Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure

doi:10.1016/j.yjmcc.2005.04.008

Journal of Molecular and Cellular Cardiology

Volume 39, Issue 3, September 2005, Pages 531-536

https://doi.org/10.1016/j.yjmcc.2005.04.008 Get rights and content

Abstract

We hypothesized that chronic xanthine oxidase inhibition (XOI) would have favorable effects on both ventricular and vascular performance in evolving heart failure (HF), thereby preserving ventricular–vascular coupling. In HF, XOI reduces oxidative stress and improves both vascular and myocardial function. Dogs were randomized to receive either allopurinol (100 mg/day p.o.) or placebo following surgical instrumentation for chronic measurement of left-ventricular pressure and dimension and during induction of HF by rapid pacing. In the placebo group (n = 8), HF was characterized by increased LV end-diastolic pressure (LVEDP, 10.2 ± 5.5 and 29.8 ± 3.9 mmHg, before and after HF, respectively, P < 0.05), end-diastolic dimension (LVEDD, from 29.5 ± 3.2 to 34.3 ± 3.2 mm, P < 0.001), and afterload (arterial elastance, Ea, from 17.9 ± 1.2 to 42.6 ± 7.9 mmHg/mm, P < 0.05), and reduced contractility (End-systolic ventricular elastance, Ees, from 10.8 ± 1.3 to 5.6 ± 2.3 mmHg/mm, P < 0.05). Thus, ventricular–vascular coupling (Ees/Ea ratio) fell 57.6 ± 9% (0.61 ± 0.1 to 0.16 ± 0.1, P < 0.05). Allopurinol (n = 9) profoundly attenuated both the Ea increase (from 22.3 ± 3 to 25.6 ± 4.6 mmHg/mm, P = NS) and the fall in Ees (from 11.8 ± 1.1 to 11.7 ± 1, P = NS), thereby preserving the Ees/Ea ratio (from 0.58 ± 0.1 to 0.56 ± 0.1, P < 0.001 vs. placebo). Allopurinol did not affect the increase in preload (LVEDP and LVEDD). XO cardiac mRNA and protein were similarly upregulated approximately fourfold in both groups. Allopurinol ameliorates increases in afterload and reductions in myocardial contractility during evolving HF, thereby preserving ventricular–vascular coupling. These results demonstrate a unique and potent hemodynamic profile of XOI, thereby providing further rationale for developing XOIs as a novel HF therapy.

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.

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Original articleXanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure✰

Abstract

Introduction

Section snippets

Animal model

Results

Discussion

Acknowledgments

J. Card. Fail.

J. Mol. Cell. Cardiol.

Am. Heart J.

Allopurinol improves endothelial dysfunction in chronic heart failure

Circ.

Effects of xanthine oxidase inhibition with allopurinol on endothelial function and peripheral blood flow in hyperuricemic patients with chronic heart failure: results from 2 placebo-controlled studies

Circ.

Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure

Circ.

Novel myofilament Ca2+-sensitizing property of xanthine oxidase inhibitors

Circ. Res.

Vascular oxidative stress and endothelial dysfunction in patients with chronic heart failure: role of xanthine–oxidase and extracellular superoxide dismutase

Circ.

Imbalance between xanthine oxidase and nitric oxide synthase signaling pathways underlies mechanoenergetic uncoupling in the failing heart

Circ. Res.

Role of xanthine oxidoreductase and NAD(P)H oxidase in endothelial superoxide production in response to oscillatory shear stress

Am. J. Physiol. Heart Circ. Physiol.

Oxygen radical inhibition of nitric oxide-dependent vascular function in sickle cell disease

Proc. Natl. Acad. Sci. USA

Allopurinol improves myocardial efficiency in patients with idiopathic dilated cardiomyopathy

Cir.

Intravenous allopurinol decreases myocardial oxygen consumption and increases mechanical efficiency in dogs with pacing-induced heart failure

Circ. Res.

Allopurinol attenuates left ventricular remodeling and dysfunction after experimental myocardial infarction: a new action for an old drug?

Circ.

Chronic treatment with allopurinol boosts survival and cardiac contractility in murine postischemic cardiomyopathy

Circ. Res.

Relative contribution of preload and afterload to the reduction in cardiac output caused by nitric oxide synthase inhibition with l-N(G)-methylarginine hydrochloride 546C88

Crit. Care Med.

The physiological response to cardiovascular 'orphan' G protein-coupled receptor agonists

Nat. Med.

Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure: roles of oxidative stress and inflammation

Circ.

Original article
Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure✰

Novel myofilament Ca²⁺-sensitizing property of xanthine oxidase inhibitors