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

Abstract

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 as 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. We measured myocardial blood flow (contrast echocardiography) during norepinephrine-induced increases in cardiac work (heart rate x mean arterial pressure) in 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. 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 H₂ O₂ 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 H₂ O₂ -dependent dilation in vessels from Kv1.3^-/- mice. We conclude that Kv1.3 channels participate in the connection between myocardial blood flow and cardiac metabolism.

Keywords: Kv 1.3 channels; contrast echocardiography; coronary blood flow; coronary microcirculation.

Figure 1

Left: Hemodynamics (heart rate, mean arterial pressure) in WT (n=14) and Kv.1.3^−/− (n=15) mice under basal conditions, during hexamethonium, and during norepinephrine infusion (with hexamethonium). Right: Hemodynamics of WT mice following correolide administration (Corr80 [80 ng/kg, n=6] and Corr800 [800 ng/kg, n=8]) before and during norepinephrine.

Figure 2

Relaxation of isolated small coronary arteries and arterioles to acetylcholine, adenosine, and hydrogen peroxide (H₂O₂) from wild type (WT) and Kv1.3^−/− (KO) mice. Relaxation was assessed under control conditions (without correolide) and after addition of correolide in the WT and KO mice.

Figure 3

Relationship between Pressure-Rate Product (PRP, mean arterial pressure X heart rate) and myocardial blood flow (MBF). MBF and DP were measured under basal conditions, hexamethonium and norepinephrine (0.5–5.0 µg/kg/min iv; in the presence of hexamethonium). In Kv 1.3^−/− mice (n=15) MBF was significantly lower compared to WT mice (n=14) at any level of the PRP.

Figure 4

Percent increases in myocardial blood flow during norepinephrine infusion in WT, correolide-treated WT (Corr80 [80 ng/g]; Corr800 [800 ng/g]) or Kv1.3^−/− groups. Note the increases in blood flow were less (compared to WT) in both Corr and Kv1.3^−/− groups. Corr800 suppressed the increase in flow more than Corr 80 and Kv1.3^−/−.