Kv1.3 channels facilitate the connection between metabolism and blood flow in the heart

Abstract

Objective The connection between metabolism and flow in the heart, metabolic dilation, is essential for cardiac function. We recently found redox-sensitive Kv1.5 channels play a role in coronary metabolic dilation; however, more than one ion channel likely plays a role in this process since animals null for these channels still showed limited coronary metabolic dilation. Accordingly, we examined the role of another Kv1 family channel, the energetically-linked Kv1.3 channel, in coronary metabolic dilation. Methods We measured myocardial blood flow (contrast echocardiography) during norepinephrine-induced increases in cardiac work (heart rate × mean arterial pressure) in wild type mice (WT), WT mice given correolide (preferential Kv1.3 antagonist), and Kv1.3 null mice (Kv1.3−/−). We also measured relaxation of isolated small arteries mounted in a myograph. Results During increased cardiac work, myocardial blood flow was attenuated in Kv1.3−/− and in correolide-treated mice. In isolated vessels from Kv1.3−/− mice, relaxation to H2O2 was impaired (vs WT), but responses to adenosine and acetylcholine were equivalent to WT. Correolide reduced dilation to adenosine and acetylcholine in WT and Kv1.3−/−, but had no effect on H2O2-dependent dilation in vessels from Kv1.3−/− mice. Conclusion Kv1.3 channels participate in the connection between myocardial blood flow and cardiac metabolism.

Myocardial Ischemia and Diabetes Mellitus: Role of Oxidative Stress in the Connection between Cardiac Metabolism and Coronary Blood Flow

“…The effect of metabolic regulation is mediated by several molecules produced by cardiomyocytes whose targets are represented by specific receptors and ion channels. Among these molecules, there are carbon dioxide (CO2), adenosine, oxygen, H2O2, superoxide, and other reactive oxygen species [90, 95–97] (Figure 4).…”

“…Vasodilating molecules open Kv via the cAMP-dependent pathway while vasoconstrictor ones close Kv, increasing Ca 2+ cell levels [8, 99]. Several channels of the Kv family, such as Kv1.5 and Kv1.3, are involved in H2O2-mediated CBF regulation [95, 100]. KCa channels are expressed by both endothelial and smooth muscle cells, and they have a crucial role in preserving the rest membrane potential [7, 8].…”

“…For this reason, it may be other ion channels involved in the oxygen and redox-sensitive coronary blood flow regulation [100, 113, 114]. For this reason, Ohanyan et al focused on Kv1.3 channels and they demonstrated that these channels have a crucial role in the connection between cardiac metabolism and coronary blood flow [95]. Kv1.3 channels participate in H2O2-induced vasodilatation, but they did not involve in that one induced by adenosine and acetylcholine [95].…”

“…For this reason, Ohanyan et al focused on Kv1.3 channels and they demonstrated that these channels have a crucial role in the connection between cardiac metabolism and coronary blood flow [95]. Kv1.3 channels participate in H2O2-induced vasodilatation, but they did not involve in that one induced by adenosine and acetylcholine [95]. Indeed, Kv1.3 −/− mice showed an impaired blood flow regulation in response to cardiac work increase [95].…”

KV channels and the regulation of vascular smooth muscle tone

“…These data support a major role for VSMC K V 1.5 in matching blood flow to metabolism in mouse hearts. A role for K V 1.3 in coronary functional hyperemia in the mouse also has been proposed . However, because a global K V 1.3 knockout was used, the location of the K V 1.3 in the signaling pathway that couples cardiac metabolism to blood flow was not established.…”