Original articleXanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure✰
Introduction
Xanthine oxidase inhibition (XOI) has beneficial effects on both the vasculature [1], [2] and the myocardium [3], [4], making it a potentially novel therapeutic modality for heart failure. Experimental and human studies indicate that acute XOI leads to reduced oxidative stress [5], [6], [7], improved vascular reactivity [5], [8], and improved myocardial contractility and energetics [6], [9], [10]. In addition, chronic administration of XOI ameliorates remodeling [11] and improves survival [12] in rodents post-myocardial infarction (MI). However, whether XOI affects primarily myocardial function, vascular tone, or both remains unknown [5], [6], [8], [9], [10]. Accordingly, we examined the impact of chronic administration of allopurinol, a known XOI, in dogs with pacing-induced heart failure (HF), testing the hypothesis that its hemodynamic effects cause long term restoration of normal ventricular–vascular coupling in the failing circulation. Here we show that chronic XOI profoundly ameliorates both vascular and myocardial changes characteristic of the failing cardiovascular system independent of cardiac remodeling.
Section snippets
Animal model
All animal studies were approved by our Institutional Animal Care and Use Committee and comply with the “Guide for the Care and Use of Laboratory Animals” (NIH Publication no. 80–23, revised 1985). Dilated cardiomyopathy was induced in seventeen adult mongrel dogs (25–30 kg) by chronic rapid ventricular pacing at a rate of 210 bpm for 3 weeks, followed by 240 bpm for a fourth week, as previously described [13]. The detailed surgical instrumentation used for this protocol has been described
Results
Table 1 summarizes hemodynamic variables before and after HF induction in both groups. As previously shown for this model [6], [10], rapid pacing leads to characteristic cardiac enlargement increased preload filling pressures (Table 1) and afterload (Ea, Table 1 and Fig. 1), as well as reduced myocardial contractility, as evidenced by reductions in both ejection phase (peak + dP/dt) and end-systolic indices of contraction (Ees) (Table 1 and Fig. 2). Together, this resulted in a 57.6 ± 9%
Discussion
Among sources of oxidative stress (OS) in HF, XO is established to play important roles in both heart and vasculature. The major new finding of this study is that XOI with allopurinol completely prevents increases in systemic vasoconstriction and ameliorates reductions in myocardial contractility in dogs with pacing induced heart failure. Together these effects maintain normal ventricular–vascular coupling in the failing circulation. We also show that XO in total heart extracts is upregulated
Acknowledgments
Dr. Hare is a paid consultant at Cardiome Pharma Corporation. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.
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This work was funded by NIH RO1 HL-06455 and a Paul Beeson Physician Faculty Scholars in Aging Research Award.