PRECLINICAL STUDIES
Important Role of Endogenous Hydrogen Peroxide in Pacing-Induced Metabolic Coronary Vasodilation in Dogs In Vivo
Toyotaka Yada, MD, PhD*,*,
Hiroaki Shimokawa, MD, PhD ,
Osamu Hiramatsu, PhD*,
Yoshiro Shinozaki, BS ,
Hidezo Mori, MD, PhD ,
Masami Goto, MD, PhD*,
Yasuo Ogasawara, PhD* and
Fumihiko Kajiya, MD, PhD*
* Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, Kurashiki, Japan
Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
Department of Physiology, Tokai University School of Medicine, Isehara, Japan
Department of Cardiac Physiology, National Cardiovascular Center Research Institute, Suita, Japan
Manuscript received September 11, 2006;
revised manuscript received April 25, 2007,
accepted May 1, 2007.
* Reprint requests and correspondence: Dr. Toyotaka Yada, Department of Medical Engineering and Systems Cardiology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192, Japan. (Email: yada{at}me.kawasaki-m.ac.jp).
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Abstract
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Objectives: We examined whether endogenous hydrogen peroxide (H2O2) is involved in pacing-induced metabolic vasodilation in vivo.
Background: We have previously demonstrated that endothelium-derived H2O2 is an endothelium-derived hyperpolarizing factor in canine coronary microcirculation in vivo. However, the role of endogenous H2O2 in metabolic coronary vasodilation in vivo remains to be examined.
Methods: Canine subepicardial small coronary arteries ( 100 µm) and arterioles (<100 µm) were continuously observed by a microscope under cyclooxygenase blockade (ibuprofen, 12.5 mg/kg intravenous [IV]) (n = 60). Experiments were performed during paired right ventricular pacing under the following 7 conditions: control, nitric oxide (NO) synthase inhibitor (NG-monomethyl-L-arginine [L-NMMA], 2 µmol/min for 20 min intracoronary [IC]), catalase (a decomposer of H2O2, 40,000 U/kg IV and 240,000 U/kg/min for 10 min IC), 8-sulfophenyltheophylline (SPT) (an adenosine receptor blocker, 25 µg/kg/min for 5 min IC), L-NMMA+catalase, L-NMMA+tetraethylammonium (TEA) (KCa-channel blocker, 10 µg/kg/min for 10 min IC), and L-NMMA+catalase+8-SPT.
Results: Cardiac tachypacing (60 to 120 beats/min) caused coronary vasodilation in both-sized arteries under control conditions in response to the increase in myocardial oxygen consumption. The metabolic coronary vasodilation was decreased after L-NMMA in subepicardial small arteries with an increased fluorescent H2O2 production compared with catalase group, whereas catalase decreased the vasodilation of arterioles with an increased fluorescent NO production compared with the L-NMMA group, and 8-SPT also decreased the vasodilation of arterioles. Furthermore, the metabolic coronary vasodilation was markedly attenuated after L-NMMA+catalase, L-NMMA+TEA, and L-NMMA+catalase+8-SPT in both-sized arteries.
Conclusions: These results indicate that endogenous H2O2 plays an important role in pacing-induced metabolic coronary vasodilation in vivo.
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Abbreviations and Acronyms
| | CBF = coronary blood flow | | DAR = diaminorhodamine-4M AM | | DCF = 2',7'-dichlorodihydrofluorescein diacetate | | EDHF = endothelium-derived hyperpolarizing factor | | H2O2
= hydrogen peroxide | | L-NMMA = NG-monomethyl-L-arginine | | LAD = left anterior descending coronary artery | | MVO2
= myocardial oxygen consumption | | NO = nitric oxide | | PGI2
= prostacyclin | | SPT = sulfophenyltheophylline | | TEA = tetraethylammonium |
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Cardiac tachycardia by pacing or exercise increases myocardial oxygen consumption (MVO2) and increases coronary blood flow by several mechanisms (1–3). Shear stress plays a crucial role in modulating vascular tone by endothelium-derived releasing factors (EDRFs), including nitric oxide (NO), prostacyclin (PGI2), and endothelium-derived hyperpolarizing factor (EDHF) (4,5). Flow-induced vasodilation is mediated by either NO (6,7), PGI2 (8), both of them (9), or EDHF (10). Matoba et al. have previously identified that endothelium-derived hydrogen peroxide (H2O2) is a primary EDHF in mesenteric arteries of mice and humans (11,12). Morikawa et al. (13,14) subsequently confirmed that endothelial Cu,Zn-superoxide dismutase (SOD) plays an important role as an EDHF synthase in mice and humans. Miura et al. (15) demonstrated that endothelium-derived H2O2 is involved as an EDHF in the flow-induced vasodilation of isolated human coronary arterioles in vitro. We have recently confirmed that endogenous H2O2 plays an important compensatory role during coronary autoregulation (16) and reperfusion injury in vivo (17) through the interactions with NO and adenosine.
It is known that vascular  -adrenergic receptor is modulated by the endothelium in dogs (18), whereas cardiac ß-adrenergic receptor is modulated by KCa channels in pigs (19) and H2O2 in mice (20). However, the role of endogenous H2O2 in metabolic coronary vasodilation in vivo remains largely unknown. In the present study, we thus examined whether H2O2 is involved in pacing-induced metabolic coronary vasodilation in canine coronary microcirculation in vivo.
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Methods
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This study conformed to the Guideline on Animal Experiments of Kawasaki Medical School and the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health.
Animal preparation.
Anesthetized mongrel dogs of either gender (15 to 25 kg in body weight, n = 60) were ventilated with a ventilator (Model VS600, IDC, Pittsburgh, Pennsylvania). We continuously monitored aortic pressure and left ventricular pressure (LVP) with a catheter (SPC-784A, Millar, Houston, Texas) and blood flow of the left anterior descending coronary artery (LAD) with a transonic flow probe (T206, Transonic Systems, Ithaca, New York).
Measurements of coronary diameter by intravital microscope.
We continuously monitored coronary vascular responses by an intravital microscope (VMS 1210, Nihon Kohden, Tokyo, Japan) with a needle-probe in vivo, as previously described (21). We gently placed the needle-probe on subepicardial microvessels. When a clear vascular image was obtained, end-diastolic vascular images were taken with 30 pictures/s (21).
Measurements of regional myocardial blood flow.
Regional myocardial blood flow was measured by the non-radioactive microsphere (Sekisui Plastic Co. Ltd., Tokyo, Japan) technique, as previously described (22). Briefly, the microspheres suspension was injected into the left atrium 3 min after tachypacing. Myocardial flow in the LAD area was calculated according to the formula "time flow = tissue counts x (reference flow/reference counts)" and was expressed in ml/g/min (22).
Detection of H2O2 and NO production in coronary microvessels.
2',7'-dichlorodihydrofluorescein diacetate (DCF) (Molecular Probes, Eugene, Oregon) and diaminorhodamine-4M AM (DAR) (Daiichi Pure Chemicals, Tokyo, Japan) were used to detect H2O2 and NO production in coronary microvessels, respectively, as previously described (17). Briefly, fresh and unfixed heart tissues were cut into several blocks and immediately frozen in optimal cutting temperature compound (Tissue-Tek, Sakura Fine Chemical, Tokyo, Japan). Fluorescent images of the microvessels were obtained 3 min after application of acetylcholine (ACh) by using a fluorescence microscope (OLYMPUS BX51, Tokyo, Japan) (17).
Experimental protocols.
After the surgical procedure and instrumentation, at least 30 min were allowed for stabilization while monitoring hemodynamic variables. Coronary vasodilator responses were examined before and after cardiac tachypacing (60 to 120 beats/min) under the following 7 conditions with cyclooxygenase blockade (ibuprofen, 12.5 mg/kg, IV) to evaluate the role of H2O2 and NO without PGI2 in a different set of animals (Fig. 1): 1) control conditions without any inhibitor; 2) L-NMMA alone (2 µmol/min intracoronary [IC] for 20 min); 3) catalase alone (40,000 U/kg intravenous [IV] and 240,000 U/kg/min IC for 10 min, an enzyme that dismutates H2O2 into water and oxygen); 4) adenosine receptor blockade alone (8-sulfophenyltheophylline [8-SPT], 25 µg/kg/min IC for 5 min); 5) catalase plus L-NMMA; 6) catalase plus tetraethylammonium (TEA) (10 µg/kg/min IC for 10 min, an inhibitor of large conductance KCa channels to inhibit EDHF-mediated responses) (23); and 7) catalase plus L-NMMA with 8-SPT (16). These inhibitors were given at 30 min before cardiac tachypacing (Fig. 1). The basal coronary diameter was defined as that before pacing. We continuously observed the diameter change in subepicardial small coronary arteries (100 µm) and arterioles (<100 µm) with an intravital microscope before and at 2 min after pacing. Microspheres were administered at 3 min after the pacing was started (Fig. 1). In the combined infusion protocol (L-NMMA+catalase+8-SPT), L-NMMA infusion was first started, followed by catalase infusion, and then 8-SPT was added at 15 min after the initiation of L-NMMA infusion (Fig. 1). Then, fresh and unfixed heart tissues were cut into several blocks and immediately frozen in optimal cutting temperature compound after the pacing. The flow and MVO2 were measured as full-thickness values.
Drugs.
All drugs were obtained from Sigma Chemical Co. and were diluted in a physiological saline immediately before use.
Statistical analysis.
Results are expressed as means ± SEM. Differences in the vasodilation of subepicardial coronary microvessels before and after pacing (Fig. 2) were examined by a multiple regression analysis using a model, in which the change in coronary diameter was set as a dependent variable (y) and vascular size as an explanatory variable (x), while the statuses of control and other inhibitors were set as dummy variables (D1, D2) in the following equation: y = a0 + a1x + a2D1 + a3D2, where a0 through a3 are partial regression coefficients (16). Significance tests were made as simultaneous tests for slope and intercept differences. Pairwise comparisons against control were made without adjustment for multiple comparisons. The vessel was the unit of analysis without correction for correlated observations. The power of this analysis is greater than that of using the animal as the unit of analysis, giving smaller p values. Vascular fluorescent responses (Figs. 3 and 4) were analyzed by one-way analysis of variance followed by Scheffe's post hoc test for multiple comparisons. The criterion for statistical significance was at p < 0.05.
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Figure 2 Coronary Vascular Responses to Cardiac Pacing
The coronary vasodilating responses of both-sized coronary arteries were significantly inhibited in all experimental conditions except L-NMMA alone. **p < 0.01. Abbreviations as in Figure 1.
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Figure 3 Detection of H2O2 Production With DCF Fluorescent Method
Hydrogen peroxide (H2O2) production was unaltered after NG-monomethyl-L-arginine (L-NMMA) but was markedly suppressed by catalase. Number of arterioles/animals used was 5/5 for each group. *p < 0.05, **p < 0.01. DCF = 2',7'-dichlorodihydrofluorescein diacetate.
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Figure 4 Detection of NO Production With DAR Fluorescent Method
Nitric oxide (NO) production was unaltered after catalase but was markedly suppressed by NG-monomethyl-L-arginine (L-NMMA). Number of arterioles/animals used was 5/5 for each group. *p < 0.05, **p < 0.01. DAR = diaminorhodamine-4M AM.
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Results
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Hemodynamic status and blood gases during pacing.
Throughout the experiments, mean aortic pressure was constant and comparable (Table 1), and pO2, pCO2, and pH were maintained within the physiological ranges (pO2 >70 mm Hg, pCO2 25 to 40 mm Hg, and pH 7.35 to 7.45). Baseline coronary diameter was comparable in the absence and presence of inhibitors under the 7 different experimental conditions (Table 1). Cardiac tachypacing increased coronary blood flow and MVO2 from the baseline values (Table 2, both p < 0.01). Combined infusion of L-NMMA+catalase+8-SPT significantly decreased coronary blood flow (CBF) and MVO2 as compared with control, L-NMMA alone (both p < 0.01), catalase alone (both p < 0.01), 8-SPT alone (both p < 0.01), L-NMMA+catalase (both p < 0.05), L-NMMA+TEA (both p < 0.05). Combined infusion of L-NMMA+catalase or L-NMMA+TEA significantly decreased CBF (both p < 0.05) and MVO2 (both p < 0.05) as compared with control after the pacing.
Coronary vasodilation before and after cardiac tachypacing.
Cardiac tachypacing caused coronary vasodilation in both-sized arteries under control conditions (small coronary arteries, 5 ± 1%; arterioles, 14 ± 2%) (Fig. 2A) with decreased coronary venous pO2 (Table 2). The metabolic coronary vasodilation was significantly decreased after L-NMMA in small coronary arteries (3 ± 1%) but not in arterioles (14 ± 2%), whereas catalase and 8-SPT decreased the vasodilation of arterioles (both 4 ± 1%) but not in small coronary arteries (both 7 ± 1%) (Figs. 2B and 2C). Furthermore, the metabolic coronary vasodilation was markedly attenuated after L-NMMA+catalase and L-NMMA+TEA in small coronary arteries (both 2 ± 1%), and L-NMMA+catalase+8-SPT almost abolished the vasodilating responses in both-sized arteries (small coronary arteries, –1 ± 1%; arterioles, 1 ± 1%) (Figs. 2D to 2F). When expressed in a linear regression analysis, the coronary vasodilating responses of both-sized coronary arteries were significantly inhibited in all experimental conditions except L-NMMA alone (Fig. 2A).
Detection of H2O2 and NO production.
Fluorescent microscopy with DCF showed that cardiac tachypacing increased coronary H2O2 production compared with baseline conditions in arterioles (Fig. 3). The pacing-induced H2O2 production as assessed by DCF fluorescent intensity was unaltered after L-NMMA but was markedly suppressed by catalase (Fig. 3). By contrast, in small coronary arteries, vascular NO production as assessed by DAR fluorescent intensity was significantly increased in response to the pacing compared with baseline conditions (Fig. 4). The pacing-induced NO production was unaltered after catalase but was markedly suppressed by L-NMMA (Fig. 4). Pacing caused no significant increase in H2O2 production in small coronary arteries or NO production in arterioles (data not shown).
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Discussion
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The major finding of the present study is that endogenous H2O2 plays an important role in pacing-induced metabolic coronary dilation as a compensatory mechanism for NO in vivo. We demonstrated the important role of endogenous H2O2 in the mechanisms for metabolic coronary dilation in vivo.
Validations of experimental model and methodology.
We chose, on the basis of our previous reports (16,17), the adequate dose of L-NMMA, catalase, TEA, and 8-SPT in order to inhibit NO synthesis, H2O2, KCa channels, and the adenosine receptor, respectively. The TEA at low doses is fairly specific for KCa channel, but at higher doses it might block a number of other K channels. Because several KCa channels might be involved in H2O2-mediated responses (5), we selected nonselective KCa inhibitor, TEA, to inhibit all KCa channels (23). We have previously confirmed the validity of our present methods (21).
Role of NO and H2O2 after cardiac pacing.
Matoba et al. have demonstrated that endothelium-derived H2O2 is an EDHF in mouse (11) and human (12) mesenteric arteries and pig coronary microvessels (24). Morikawa et al. also have demonstrated that endothelial Cu,Zn-SOD plays an important role as an H2O2/EDHF synthase in mouse (13) and human (14) mesenteric arteries. Subsequently, we (16,17) and others (15) confirmed that endogenous H2O2 exerts important vasodilator effects in canine coronary microcirculation in vivo and in isolated human coronary microvessels, respectively. In the present study, the pacing-induced metabolic coronary vasodilation was significantly decreased after L-NMMA in small coronary arteries but not in arterioles, whereas catalase decreased the vasodilation of arterioles but not that of small arteries, and the coronary vasodilation was markedly attenuated after L-NMMA+catalase (Fig. 2). These findings indicate that NO and H2O2 compensate for each other to maintain coronary vasodilation in response to increased myocardial oxygen demand. Coronary venous pO2 tended to be lower after L-NMMA+catalase, suggesting that NO and H2O2 coordinately cause coronary vasodilation during cardiac tachypacing.
Saitoh et al. (25) suggested that the production of H2O2, which stems from the dismutation of •O2
– that is formed during mitochondrial electron transport, is seminal in the coupling between oxygen metabolism and blood flow in the heart. Thus, the contribution of H2O2 production in response to the change in metabolism cannot be excluded.
Endothelial Cu,Zn-SOD plays an important role in the synthesis of H2O2 as an EDHF synthase in mouse (13) and human (14) mesenteric arteries, and exercise training enhances expression of Cu,Zn-SOD in normal pigs (26). It remains to be examined whether exercise-induced up-regulation of Cu,Zn-SOD enhances metabolic coronary vasodilation mediated by endogenous H2O2.
Compensatory vasodilator mechanism among H2O2, NO, and adenosine.
The EDHF acts as a partial compensatory mechanism to maintain endothelium-dependent vasodilation in the forearm microcirculation of patients with essential hypertension, where NO activity is impaired owing to oxidative stress (27). We have recently demonstrated in the fluorescent microscopy study that coronary vascular production of H2O2 and NO is enhanced after myocardial ischemia/reperfusion in small coronary arteries and arterioles, respectively (17). In the present study, the DCF fluorescent intensity was comparable between control and L-NMMA, and that of DAR was also comparable between control and catalase (Figs. 3 and 4). Although the exact source of vascular production of H2O2 and NO remains to be elucidated, it is highly possible that endothelium-derived NO and H2O2 compensate for each other to maintain coronary vasodilation in response to increased MVO2.
In the dog, blockade of any vasodilator mechanisms fails to blunt the increase in coronary blood flow in response to exercise, indicating that adenosine, K+
ATP-channel opening, prostanoids, or NO might not be mandatory for exercise-induced coronary vasodilation, or that these redundant vasodilator mechanisms compensate for each other when one mechanism is blocked (28). In the present study, adenosine blockade with 8-SPT alone inhibited the pacing-induced vasodilation of arteriole but not that of small artery, whereas combined administration of L-NMMA+catalase+8-SPT almost abolished the pacing-induced coronary vasodilation of both-sized arteries with an increase in coronary blood flow (Fig. 2). The discrepancy between the diameter and flow responses is likely due to the metabolic autoregulation of smaller arterioles. These results indicate that adenosine also plays an important role to maintain metabolic coronary vasodilation in cooperation with NO and H2O2, a finding consistent with our previous study on coronary autoregulatory mechanisms (15).
Study limitations.
Several limitations should be mentioned for the present study. First, although we were able to demonstrate the production of H2O2 with fluorescent microscopy with DCF, we were unable to quantify the endothelial H2O2 production, because DCF reacts with H2O2, peroxynitrite, and hypochlorous acid (13). Second, we were unable to find smaller arterioles, owing to the limited spatial resolution of our charge-coupled device intravital microscope. With an intravital camera with higher resolution, we would be able to observe coronary vasodilation of smaller arterioles. Third, we were unable to determine whether H2O2 is produced by shear stress or cardiac metabolism. This point remains to be elucidated in a future study.
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Conclusions
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We were able to demonstrate that endogenous H2O2 plays an important role in pacing-induced metabolic coronary vasodilation in canine coronary microcirculation in vivo and that there are substantial compensatory interactions among NO, H2O2, and adenosine to maintain metabolic coronary vasodilation, which is one of the most important mechanisms for cardiovascular homeostasis in vivo.
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Footnotes
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Dr. Yada is the winner of the Endothelium-Derived Hyperpolarizing Factor (EDHF) Tanabe Award from the Scientific Sessions of the American Heart Association, November 2005, Dallas, Texas.
This work was supported in part by grants from the Japanese Ministry of Education, Science, Sports, Culture, and Technology, Tokyo, Japan, Nos. 16209027 (to Dr. Shimokawa) and 16300164 (to Dr. Yada), the Program for Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research of Japan (to Dr. Shimokawa), and Takeda Science Foundation 2002 (to Dr. Yada).
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References
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Abstract
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