Hydrogen Peroxide Derived From Beating Heart Mediates Coronary Microvascular Dilation During Tachycardia

Abstract

Objective-Coronary flow is closely correlated to the myocardial metabolic demand. We tested the hypothesis that hydrogen peroxide (H 2 O 2 ) derived from beating hearts mediates metabolic coronary microvascular dilation. Methods and Results-We used a bioassay method in which an isolated microvessel is placed on a beating heart to detect myocardium-derived vasoactive mediators. A rabbit coronary arterial microvessel (detector vessel [DV], nϭ25) was pressurized and placed on a canine beating heart. After intrinsic tone of DV had developed, we observed DV at rest (heart rate, 120 bpm) and during tachypacing (heart rate, 240 bpm) using an intravital microscope equipped with a floating objective. The tachypacing produced DV dilation by 8.2% (PϽ0.01 versus baseline), and the dilation was abolished by cell-impermeable catalase (a H 2 O 2 scavenger, 500 U/mL). We performed myocardial biopsy at rest and tachypacing. The biopsy specimens were loaded with 2Ј,7Ј-dichlorodihydrofluorescein diacetate (10 mol/L) to visualize H 2 O 2, and observed with confocal microscopy. Dichlorofluorescein fluorescence was diffusely identified in the myocardium and the tachypacing increased the fluorescence intensity (PϽ0.01). Exogenous H 2 O 2 caused vasodilation of arterial microvessels in vitro in a concentration-dependent manner that was abolished by catalase. Conclusions-H 2 O 2 derived from the beating heart mediates tachypacing-induced metabolic coronary vasodilation in vivo.(Arterioscler Thromb Vasc Biol. 2007;27:1057-1063.)Key Words: coronary circulation Ⅲ myocardium Ⅲ reactive oxygen species Ⅲ tachycardia Ⅲ vasodilation C oronary blood flow is linearly correlated to the myocardial oxygen consumption. 1,2 The tight coupling between the cardiac metabolism and the flow conductance underlies the widely accepted assumption that the myocardium-derived vasoactive factor, so-called metabolic factor, rapidly regulates the vascular tone of coronary microvessels for matching the coronary flow to the cardiac metabolic state. However, the metabolic factor that is transmitted from the myocardium to the coronary microvessels has not been identified yet. Although there are many candidates for the mediators such as adenosine, prostanoids, autacoids, nitric oxide (NO), factors activating potassium channels, and so on, no substance solely explains the metabolic microvascular dilation. 3,4 Although excessive reactive oxygen species (ROS) are produced in various pathological conditions such as ischemia/reperfusion and cardiac failure 5,6 and are often hazardous for living organisms, increasing evidence has shown that ROS also play important roles as biological signals that mediate physiological phenomena at low concentrations. 7,8 In the field of vascular biology, hydrogen peroxide (H 2 O 2 ) has been known as one of the possible endothelium-derived hyperpolarizing factors. 9 The cardiac myocyte is another major source of ROS. 5,10 Superoxide (O 2 Ϫ ⅐ ) and H 2 O 2 are produced as byproducts of electron transfer reactions during normal aerobic meta...

Unveiling the Mechanism of Coronary Metabolic Vasodilation

“…Pacing the dog heart induced a catalase-inhibitable dilation in the overlying rabbit arteriole, suggesting a role for H 2 O 2 in metabolic dilation. Similar support for a role for H 2 O 2 was observed in an in vivo dog model, where pacing-induced epicardial coronary arteriolar dilation was observed during increases in metabolism 4, 5 .…”

“…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 employed by Shimokawa’s laboratory, where pressurized coronary arterioles from a rabbit were placed on a canine beating heart 4 . Pacing the dog heart induced a catalase-inhibitable dilation in the overlying rabbit arteriole, suggesting a role for H 2 O 2 in metabolic dilation.…”

Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation

“…One potential, but untested, mediator of reactive hyperemia is H 2 O 2 , which we previously demonstrated (43,44,47) mediates coronary metabolic vasodilation via K V channels. The role of H 2 O 2 in metabolic vasodilation has recently been confirmed by others (32,55), but the hypothesis that H 2 O 2 functions in reactive hyperemia remains to be addressed in future studies.…”

Formation of Hydrogen Peroxide and Reduction of Peroxynitrite via Dismutation of Superoxide at Reperfusion Enhances Myocardial Blood Flow and Oxygen Consumption in Postischemic Mouse Heart

“…This means that the burst formation of superoxide after reperfusion (Zweier, 1988) is dismutated to hydrogen peroxide selectively by SOD m . It has also been reported that hydrogen peroxide can dilate vasculature in the heart and cause an increase of tissue blood perfusion (Burgoyne et al, 2007; Kokusho et al, 2007; Yada et al, 2008). To test whether hydrogen peroxide contributes to this transient peak of tissue Po 2 after the treatment of SOD m , we performed EPR oximetry on the wild-type mice treated with EUK134, which is a superoxide dismutase mimetic with catalase activity (Izumi et al, 2002).…”