TY - JOUR
T1 - Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation
AU - Ohanyan, Vahagn
AU - Yin, Liya
AU - Bardakjian, Raffi
AU - Kolz, Christopher
AU - Enrick, Molly
AU - Hakobyan, Tatevik
AU - Kmetz, John
AU - Bratz, Ian
AU - Luli, Jordan
AU - Nagane, Masaki
AU - Khan, Nadeem
AU - Hou, Huagang
AU - Kuppusamy, Periannan
AU - Graham, Jacqueline
AU - Fu, Frances Kwan
AU - Janota, Danielle
AU - Oyewumi, Moses O.
AU - Logan, Suzanna
AU - Lindner, Jonathan R.
AU - Chilian, William M.
N1 - Publisher Copyright:
© 2015 American Heart Association, Inc.
PY - 2015/9/11
Y1 - 2015/9/11
N2 - Rationale: In the working heart, coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels (Kv), which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox-sensitive. Objective: To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. Methods and Results: In mice (wild-type [WT], Kv1.5 null [Kv1.5-/-], and Kv1.5-/- and WT with inducible, smooth muscle-specific expression of Kv1.5 channels), we measured mean arterial pressure, myocardial blood flow, myocardial tissue oxygen tension, and ejection fraction before and after inducing cardiac stress with norepinephrine. Cardiac work was estimated as the product of mean arterial pressure and heart rate. Isolated arteries were studied to establish whether genetic alterations modified vascular reactivity. Despite higher levels of cardiac work in the Kv1.5-/- mice (versus WT mice at baseline and all doses of norepinephrine), myocardial blood flow was lower in Kv1.5-/- mice than in WT mice. At high levels of cardiac work, tissue oxygen tension dropped significantly along with ejection fraction. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5-/- mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared with those from WT mice. Conclusions: Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow, resulting in cardiac pump dysfunction and tissue hypoxia.
AB - Rationale: In the working heart, coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels (Kv), which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox-sensitive. Objective: To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. Methods and Results: In mice (wild-type [WT], Kv1.5 null [Kv1.5-/-], and Kv1.5-/- and WT with inducible, smooth muscle-specific expression of Kv1.5 channels), we measured mean arterial pressure, myocardial blood flow, myocardial tissue oxygen tension, and ejection fraction before and after inducing cardiac stress with norepinephrine. Cardiac work was estimated as the product of mean arterial pressure and heart rate. Isolated arteries were studied to establish whether genetic alterations modified vascular reactivity. Despite higher levels of cardiac work in the Kv1.5-/- mice (versus WT mice at baseline and all doses of norepinephrine), myocardial blood flow was lower in Kv1.5-/- mice than in WT mice. At high levels of cardiac work, tissue oxygen tension dropped significantly along with ejection fraction. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5-/- mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared with those from WT mice. Conclusions: Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow, resulting in cardiac pump dysfunction and tissue hypoxia.
KW - cardiac function
KW - contrast echocardiography
KW - hydrogen peroxide
KW - ion channel
KW - transgenic mice
KW - vasodilation
KW - voltage-gated potassium channels
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U2 - 10.1161/CIRCRESAHA.115.306642
DO - 10.1161/CIRCRESAHA.115.306642
M3 - Article
C2 - 26224794
AN - SCOPUS:84941283159
SN - 0009-7330
VL - 117
SP - 612
EP - 621
JO - Circulation research
JF - Circulation research
IS - 7
ER -