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

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.

• Authors: 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 M Hare
• Journal: Journal of molecular and cellular cardiology (J Mol Cell Cardiol) Vol. 39 Issue 3 Pg. 531-6 (Sep 2005) ISSN: 0022-2828 [Print] England
• PMID: 15963530 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• RNA, Messenger
• Allopurinol
• Xanthine Oxidase

Topics

• Allopurinol (pharmacology)
• Animals
• Cardiac Pacing, Artificial (adverse effects)
• Cardiovascular System (physiopathology)
• Dogs
• Enzyme Inhibitors (pharmacology)
• Gene Expression Regulation (drug effects)
• Heart Failure (drug therapy, etiology, physiopathology)
• Hemodynamics (drug effects)
• Oxidative Stress (drug effects)
• RNA, Messenger (metabolism)
• Random Allocation
• Up-Regulation (drug effects)
• Ventricular Function, Left (drug effects)
• Xanthine Oxidase (antagonists & inhibitors)