title: Disruption of TRPV1-mediated coupling of coronary blood flow to cardiac metabolism in diabetic mice: role of nitric oxide and BK channels.
abstract: 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 μg·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.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH 44272, USA.
authors.forename: Giacinta
authors.initials: G
authors.lastname: Guarini
authors.forename: Vahagn A
authors.initials: VA
authors.lastname: Ohanyan
authors.forename: John G
authors.initials: JG
authors.lastname: Kmetz
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: DelloStritto
authors.forename: Roslin J
authors.initials: RJ
authors.lastname: Thoppil
authors.forename: Charles K
authors.initials: CK
authors.lastname: Thodeti
authors.forename: J Gary
authors.initials: JG
authors.lastname: Meszaros
authors.forename: Derek S
authors.initials: DS
authors.lastname: Damron
authors.forename: Ian N
authors.initials: IN
authors.lastname: Bratz
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000813:Anilides / Q000494:pharmacology; D000818:Animals; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002934:Cinnamates / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D055806:Microvessels / Q000187:drug effects / Q000503:physiopathology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000813:Anilides; D002934:Cinnamates; D004791:Enzyme Inhibitors; D051036:Large-Conductance Calcium-Activated Potassium Channels; C477659:N-(3-methoxyphenyl)-4-chlorocinnamanilide; D010455:Peptides; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C064719:iberiotoxin; C071423:capsazepine; D002211:Capsaicin; D019331:NG-Nitroarginine Methyl Ester