Attenuation of nitrate tolerance and oxidative stress by an angiotensin II receptor blocker in patients with coronary spastic angina.
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.


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 micro;g/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.
Hirai
Nobutaka
N
Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 1-1-1 Honjo, Kumamoto City 860-8556, Japan. nobutaka@krmc.or.jp
Kawano
Hiroaki
H
Yasue
Hirofumi
H
Shimomura
Hideki
H
Miyamoto
Shinzo
S
Soejima
Hirofumi
H
Kajiwara
Ichiro
I
Sakamoto
Tomohiro
T
Yoshimura
Michihiro
M
Nakamura
Hajime
H
Yodoi
Junji
J
Ogawa
Hisao
H
D000279:Administration, Cutaneous; D000368:Aged; D000787:Angina Pectoris / Q000188:drug therapy* / Q000209:etiology; D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001713:Biphenyl Compounds; D001916:Brachial Artery / Q000000981:diagnostic imaging / Q000187:drug effects; D003329:Coronary Vasospasm / Q000150:complications / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D006261:Headache / Q000209:etiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009566:Nitrates / Q000009:adverse effects / Q000627:therapeutic use*; D005996:Nitroglycerin / Q000008:administration & dosage / Q000009:adverse effects; D018384:Oxidative Stress / Q000187:drug effects*; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles / Q000627:therapeutic use*; D013879:Thioredoxins / Q000097:blood; D016896:Treatment Outcome; D014463:Ultrasonography; D014654:Vascular Patency / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D015415:Biomarkers; D001713:Biphenyl Compounds; D009566:Nitrates; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D013879:Thioredoxins; D005996:Nitroglycerin; C081643:candesartan