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URL Address
<a href="http://doi.org/10.1152/ajpheart.00011.2012" target="_blank" rel="noreferrer noopener">http://doi.org/10.1152/ajpheart.00011.2012</a>
Pages
H216–223
Issue
2
Volume
303
Dublin Core
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Title
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Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels.
Publisher
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American journal of physiology. Heart and circulatory physiology
Date
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2012
2012-07
Subject
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13-dienoic Acid/pharmacology; 15-Hydroxy-11 alpha; 9 alpha-(epoxymethano)prosta-5; Anilides/pharmacology; Animals; Capsaicin/analogs & derivatives/pharmacology; Cinnamates/pharmacology; Coronary Vessels/drug effects/*metabolism/physiopathology; Diabetes Mellitus; Diabetic Cardiomyopathies/drug therapy/*metabolism; Enzyme Inhibitors/pharmacology; Inbred C57BL; Large-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors/*metabolism; Male; Mice; Microvessels/drug effects/physiopathology; NG-Nitroarginine Methyl Ester/pharmacology; Nitric Oxide/*metabolism; Peptides/pharmacology; TRPV Cation Channels/agonists/antagonists & inhibitors/biosynthesis/*metabolism; Type 2/drug therapy/*metabolism; Vasoconstrictor Agents/pharmacology; Vasodilation/drug effects
Creator
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Guarini Giacinta; Ohanyan Vahagn A; Kmetz John G; DelloStritto Daniel J; Thoppil Roslin J; Thodeti Charles K; Meszaros J Gary; Damron Derek S; Bratz Ian N
Description
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We have previously shown transient receptor potential vanilloid subtype 1 (TRPV1) channel-dependent coronary function is compromised in pigs with metabolic syndrome (MetS). However, the mechanisms through which TRPV1 channels couple coronary blood flow to metabolism are not fully understood. We employed mice lacking TRPV1 [TRPV1((-/-))], db/db diabetic, and control C57BKS/J mice to determine the extent to which TRPV1 channels modulate coronary function and contribute to vascular dysfunction in diabetic cardiomyopathy. Animals were subjected to in vivo infusion of the TRPV1 agonist capsaicin to examine the hemodynamic actions of TRPV1 activation. Capsaicin (1-100 mug.kg(-1).min(-1)) dose dependently increased coronary blood flow in control mice, which was inhibited by the TRPV1 antagonist capsazepine or the nitric oxide synthase (NOS) inhibitor N-nitro-l-arginine methyl ester (L-NAME). In addition, the capsaicin-mediated increase in blood flow was attenuated in db/db mice. TRPV1((-/-)) mice exhibited no changes in coronary blood flow in response to capsaicin. Vasoreactivity studies in isolated pressurized mouse coronary microvessels revealed a capsaicin-dependent relaxation that was inhibited by the TRPV1 inhibitor SB366791 l-NAME and to the large conductance calcium-sensitive potassium channel (BK) inhibitors iberiotoxin and Penetrim A. Similar to in vivo responses, capsaicin-mediated relaxation was impaired in db/db mice compared with controls. Changes in pH (pH 7.4-6.0) relaxed coronary vessels contracted to the thromboxane mimetic U46619 in all three groups of mice; however, pH-mediated relaxation was blunted in vessels obtained from TRPV1((-/-)) and db/db mice compared with controls. Western blot analysis revealed decreased myocardial TRPV1 protein expression in db/db mice compared with controls. Our data reveal TRPV1 channels mediate coupling of myocardial blood flow to cardiac metabolism via a nitric oxide-dependent, BK channel-dependent pathway that is corrupted in diabetes.
Identifier
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<a href="http://doi.org/10.1152/ajpheart.00011.2012" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00011.2012</a>
Rights
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Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
13-dienoic Acid/pharmacology
15-Hydroxy-11 alpha
2012
9 alpha-(epoxymethano)prosta-5
American journal of physiology. Heart and circulatory physiology
Anilides/pharmacology
Animals
Bratz Ian N
Capsaicin/analogs & derivatives/pharmacology
Cinnamates/pharmacology
Coronary Vessels/drug effects/*metabolism/physiopathology
Damron Derek S
DelloStritto Daniel J
Department of Integrative Medical Sciences
Diabetes Mellitus
Diabetic Cardiomyopathies/drug therapy/*metabolism
Enzyme Inhibitors/pharmacology
Guarini Giacinta
Inbred C57BL
Kmetz John G
Large-Conductance Calcium-Activated Potassium Channels/antagonists & inhibitors/*metabolism
Male
Meszaros J Gary
Mice
Microvessels/drug effects/physiopathology
NEOMED College of Medicine
NG-Nitroarginine Methyl Ester/pharmacology
Nitric Oxide/*metabolism
Ohanyan Vahagn A
Peptides/pharmacology
Thodeti Charles K
Thoppil Roslin J
TRPV Cation Channels/agonists/antagonists & inhibitors/biosynthesis/*metabolism
Type 2/drug therapy/*metabolism
Vasoconstrictor Agents/pharmacology
Vasodilation/drug effects