Abstract 506: Crucial Role of Hydrogen Peroxide as an Endogenous Endothelium-Derived Hyperpolarizing Factor during Pacing-Induced Metabolic Dilatation in Canine Coronary Microvessels in Vivo
Background: We have previously demonstrated that endothelium-derived hydrogen peroxide (H2O2) is an endothelium-derived hyperpolarizing factor (EDHF) in canine coronary microcircu-lation in vivo. However, the role of H2O2/EDHF in metabolic coronary dilatation in vivo remains to be examined. We examined whether H2O2 is involved in pacing-induced metabolic coronary vasodilatation in vivo.
Methods: Canine subepicardial small coronary arteries (SA, >100 μm) and arterioles (A, <100 μm) were continuously observed by an intravital microscope under cyclooxygenase blockade (ibuprofen, 12.5 mg/kg, IV) (n=49). Experiments were performed during paired right ventricular pacing under the following 7 conditions; control, NO synthase inhibitor (L-NMMA, 2 μmol/min for 20 min, IC), catalase (a decomposer of H2O2, 40,000 U/kg IV and 240,000 U/kg/min for 10 min, IC), 8-sulfophenyltheophylline (8-SPT, an adenosine receptor blocker, 25 μg/kg/min for 5 min, IC), L-NMMA+catalase, L-NMMA+tetraethylammonium (TEA, KCa channels blocker, 10 μg/kg/min for 10 min, IC), and L-NMMA+catalase+8-SPT.
Results: Cardiac tachypacing (60 to 120 bpm) caused coronary vasodilatation in both-sized arteries under control conditions (SA: 8±3%, A: 18±3%) with an increase in coronary blood flow (0.87±0.1 to 1.84±0.3 ml/min/g, P<0.01) and myocardial oxygen consumption (90±10 to 212±25 μl/min/g, P<0.01). The metabolic coronary vasodilatation was significantly decreased after L-NMMA in SA (SA 2±1% vs. control, P<0.05) with increased fluorescent H2O2 production compared with catalase group by fluorescent microscope, whereas catalase decreased the vasodilatation of A (A 8±1% vs. control, P<0.01) with increased fluorescent NO production compared with L-NMMA group, and 8-SPT also decreased the vasodilatation of A (A 8±1% vs. control, P<0.01). The metabolic vasodilatation was markedly attenuated after L-NMMA+catalase, L-NMMA+TEA, and L-NMMA+catalase+8-SPT in both-sized arteries (L-NMMA+catalase, SA -2±1% A 1±1%; L-NMMA+ TEA, SA -1±1% A 1±1%; and L-NMMA+catalase+8-SPT, SA -4±1%, A -2±1%, all P<0.01 vs. control).
Conclusions: These results indicate that H2O2, an EDHF, plays an important role in pacing-induced metabolic coronary vasodilatation in dogs in vivo.