Improved coronary supply: Prevailing mechanism of action of nitrates in chronic stable angina

Abstract

Exercise tolerance before and after sublingual isosorbide dinitrate (ISDN), 10 mg, was assessed in 217 consecutive patients with stable angina, positive exercise test, and angiographically proved coronary artery disease. In 65 patients (30%), ISDN prevented exercise-induced ST segment depression and/or increased exercise time to 1 mm ST segment depression (≥ 3 minutes), despite the significantly higher (≥ 25 × 10 2 increment) rate-pressure product attained (increased coronary reserve). On the contrary, in 40 other patients, exercise test remained positive, and neither time to 1 mm ST segment depression nor rate-pressure product increased significantly (fixed coronary reserve). The remaining 106 patients had an intermediate response. To assess the mechanisms underlying the beneficial action of nitrates, we further investigated 13 patients with increased coronary reserve (group 1) and five with fixed coronary reserve (group 2) by (1) the exercise response to ISDN and verapamil, (2) the changes in left ventricular volumes after ISDN and verapamil, (3) the ECG response to intravenous ergonovine, and (4) the changes in coronary stenosis severity following intravenous ergonovine and intracoronary nitrates. ISDN dramatically improved exercise capacity only in group 1 patients. However, it induced a significant reduction of left ventricular volumes in both groups ( p < 0.01). Ergonovine provoked angina and ST segment depression in 62% of group 1 patients and significantly increased the severity of their coronary stenoses ( p < 0.01). In all group 2 patients, ergonovine was negative, and no significant increase in stenosis severity was observed. Intracoronary nitrates reduced stenosis severity in group 1 ( p < 0.01) but not in group 2. The results of our study suggest that in a large proportion of patients with chronic stable angina who dramatically improve exercise capacity with sublingual nitrates, the beneficial effects of these drugs are due to an increase in coronary flow reserve rather than to a decreased myocardial oxygen demand.