Published Online
on September 2, 2003

A more recent version of this article appeared on September 23, 2003

This Article Full Text (PDF) All Versions of this Article: 108/12/1446    most recent 01.CIR.0000089092.61590.A8v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hirai, N. Articles by Ogawa, H. Search for Related Content PubMed PubMed Citation Articles by Hirai, N. Articles by Ogawa, H. Related Collections Cardiovascular Pharmacology

Submitted on October 17, 2001
Revised on July 11, 2003
Accepted on July 14, 2003

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, and 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.

^* To whom correspondence should be addressed. E-mail: nobutaka{at}krmc.or.jp.

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

This article has been cited by other articles:

				D. Rhoney and W. F. Peacock Intravenous therapy for hypertensive emergencies, part 1 Am. J. Health Syst. Pharm., August 1, 2009; 66(15): 1343 - 1352. [Abstract] [Full Text] [PDF]

				M. White, H. Ross, S. Levesque, L. Whittom, G. B Pelletier, N. Racine, S. Meloche, and L. Voisin Effects of Angiotensin-Converting Enzyme Inhibitor Versus Valsartan on Cellular Signaling Events in Heart Transplant Ann. Pharmacother., May 1, 2009; 43(5): 831 - 839. [Abstract] [Full Text] [PDF]

				T. Thum, D. Fraccarollo, S. Thum, M. Schultheiss, A. Daiber, P. Wenzel, T. Munzel, G. Ertl, and J. Bauersachs Differential Effects of Organic Nitrates on Endothelial Progenitor Cells Are Determined by Oxidative Stress Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 748 - 754. [Abstract] [Full Text] [PDF]

				A. Shamaei-Tousi, J. P. Halcox, and B. Henderson Stressing the obvious? Cell stress and cell stress proteins in cardiovascular disease Cardiovasc Res, April 1, 2007; 74(1): 19 - 28. [Abstract] [Full Text] [PDF]

				M. Yamauchi, H. Nakano, J. Maekawa, Y. Okamoto, Y. Ohnishi, T. Suzuki, and H. Kimura Oxidative Stress in Obstructive Sleep Apnea Chest, May 1, 2005; 127(5): 1674 - 1679. [Abstract] [Full Text] [PDF]