The Role of Kv1.2 Channels in Coronary Metabolic Dilation

Abstract

The coupling between metabolism and flow in the heart is critical for normal cardiac function, because the myocardium depends on a continuous supply of oxygenated blood for aerobic metabolism and energy production. If this coupling is altered, the imbalance could lead coronary insufficiency causing areas of hypoxia and ischemia in the heart. Recently we proposed that one component of this coupling is mediated by mitochondrial production of hydrogen peroxide (H2O2), which activates Kv1.5 channels in coronary smooth muscle. Our present goal was to ascertain if Kv1.2 channels, that are known to be redox sensitive, serve as a metabolic sensor in the heart to engender coupling of flow to metabolism. To accomplish this goal, we used Kv1.2+/− mice (Kv1.2−/− is lethal) to evaluate coronary metabolic dilation, i.e., the relationship between myocardial blood flow and cardiac work. Myocardial blood flow was measured using contrast echocardiography. Graded doses of norepinephrine (NE) were used to increase cardiac work (CW) and myocardial blood flow was measured during these incremental changes in work. Cardiac work was calculated as a triple product of mean arterial pressure × heart rate × stroke volume. We also isolated coronary arterioles and tested their vasodilatory responses to endothelium-dependent and –independent agonists. As shown in panel A, vasodilation to hydrogen peroxide was significantly lower in arterioles isolated from Kv1.2+/− mice compared to wild-type mice (WT). Vasodilation was lower at any given concentration of H2O2. Although not shown, the responses between the two groups were similar for acetylcholine and sodium nitroprusside. Panel B shows the relationship between myocardial blood flow and cardiac work. In Kv1.2+/− mice myocardial blood flow at baseline was similar to WT mice. However, when CW was increased via NE infusion, for any incremental increase in work, myocardial blood flow was less in Kv1.2+/− compared to WT mice (P<0.05). For example, at the highest dose of NE, myocardial blood flow in the Kv1.2+/− and WT were 23±3 vs 34±2 ml/min/g, respectively (P<0.05). Taken together, our results indicate that Kv1.2 channels, a redox sensitive channel in the Kv1 family, are involved in the coupling of myocardial blood flow to cardiac work. Support or Funding Information AHA10POST4360030; R01 HL135024; RO1HL135110 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.