Abstract 1135: Hydrogen Peroxide Plays a Crucial Role in Coronary Microvascular Vasodilation with Increased Oxidative Stress in Right Ventricles of Pulmonary Hypertensive Rats
Background: Hydrogen peroxide (H2O2) is a well recognized candidate for EDHF. The aim of this study was to examine H2O2-EDHF function in coronary arterial microvessels under conditions of increased oxidative stress in RV of pulmonary hypertension (PH).
Methods: Monocrotaline (60 mg/kg SC) was administrated in 5 week-age male Sprague-Dawley rats to induce PH (PH; n=52). Saline was injected in control rats (n=47). After 3 weeks, RV coronary arterioles (CA; 30 –100 μm) and small arteries (CSA; 100 –200 μm) were visualized in vivo using our intravital videomicroscopy. After cyclooxigenase blockade, Acetylcholine (ACh; 2 μg/kg/min IV) induced vasodilation was evaluated under three conditions; ACh alone, Nωnitro-L-arginine methyl ester (L-NAME), L-NAME+catalase. Differences of percentage vasodilation between ACh alone and L-NAME, and between L-NAME and L-NAME+catalase were used as relative indices for the contributions of NO and H2O2-EDHF, respectively. Malondialdehyde (MDA) in plasma was measured with colormetric assay. Superoxide production in RV was determined by lucigenin-derived chemiluminescence.
Results: RV systolic pressure was significantly increased in PH (75±13 vs. 31±3 mmHg; p<0.05). In PH, Ach-induced vasodilation was significantly reduced in both CA and CSA compared with control (CA; 5.2±1.5% vs. 10.8±3.5%, CSA; 3.8±1.0% vs. 6.0±1.9%, both p<0.05). Inhibition of vasodilation by L-NAME in PH was markedly decreased for both CA (from 4.0% to 1.0%) and CSA (from 3.6% to 1.0%) (both p<0.05). Suppression of vasodilation by the addition of catalase in PH was decreased for CA (from 5.2% to 3.1%, p<0.05), but maintained or even increasing tendency for CSA (from 1.7% to 2.0%, NS). Notably, the relative contribution of H2O2-EDHF in PH was greatly increased for both CA (from 48% to 60%) and CSA (from 28% to 53%) (both p<0.05). Plasma MDA and RV superoxide in PH were markedly higher than those in control (MDA; 1.63±0.53 vs. 0.93±0.11 μm, superoxide; 290±52 vs 158±25 cpm/mg, both p<0.05). Collectively, increased oxidative stress may augment H2O2 produciton and contribute to the robust EDHF function.
Conclusion: Under conditions of increased oxidative stress in PH, H2O2-EDHF plays a crucial role against NO dysfunction in RV coronary microcirculation.