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(Circulation. 2003;108:1446.)
© 2003 American Heart Association, Inc.

Clinical Investigation and Reports

Attenuation of Nitrate Tolerance and Oxidative Stress by an Angiotensin II Receptor Blocker in Patients With Coronary Spastic Angina

Nobutaka Hirai, MD; Hiroaki Kawano, MD; Hirofumi Yasue, MD; Hideki Shimomura, MD; Shinzo Miyamoto, MD; Hirofumi Soejima, MD; Ichiro Kajiwara, MD; Tomohiro Sakamoto, MD; Michihiro Yoshimura, MD; Hajime Nakamura, MD; Junji Yodoi, MD; Hisao Ogawa, MD

From the Department of Cardiovascular Medicine, Kumamoto University School of Medicine (N.H., H.K., K.T., H.S., S.M., H.S., T.S., K.K., H.O.) and Kumamoto Aging Research Institute (H.Y.), Kumamoto, and Department of Biological Responses (H.N., J.Y.), Institute for Virus Research, Kyoto University Graduate School, Kyoto, Japan.

Correspondence to Nobutaka Hirai, MD, Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City 860-8556, Japan. E-mail nobutaka{at}krmc.or.jp

Received October 17, 2001; de novo received May 22, 2003; revision received July 11, 2003; accepted July 14, 2003.

Background— Nitrates are widely used to treat coronary artery disease, but their therapeutic value is compromised by the rapid development of tolerance. Recently, the renin-angiotensin system has been suggested to play an important role in the development of nitrate tolerance.

Methods and Results— Sixty-four patients with coronary spastic angina were investigated to clarify the effect of angiotensin II type 1 receptor blocker (ARB) therapy on nitrate tolerance. Transdermal nitroglycerin (10 mg/d) and an ARB (candesartan, 8 mg/d) were administered to 21 patients (GTN+ARB group) for 3 days, whereas transdermal nitroglycerin and placebo were administered to 19 patients (GTN group). Another 18 patients were treated with placebo skin patches and placebo tablets for 3 days (control group). The brachial artery response to incremental doses of intravenous nitroglycerin (0.01, 0.1, and 1.0 µg/kg) was measured by ultrasound before and after transdermal nitroglycerin therapy. Before treatment, the arterial diameter was increased by nitroglycerin injection in each group. After treatment, the increase of arterial diameter was significantly suppressed in the GTN group but not in the control or GTN+ARB groups. The plasma level of thioredoxin (a marker of oxidative stress) was increased in the GTN group after treatment (P<0.01) but not in the control or GTN+ARB groups.

Conclusions— An ARB suppressed the development of nitrate tolerance during transdermal nitroglycerin therapy. These results suggest that increased oxidative stress induced by activation of angiotensin II may play an important role in the development of nitrate tolerance.

Key Words: angiotensin • nitroglycerin • ultrasonics • vasodilation

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