Beneficial effects of acute inhibition of the oxidative pentose phosphate pathway in the failing heart.

Abstract

In vitro studies suggested that glucose metabolism through the oxidative pentose phosphate pathway (oxPPP) can paradoxically feed superoxide-generating enzymes in failing hearts. We therefore tested the hypothesis that acute inhibition of the oxPPP reduces oxidative stress and enhances function and metabolism of the failing heart, in vivo. In 10 chronically instrumented dogs, congestive heart failure (HF) was induced by high-frequency cardiac pacing. Myocardial glucose consumption was enhanced by raising arterial glycemia to levels mimicking postprandial peaks, before and after intravenous administration of the oxPPP inhibitor 6-aminonicotinamide (80 mg/kg). Myocardial energy substrate metabolism was measured with radiolabeled glucose and oleic acid, and cardiac 8-isoprostane output was used as an index of oxidative stress. A group of five chronically instrumented, normal dogs served as control. In HF, raising glycemic levels from ∼ 80 to ∼ 170 mg/dL increased cardiac isoprostane output by approximately twofold, whereas oxPPP inhibition normalized oxidative stress and enhanced cardiac oxygen consumption, glucose oxidation, and stroke work. In normal hearts glucose infusion did not induce significant changes in cardiac oxidative stress. Myocardial tissue concentration of 6P-gluconate, an intermediate metabolite of the oxPPP, was significantly reduced by ∼ 50% in treated versus nontreated failing hearts, supporting the inhibitory effect of 6-aminonicotinamide. Our study indicates an important contribution of the oxPPP activity to cardiac oxidative stress in HF, which is particularly pronounced during common physiological changes such as postprandial glycemic peaks.

• Authors: Claudio Vimercati, Khaled Qanud, Gianfranco Mitacchione, Danuta Sosnowska, Zoltan Ungvari, Roberto Sarnari, Daniella Mania, Neel Patel, Thomas H Hintze, Sachin A Gupte, William C Stanley, Fabio A Recchia
• Journal: American journal of physiology. Heart and circulatory physiology (Am J Physiol Heart Circ Physiol) Vol. 306 Issue 5 Pg. H709-17 (Mar 01 2014) ISSN: 1522-1539 [Electronic] United States
• PMID: 24414069 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Blood Glucose
• Cardiotonic Agents
• Gluconates
• Superoxides
• 8-epi-prostaglandin F2alpha
• 6-Aminonicotinamide
• Dinoprost
• 6-phosphogluconic acid

Topics

• 6-Aminonicotinamide (pharmacology)
• Animals
• Blood Glucose (metabolism)
• Cardiotonic Agents (pharmacology)
• Dinoprost (analogs & derivatives, metabolism)
• Disease Models, Animal
• Dogs
• Gluconates (metabolism)
• Glycolysis (drug effects)
• Heart Failure (drug therapy, metabolism, physiopathology)
• Male
• Myocardium (metabolism)
• Oxidation-Reduction
• Oxidative Stress (drug effects)
• Oxygen Consumption (drug effects)
• Pentose Phosphate Pathway (drug effects)
• Recovery of Function
• Stroke Volume (drug effects)
• Superoxides (metabolism)
• Time Factors
• Ventricular Function, Left (drug effects)
• Ventricular Pressure (drug effects)