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Functional hyperemia requires ATP‐sensitive potassium channels and hydrogen peroxide and not adenosine in isolated mice hearts (1079.17)
Author(s) -
Zhou Xueping,
Teng Bunyen,
Mustafa S. Jamal
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1079.17
Subject(s) - adenosine , chemistry , adenosine receptor , medicine , potassium channel , vasodilation , blockade , nitric oxide , ischemic preconditioning , reactive hyperemia , glibenclamide , theophylline , cardiology , pharmacology , anesthesia , endocrinology , receptor , ischemia , agonist , diabetes mellitus
We previously demonstrated that adenosine contributes to coronary ischemic vasodilation through A2A AR‐mediated H2O2 production and opening of ATP‐sensitive potassium channels (KATP). Whether the same mechanism applies to functional hyperemia remains unknown. This study aims to investigate the role of adenosine, KATP, and H2O2 in pacing‐induced coronary hyperemia using pharmacological approaches combined with adenosine receptor knockout (KO) mice. Coronary flow was measured in isolated Langendorff perfused hearts paced at a graded rate from 400 to 650 bpm. Coronary flow increased linearly from 17.1 ± 0.7 to 24.1 ± 0.8 ml/min/g with increased HR in WT mice (n=7). Neither non‐selective blockade of adenosine receptor by 8‐(p‐Sulfophenyl) theophylline (8‐SPT, 50 μM, n=6), nor selective A2A AR blockade by SCH58261 (1 μM, n=4) or A2A AR KO (n=9) affected the pacing‐induced coronary hyperemia, though the relationship between coronary flow and rate‐pressure product was shifted downward in a parallel manner. Combined A2A KO with A2B selective blockade (CVT6883, 1 μM, n=3) or vice versa (n=3) showed similar effect as 8‐SPT. Inhibition of nitric oxide synthesis by L‐NAME (100 μM) or combined administration with 8‐SPT did not affect the pacing‐induced coronary hyperemia, but attenuated the resting flow to a similar extent (by ~20%, n=5 per group). However, glibenclamide (KATP channel blocker, 10 μM) significantly decreased both pacing‐induced hyperemia (by ~80%) and baseline flow (by ~45%, n=4). Scavenging of H2O2 by catalase (2500 U/min) also decreased baseline flow (by ~16%) and pacing‐induced coronary hyperemia (by ~24%, n=4), but to a lesser extent than glibenclamide. These findings suggest that adenosine modulates coronary vascular tone under both resting and ischemic conditions but not functional hyperemia. However, H2O2 and KATP channels are important local mechanisms responsible for both coronary ischemic and metabolic vasodilation. Grant Funding Source : Supported by HL027339 and HL 094447