity reduces the plasma levels of uric acid as its precursors are eliminated by the kidney. Therefore, allopurinol has long been used in the treatment of gout. XO also converts allopurinol to oxypurinol. Oxypurinol is not available as a commercial drug. Increased XO activity may lead to reperfusion injury by modifying contractile proteins and thereby reducing Ca2+ sensitivity of the myofilaments [2]. In previous reports, allopurinol improved cardiac performance, hastened postoperative recovery of cardiac output, and reduced the need for inotropic support or mechanical postoperative support in patients undergoing coronary bypass therapy [3,4]. Intracoronary infusion of allopurinol in patients suffering from idiopathic cardiomyopathy (who were otherwise on standard drug treatment) decreased myocardial oxygen consumption at constant dP/dtmax indicating improved efficiency of cardiac contraction [5]. In contrast, classical positive inotropic compounds like β-adrenoceptor agonists or phosphodiesterase inhibitors usually decrease myocardial efficiency. In patients undergoing cardiac transplantation for terminal heart failure, the protein expression of XO was increased compared to control samples [3]. In isolated cardiac muscles from rat, allopurinol and oxypurinol increased developed tension at constant intracellular Ca2+ levels when given acutely [6]. This indicates a direct positive inotropic effect due to increased Ca2+ sensitivity of the myofilaments, at least in intact rat tissue. Allopurinol and oxypurinol apparently are the first Ca2+ sensitizers that purely increase maximum force without shifting the range of contractile activation to lower [Ca2+]. This should be advantageous because other Ca2+ sensitizers impair diastolic relaxation [7]. The blunted β-adrenergic response in a canine heart failure model could be in part restored by allopurinol treatment [8]. It will be worthwhile to study whether this improvement by oxypurinol of the effect of inotropic support is present in humans as well.

Previous findings are being extended by the paper of Kögler et al. [1]. They show that the myocardial activity of XO is increased in a well-characterized rat model of cardiac hypertrophy/failure, that myocardial XO activity is greatly reduced by application of oxypurinol, and that oxypurinol exerts a positive inotropic effect that is larger in isolated failing than in nonfailing rat hearts. This indicates (but does not prove) a causal link between heart failure and increased XO activity, as well as between XO inhibition and positive inotropy. The cellular source of increased XO activity in a canine heart failure model is, at least in part, the cardiomyocyte [9]. It should be considered, however, that allopurinol and oxypurinol themselves have hydroxyl radical scavenging properties, with no requirement of any enzyme activity [10].

From a mechanistical point of view, these data support a causal link between free radical formation and the development of heart failure. However, one could argue that free radical formation is only an aggravating factor of inadequate relative or absolute oxygen supply. Moreover, how inhibition of free radical formation should increase the Ca2+ sensitivity of the myofilaments remains unclear. Perhaps tonic levels of free radical species in normal hearts decrease Ca2+ sensitivity of the myofilaments and this tonic inhibition is blocked by XO inhibitors [6]. On the other hand, one cannot rule out the possibility that the Ca2+ sensitizing properties of oxypurinol or allopurinol are independent of their ability to inhibit XO activity: the chemical structure of XO inhibitors is reminiscent of sulmazole, a well-characterized Ca2+ sensitizer [11].

Of course, the commercial potential of oxypurinol has not been overlooked by the pharmaceutical industry. There is a company (Cardiome Pharma Corp., Vancouver, Canada, www.cardiome.com [12]) that claims to have started phase II studies of oxypurinol as proof of concept for the treatment of heart failure. State of the art mortality studies will be needed to define for what patients (acute vs. chronic heart failure, comorbidities) oxypurinol may offer a true advantage. Results of such studies are awaited with interest.


   References
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 References
 

  1. Kögler H, Fraser H, McCune S, Altschuld R, Marban E. Disproportionate enhancement of myocardial contractility by the xanthine oxidase inhibitor oxypurinol in failing rat myocardium. Cardiovasc Res (2003) 59:582–592.[Abstract/Free Full Text]
  2. Gao W.D, Liu Y, Marban E. Selective effects of oxygen free radicals on excitation-contraction coupling in ventricular muscle. Implications for the mechanism of stunned myocardium. Circulation (1996) 94:2597–2604.[Abstract/Free Full Text]
  3. Castelli P, Condemi A.M, Brambillasca C, Fundaro P, Botta M, Lemma M, Vanelli P, Santoli C, Gatti S, Riva E. Improvement of cardiac function by allopurinol in patients undergoing cardiac surgery. J Cardiovasc Pharmacol. (1995) 25:119–125.[Web of Science][Medline]
  4. Johnson W.D, Kayser K.L, Brenowitz J.B, Saedi S.F. A randomized controlled trial of allopurinol in coronary bypass surgery. Am Heart J (1991) 121:20–24.[CrossRef][Web of Science][Medline]
  5. Cappola T.P, Kass D.A, Nelson G.S, Berger R.D, Rosas G.O, Kobeissi Z.A, Marban E, Hare J.M. Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy. Circulation (2001) 104:2407–2411.[Abstract/Free Full Text]
  6. Perez N.G, Gao W.D, Marban E. Novel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors. Circ Res (1998) 83:423–430.[Abstract/Free Full Text]
  7. Neumann J, Eschenhagen T, Grupp I.L, Haverich A, Herzig J.W, Hirt S, Kalmar P, Schmitz W, Scholz H, Stein B, Wenzlaff H, Zimmermann N. Positive inotropic effects of the calcium sensitizer CGP 48506 in failing human myocardium. J Pharmacol Exp Ther (1996) 277:1579–1585.[Abstract/Free Full Text]
  8. Ukai T, Cheng C.P, Tachibana H, Igawa A, Zhang Z.S, Cheng H.J, Little W.C. Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure. Circulation (2001) 103:750–755.[Abstract/Free Full Text]
  9. Saavedra W.F, Paolocci N, St John M.E, Skaf M.W, Stewart G.C, Xie J.S, Harrison R.W, Zeichner J, Mudrick D, Marban E, Kas D.A, Hare J.M. Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart. Circ Res (2002) 90:297–304.[Abstract/Free Full Text]
  10. Hoey B.M, Butler J, Halliwell B. On the specificity of allopurinol and oxypurinol as inhibitors of xanthine oxidase. A pulse radiolysis determination of rate constants for reaction of allopurinol and oxypurinol with hydroxyl radicals. Free Radic Res Commun (1988) 4:259–263.[Medline]
  11. Scholz H. Inotropic drugs and their mechanisms of action. J Am Coll Cardiol (1984) 4:389–397.[Abstract]
  12. http://www.cardiome.com (available on 7/4/03).

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