title: Metabolic hyperemia requires ATP-sensitive K+ channels and H2O2 but not adenosine in isolated mouse hearts.
abstract: We have previously demonstrated that adenosine-mediated H2O2 production and opening of ATP-sensitive K(+) (KATP) channels contributes to coronary reactive hyperemia. The present study aimed to investigate the roles of adenosine, H2O2, and KATP channels in coronary metabolic hyperemia (MH). Experiments were conducted on isolated Langendorff-perfused mouse hearts using combined pharmacological approaches with adenosine receptor (AR) knockout mice. MH was induced by electrical pacing at graded frequencies. Coronary flow increased linearly from 14.4 ± 1.2 to 20.6 ± 1.2 ml·min(-1)·g(-1) with an increase in heart rate from 400 to 650 beats/min in wild-type mice. Neither non-selective blockade of ARs by 8-(p-sulfophenyl)theophylline (8-SPT; 50 μM) nor selective A2AAR blockade by SCH-58261 (1 μM) or deletion affected MH, although resting flow and left ventricular developed pressure were reduced. Combined A2AAR and A2BAR blockade or deletion showed similar effects as 8-SPT. Inhibition of nitric oxide synthesis by N-nitro-l-arginine methyl ester (100 μM) or combined 8-SPT administration failed to reduce MH, although resting flows were reduced (by ∼20%). However, glibenclamide (KATP channel blocker, 5 μM) decreased not only resting flow (by ∼45%) and left ventricular developed pressure (by ∼36%) but also markedly reduced MH by ∼94%, resulting in cardiac contractile dysfunction. Scavenging of H2O2 by catalase (2,500 U/min) also decreased resting flow (by ∼16%) and MH (by ∼24%) but to a lesser extent than glibenclamide. Our results suggest that while adenosine modulates coronary flow under both resting and ischemic conditions, it is not required for MH. However, H2O2 and KATP channels are important local control mechanisms responsible for both coronary ischemic and metabolic vasodilation.
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, West Virginia;
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, West Virginia;
authors.forename: Bunyen
authors.initials: B
authors.lastname: Teng
authors.affiliation: Department of Medicine, University of North Carolina, Chapel Hill, North Carolina; and.
authors.forename: Stephen
authors.initials: S
authors.lastname: Tilley
authors.affiliation: Universite Libre de Bruxelles, Brussels, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Ledent
authors.affiliation: Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia; Center for Cardiovascular and Respiratory Sciences, West Virginia University, Morgantown, West Virginia; sjmustafa@hsc.wvu.edu.
authors.forename: S Jamal
authors.initials: SJ
authors.lastname: Mustafa
mesh_terms: D000241:Adenosine / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation; D016166:Free Radical Scavengers / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D006940:Hyperemia / Q000378:metabolism* / Q000503:physiopathology; D066298:In Vitro Techniques; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000235:genetics / Q000378:metabolism*; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D016166:Free Radical Scavengers; D054086:KATP Channels; D026902:Potassium Channel Blockers; D011743:Pyrimidines; D018047:Receptors, Purinergic P1; D014230:Triazoles; C031433:8-(4-sulfophenyl)theophylline; D006861:Hydrogen Peroxide; D013806:Theophylline; D000241:Adenosine; D005905:Glyburide; D019331:NG-Nitroarginine Methyl Ester
keywords: A2A adenosine receptor; A2B adenosine receptor; ATP-sensitive K+ channels; adenosine receptor knockouts; coronary metabolic hyperemia; hydrogen peroxide
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