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Role of Hydrogen Peroxide in Coronary Autoregulation
- 1. Hydrogen Peroxide, An Endogenous EDHF, Plays An Important Role In Coronary Autoregulation In Vivo*Toyotaka Yada, **Hiroaki Shimokawa, *Osamu Hiramatsu, *Tatsuya Kajita, *Fumiyuki Shigeto, *Masami Goto, *Yasuo Ogasawara,#Fumihiko Kajiya *Dept. of Medical Engineering, Kawasaki Medical School, Kurashiki, Japan **Dept. of Cardiovascular Medicine, Kyushu University Graduate School of Medicine, Fukuoka, Japan #Dept. of Cardiovascular Physiology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan (Circulation, T. Yada et al, 2003)
- 2. Background Catalase inhibits EDHF-mediated Responses to Bradykinin in Human Mesenteric Arteries Indo + L-NNA Indo + L-NNA + catalase 0 50 100 Relaxation,% 678910 BK (- log M) n=4 * -30 -20 -10 0 Bradykinin 10-7 M Hyperpolarization,∆mV n=3=3 * * P < 0.05 (T. Matoba and H. Shimokawa et al. Biochem Biophys. Res. Commun. 2002)
- 3. Coronary Autoregulation Low Perfusion PressureHigh Perfusion Pressure 50 100 mmHg 150 50 100 mmHg 150
- 4. AI M To evaluate the Role of Hydrogen Peroxide as an Endogenous EDHF and the Possible Interaction among Nitric Oxide, EDHF and Adenosine in Coronary Autoregulation of Canine Subepicardial Microvessels In Vivo.
- 5. Experimental Setup Venous Sampling of Coronary Sinus Blood Flow Velocimeter AoP & LVP Arterial Sampling Infusion Pump Windkessel Roller Pump CCD Microscope
- 6. Experimental Protocol (1) Coronary perfusion pressure was changed in a stepwise manner from 100 to 70, 50 and 30 mmHg before and after inhibition of NO synthase (L-NMMA, 200 µM) or of hydrogen peroxide (Catalase, 40,000U/kg iv and 240,000U/kg ic) with L-NMMA. (2) Vasodilator responses of small arteries (>100 µm) and arterioles (<100 µm) were evaluated by CCD microscope. (3) Coronary venous samples were drawn, and vascular responses were evaluated after L-NMMA and Catalase plus adenosine receptor blockade (8-sulfophenyltheopkylline, 25 µg/kg ic).
- 7. Vascular Responses to Acetylcholine 30 10 0 20 Control L-NMMAL-NMMA +Catalase ＊p<0.05 vs. Control 30 10 0 20 Control L-NMMAL-NMMA +Catalase ＊ ＊ ＊ %ChangeinDiameter %ChangeinDiameter Arteriole (< 100 µm)Small Artery (> 100 µm) (Circulation, T. Yada et al, 2003)
- 8. Microvascular Responses during Decreasing Perfusion Pressure Perfusion Pressure (mm Hg) (Circulation, T. Yada et al, 2003) Arteriole (< 100µm)Small Artery (> 100µm) %ChangeinDiameter 0 5 10 15 20 25 30 30 50 70 100 * * -10 -5 0 5 10 15 30 50 70 100 * * p<0.05,vs. Control Control afterL-NMMA (L) afterL+Catalase
- 9. Feed-back Arteriolar Responses during Coronary Autoregulation (Circulation, T. Yada et al, 2003) Catalase plus L-NMMA 0 5 10 15 20 L-NMMA plus catalase * * * * * * ** ** * P<0.05 ** P<0.01 CPP70mmHg CPP50mmHg CPP30mmHg
- 10. Coronary Venous Adenosine <0.05, **P<0.01 vs. control; #P<0.05, ##P<0.01 vs. L-NMMA; †P<0.01 vs. L-NMMA plus catala Arteriolar Responses after Adenosine Receptor Blockade %ChangeinDiameter Coronaryvenous adenosine(µM) Perfusion Pressure (mm Hg) Control diameter (µm) Compensatory Effect of Adenosine 0 50 100 150 200 250 300 350 400 30 50 70 100 † # ## * * ** -10 -5 0 5 10 15 20 25 30 35 30 40 50 60 70 80 90 100 * * * * * *# # † L-NMMA plus catalase L-NMMA Control L-NMMA plus catalase plus 8-SPT (Circulation, T. Yada et al, 2003)
- 11. SUMMAR Y After NO inhibition, vasodilator responses were attenuated mainly in small arteries (>100 µm), whereas combined infusion of NO inhibition plus catalase abolished the autoregulatory vasodilation in both small arteries and arterioles ( <100 µm).
- 12. CONCLUSIO N Hydrogen peroxide, an endogenous EDHF, plays an important role of vasodilation in coronary autoregulation of canine subepicardial microvessels in vivo.
Editor's Notes
- This panel shows the role of hydrogen peroxide, as an endogenous EDHF in human mesenteric arteries. These data are cited from the recent paper of Dr. Matoba et al. Bradykinin elicited endothelium-dependent relaxations in human mesenteric arteries in the presence of indomethacin and L-NNA. Bradykinin also caused endothelium-dependent hyperpolarization in the presence of indomethacin and L-NNA. In contrast, pretreatment with catalase markedly inhibited the bradykinin-induced EDHF-mediated relaxation as well as hyperpolarization. These findings indicate that hydrogen peroxide plays an important role in regulation of vascular tone in vitro.
- Coronary autoregulation is an important physiological compensatory mechanism that permits the myocardium to relieve when coronary perfusion pressure is low or high by vasodilation or constriction of microvessels. Coronary microvessels play an important role by vasodilation in coronary autoregulation.
- The aim of this study is to evaluate the role of hydrogen peroxide as an endogenous EDHF and the possible interaction among EDHF, NO and adenosine in coronary autoregulation of canine subepicardial microvessels in vivo.
- This panel shows experimental setup. The subepicardial microvascular response was measured by a CCD intravital microscope. To evaluate the adenosine concentration, coronary venous blood samples were drawn from coronary sinus. To manipulate coronary arterial pressure, the heart was perfused with blood from the left femoral artery.
- Coronary perfusion pressure was changed in a stepwise manner from 100, 70, 50 to 30 mmHg before and after inhibition of NO synthase as well as cyclooxygenase blockade. To determine the nature of EDHF and the mechanism of EDHF-mediated vasodilation, additional experiments were performed in coronary subepicardial microvessels during administration of catalase. Vasodilator responses of small arteries (&gt;100 µm) and arterioles (&lt;100 µm) were evaluated by a CCD microscope. To evaluate the compensatory effects of adenosine, coronary venous blood samples were drawn and vascular responses were evaluated after L-NMMA and catalase plus adenosine receptor blockade.
- This panel shows the vascular responses to acetylcholine before and after L-NMMA, and catalase with L-NMMA. Vascular responses to acetylcholine after L-NMMA were attenuated mainly in small arteries, but arteriolar responses were not attenuated after L-NMMA. However, combined infusion of L-NMMA plus catalase attenuated the residual vasodilator responses of both small arteries and arterioles.
- This panel shows microvascular responses during coronary autoregulation. Under control condition, vasodilatory response of coronary microvessels was significantly increased in response to decreasing coronary perfusion pressure. After L-NMMA, vasodilator responses were attenuated mainly in small arteries, however, arteriolar responses were not attenuated after L-NMMA. However, combined infusion of L-NMMA plus catalase attenuated the residual vasodilatory responses of arterioles.
- This panel shows the arteriolar feed-back responses during coronary autoregulation NO and EDHF. We evaluated the feed-back arteriolar response during coronary autoregulation when we infused L-NMMA first, and then catalase, or catalase and then L-NMMA. The arteriolar responses were similar to those either after L-NMMA plus catalase and after catalase plus L-NMMA. These results support the negative-feedback action between NO and EDHF during coronary autoregulation in vivo.
- This panel shows the compensatory effects of adenosine during coronary autoregulation. Coronary venous adenosine concentration was increased in response to decreasing coronary perfusion pressure. Adenosine was further increased after L-NMMA compared with control, but not further increased after L-NMMA plus catalase. Arteriolar vasodilation mostly decreased after L-NMMA plus catalase. Residual arteriolar dilation after L-NMMA plus catalase was completely suppressed by 8-SPT at 30 mmHg of coronary perfusion pressure. These findings indicated that an increase in adenosine concentration compensated for the loss of NO.
- In summary, after NO inhibition, vasodilator responses were attenuated mainly in small artery (&gt;100µm), whereas combined infusion of NO inhibition plus catalase abolished the autoregulatory vasodilation in both small artery and arterioles ( &lt;100µm).
- In conclusion, hydrogen peroxide, an endogenous EDHF, plays an important role of vasodilation in coronary autoregulation in vivo.