Abstract 5255: Kv1.3 Channels Play a Role in Coronary Metabolic Dilation

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. Recently we proposed that one component of this coupling is mediated by mitochondrial production of H2O2, which produces dilation through redox-dependent activation of 4-aminopyridine (4-AP) sensitive ion channels. 4-AP is thought to preferentially block the Kv1 family of ion channels, but its antagonistic effects also extend to other families of Kv channels, e.g., Kv4. Our goal was to ascertain if a particular Kv1 channel, Kv1.3, that is known to be redox sensitive, serves as a metabolic sensor in the heart to engender coupling of metabolism to flow. To accomplish this goal we implemented a murine model (C57/B6, n =10) of coronary metabolic dilation (during anesthesia) in which cardiac work (CW: product of stroke volume × heart rate × mean arterial pressure) was altered by i.v. infusion of norepinephrine (NE). Coronary blood flow (contrast echocardiography, units of ml/min per g) was simultaneously measured during the changes in CW. Arterial pressure and heart rate were measured using a Millar transducer in the abdominal aorta, and stroke volume was measured via echocardiography. NE at 2.5 and 5 ug/kg/min increased CW over baseline by 130% and 221%, respectively. Under these conditions coronary flow increased from a baseline of 2.3±0.9 to 5.2±1.5 (NE2.5) and to 7.4±1.8 (NE5) (both P<0.05 vs baseline [mean± SD]). To ascertain the role of Kv1.3 channels, we used the potent Kv1.3 channel antagonist correolide (C: 0.8 mg/kg, i.v.). Whereas correolide did not affect basal flow, the Kv1.3 antagonist blunted metabolic dilation during NE infusion: 4.3±0.9 (C+NE2.5) and 5.2±1.2 (C+NE5: P<0.05 vs NE5). At the highest dose of NE the % increase in flow under control conditions (229%) was greatly attenuated by correolide (132%). Since cardiac myocytes are not reported to express Kv1.3 channels, we do not believe the results are related to an effect of correolide on cardiac myocytes. Rather, we conclude that Kv1.3 channels play a role in coupling coronary flow to cardiac work and that mice have the ability to more than double coronary flow under high levels of cardiac work.