Unveiling the Mechanism of Coronary Metabolic Vasodilation

Most organs are able to modulate both blood flow and oxygen extraction to meet oxygen demand during increases in metabolism. However, the heart extracts oxygen near maximally (60%–80%) at rest and, therefore, relies almost exclusively on changes in perfusion to meet this demand.1 This requires moment-to-moment changes in arteriolar (resistance artery) tone to match changes in oxygen demand with flow. It is generally thought that a metabolic dilator substance released from the myocardium serves as the signal for vasodilation. However, despite several decades of investigation, the chemical mediator of cardiac metabolic dilation remains elusive. Recently, Chilian laboratory has proposed hydrogen peroxide (H2O2) as the link between cardiac metabolism and coronary dilation.2 Although H2O2 had been studied extensively as an endothelium-derived vasodilator, its role in metabolic dilation had not been well-defined. H2O2 has several characteristics that support a role in metabolic dilation. It is a product of cardiac metabolism, is produced in large quantities proportional to mitochondrial respiration, is cell membrane permeable, and has a sufficiently long half-life to serve as an intercellular signaling molecule. H2O2 elicits a dose-dependent dilation in coronary arterioles.3Article, see p 612 On the basis of these characteristics, H2O2 has been studied as a mediator of metabolic dilation. Chilian laboratory used a bioassay where effluent from freshly isolated cardiomyocytes was dripped onto rat coronary arterioles. The resulting dilation was shown to be catalase-sensitive and related to the metabolic rate of the cultured myocytes.2 A variation of that preparation was used by Shimokawa laboratory, where pressurized coronary arterioles from a rabbit were placed on a canine beating heart.4 Pacing the dog heart induced a …