The effect of switching the mediator of coronary endothelial dilation on coronary blood flow in metabolic syndrome

Abstract

Diabetes mellitus is a leading risk factor for cardiovascular disease. One consequence of diabetes is microvascular dysfunction, which is speculated as an initial step in diabetic cardiomyopathy. However, the mechanisms of impaired coronary microvascular function in diabetes remain incompletely understood. NO is the major endothelial vasodilatory metabolite in the coronary circulation, but endothelium‐dependent dilation (E‐DD) in patients with coronary artery diseases switches from NO to H2O2. In a murine model of diabetes, we found a similar switch. Specifically in isolated coronary arterioles from wild type (WT) mice, E‐DD to acetylcholine (Ach) was reduced by L‐NAME, but this NOS antagonist did not affect Ach dilation in diabetic mice. However, in diabetic mice Peg‐catalase inhibited Ach ED‐D coronary dilation, but this scavenger of H2O2 did not affect dilation in WT mice. These results suggest that under normal conditions, endothelium‐dependent dilation is mediated by NO, but in diabetes, the mediator is H2O2. These results were observed in vitro and whether there is a functional consequence of this switch, in terms of flow regulation in vivo, is unknown. To understand this, WT, db/db mice and diet‐induced diabetic mice were anesthetized and the tail vein was catheterized for drug administration. Myocardial blood flow (MBF) was measured by contrast echocardiography and hemodynamics (blood pressure, heart rate) were measured via a pressure transducer. Our data show: 1) In db/db mice, MBF was significantly lower than MBF in WT mice during metabolic hyperemia produced by i.v. norepinephrine. MBF in diet‐induced diabetic mice was slightly lower compared to wild type. 2) L‐NAME attenuated the norepinephrine‐induced hyperemia in WT mice, but not in db/db mice. 3), Ebselen (a H2O2 scavenger) reduced the MBF in diabetic mice. These results suggest that NO to H2O2 switch in coronary endothelial dilation ex vivo also occurs in vivo and this switch can compromise blood flow regulation. Further study of the underlying mechanism may lead to the treatment to of diabetic cardiomyopathy—a condition with not accepted standard of care.