Abstract 16997: Kv 1.5 Channels Play A Critical Role in Coronary Metabolic Dilation
Previously we found that coronary metabolic dilation (CMD), the matching of flow to cardiac metabolism or work, was compromised by 4-amino-pyridine, indicating a role for voltage- gated potassium (Kv) channels. Complicating the identification of a specific Kv channel involved in CMD is the existence of 12 Kv channel families, each with multiple members. Based on observations that regulation of Kv1.5 channels is redox-dependent and that CMD is mediated, in part, via redox signaling, we hypothesized that the Kv1.5 channel is partially responsible for CMD. To test this hypothesis, we studied mice null for Kv1.5 channels (Kv1.5−/−, n=10) and wild type (WT, n=10) in which cardiac work (CW: stroke volume × heart rate (HR) × mean arterial pressure [MAP]) was altered by i.v. infusion of norepinephrine (NE) during sevoflurane anesthesia and hexamethonium (to eliminate reflex neural adjustments). Myocardial blood flow (MBF) was measured by contrast echocardiography (ml/min per g) during changes in CW. MAP and HR were measured using a Millar transducer in the aorta, and stroke volume was measured via transthoracic echocardiography. In WT animals, NE at 2.5 and 5 ug/kg/min increased CW over baseline by 117% ± 9 and 160% ± 12, respectively, during which MBF increased 370% ± 19 and 490% ± 32, respectively. In Kv1.5−/−, CW increased 121% ± 8 and 153% ± 9 during the two doses of NE, respectively (NS vs WT), but the increase in MBF was greatly attenuated, 58% ± 10 and 96% ± 9, respectively (P<0.05 vs WT). These results of the relationship between MBF and CW are shown in the figure below, detailing the reduction in flow per unit work in Kv1.5−/−. To show that other Kv1 family channels are not up-regulated as a compensation in the Kv1.5−/−, we administered correolide (Kv1 family channel antagonist, 0.8mg/kg, i.v) and found that the flow responses in the null mice were not affected, suggesting that other Kv were not up-regulated. We conclude that Kv1.5 channels play a critical role in coupling MBF to cardiac work.
- © 2010 by American Heart Association, Inc.