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

Abstract

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 (GTNϩARB 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 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 GTNϩARB groups. The plasma level of thioredoxin (a marker of oxidative stress) was increased in the GTN group after treatment (PϽ0.01) but not in the control or GTNϩARB 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.

Nitrate Tolerance as a Possible Cause of Multidrug-Resistant Coronary Artery Spasm A Case Report and Its Implications

“…3,4) Recent studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in the development of nitrate tolerance.…”

“…He thus had a multivessel coronary spasm. To elucidate the possible role of nitrate tolerance in the genesis of the drug-resistant coronary spasm, the examination of brachial flow-mediated dilatation (FMD), an indicator of endothelial function, 4) as well as ECG monitoring were performed before and after GTN patch (20 mg/day) for 3 days. The attacks recurred and increased in frequency associated with decreased FMD on continuous GTN application ( Figure 1).…”

“…1) A major therapeutic limitation inherent to organic nitrates, however, is the development of tolerance which occurs during chronic treatment with these drugs. 3,4) Recent studies have shown that mitochondrial aldehyde dehydrogenase (ALDH2) plays a central role in the development of nitrate tolerance.…”

Successful Treatment of Refractory Angina Pectoris due to Multivessel Coronary Spasm with Valsartan

“…It has been reported that angiotensin II stimulates the generation of vascular reactive oxygen species via NADH/NADPH oxidase activation (10) and that an angiotensin II type 1 receptor blocker (ARB), valsartan, improves endothelial vasomotor dysfunction through suppression of free radical production in a rabbit infarction model (11). In addition, we previously reported that an ARB, candesartan, attenuates nitrate tolerance in patients with CSA (12). Therefore i g u r e 1 .…”

Therapy for Angina Pectoris Secondary to Coronary Disease

“…Development of tolerance is rarely a problem when nitroglycerin sublingual tablets are taken intermittently, either for relief of an acute symptom or for short-term prophylaxis before activities predictably associated with angina. Some studies have shown that angiotensin receptor blockers may prevent nitrate tolerance (Hirai et al, 2003). Patients can develop rebound symptoms after abruptly stopping nitrates.…”