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

Luciano C. Amado, Anastasios P. Saliaris, Shubha V Y Raju, Stephanie Lehrke, Marcus St. John, Jinsheng Xie, Garrick Stewart, Torin Fitton, Khalid M. Minhas, Jeff Brawn, Joshua Hare

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)531-536
Number of pages6
JournalJournal of Molecular and Cellular Cardiology
Volume39
Issue number3
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

Fingerprint

Xanthine Oxidase
Heart Failure
Dogs
Allopurinol
Blood Vessels
Placebos
Ventricular Pressure
Oxidative Stress
Hemodynamics
Blood Pressure
Messenger RNA
Proteins

Keywords

  • Afterload
  • Heart failure
  • Myocardial contractility
  • Oxidative stress
  • Remodeling
  • Ventricular-vascular coupling

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure. / Amado, Luciano C.; Saliaris, Anastasios P.; Raju, Shubha V Y; Lehrke, Stephanie; St. John, Marcus; Xie, Jinsheng; Stewart, Garrick; Fitton, Torin; Minhas, Khalid M.; Brawn, Jeff; Hare, Joshua.

In: Journal of Molecular and Cellular Cardiology, Vol. 39, No. 3, 01.09.2005, p. 531-536.

Research output: Contribution to journalArticle

Amado, LC, Saliaris, AP, Raju, SVY, Lehrke, S, St. John, M, Xie, J, Stewart, G, Fitton, T, Minhas, KM, Brawn, J & Hare, J 2005, 'Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure', Journal of Molecular and Cellular Cardiology, vol. 39, no. 3, pp. 531-536. https://doi.org/10.1016/j.yjmcc.2005.04.008
Amado, Luciano C. ; Saliaris, Anastasios P. ; Raju, Shubha V Y ; Lehrke, Stephanie ; St. John, Marcus ; Xie, Jinsheng ; Stewart, Garrick ; Fitton, Torin ; Minhas, Khalid M. ; Brawn, Jeff ; Hare, Joshua. / Xanthine oxidase inhibition ameliorates cardiovascular dysfunction in dogs with pacing-induced heart failure. In: Journal of Molecular and Cellular Cardiology. 2005 ; Vol. 39, No. 3. pp. 531-536.
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AU - Saliaris, Anastasios P.

AU - Raju, Shubha V Y

AU - Lehrke, Stephanie

AU - St. John, Marcus

AU - Xie, Jinsheng

AU - Stewart, Garrick

AU - Fitton, Torin

AU - Minhas, Khalid M.

AU - Brawn, Jeff

AU - Hare, Joshua

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N2 - 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.

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