Abstract 18100: Vascular Smooth Muscle Kv1.5 Channels Contribute to Coronary Metabolic Dilation
Many mechanisms are known to contribute to the regulation of coronary blood flow, including redox sensing voltage-gated potassium (Kv) channels. Previously we found, that one member of the Kv family, Kv1.5 channels, play a critical role in coupling myocardial blood flow to cardiac work. Specifically mice with global knockout of Kv1.5 channels (Kv1.5 -/-) have blunted metabolic dilation; however a limitation of this observation is that Kv1.5 channels are expressed in many cell types, e.g., cardiac myocytes, neurons, in addition to vascular smooth muscle (VSMC) so we cannot decisively conclude a role for VSMC Kv1.5 channels in this process. Accordingly, we hypothesized that expression of Kv 1.5 channels in VSMC in Kv1.5 -/- rescues the impaired metabolic dilatation. We created double transgenic mice (Tg) with doxycycline (Dox) inducible Kv1.5 channel expression in VSMC (SM22 promoter). To stimulate expression of Kv1.5 channels, mice were given Dox for 7 days. Myocardial blood flow (MBF) and hemodynamic measurements were done at baseline and during norepinephrine (NE) infusion (0.5-5 μg/kg/min, iv) to increase metabolic demand as defined by the pressure-rate product (PRP: mean arterial pressure x heart rate) in 4 groups: Wild type (WT), Double transgenic in WT (WT Tg), Kv1.5-/-, and the double transgenic in Kv1.5-/- (Kv1.5-/- Tg). The figure shows the relationship between MBF and PRP in the 4 groups. When Kv 1.5 channels were over-expressed (5-7 fold) in Wt-Tg animals the relationship was shifted to the left showing that for every level of cardiac work, myocardial blood flow was highest (vs other groups, P<0.05). In contrast, Kv1.5-/- had a hampered relationship between flow and PRP; MBF was low for the workloads (vs other groups, P<0.05). Importantly, expression of Kv1.5 channels in VSMC of the Kv1.5-/- Tg rescued the relationship between MBF and PRP to levels comparable to WT. In conclusion, expression of Kv 1.5 channels in VSMC is critical for coronary metabolic dilation.
Author Disclosures: R. Bardakjian: None. M. Enrick: None. K. Stevanov: None. C.L. Kolz: None. S. Logan: None. L. Yin: None. W.M. Chilian: None.
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.