Nitrate tolerance in patients with effort angina

In some patients with chronic stable angina the beneficial effects of nitrates may result not only from a reduction in venous return, but also from their action on coronary circulation. In these patients, rate-pressure product at ischemia (RPPI) increases to > 2500 bpm x mmHg after sublingual nitrates (SLN). The relative susceptibility of the venous system and the coronary circulation to the development of nitrate tolerance and the effects of two different drug schedules on the development of tolerance were investigated in patients with these characteristics.

Five patients were treated with isosorbide-5-mononitrate (IS5MN) 20 bid (8.00 am and 3.00 pm) for 1 week (Group 1) and 5 patients with IS5MN 40 bid (8.00 am and 8.00 pm) for 1 week (Group 2). Tolerance was identified as the decreased effect of SLN; the effects of nitrates were evaluated in relation to: reduction in left ventricle area (delta LVA), which had been measured using equilibrium radionuclide ventriculograms in LAO 45 degrees; this area was considered as an index of the venous return effects; increase in RPPI (delta RPPI), which had been assessed by ergometric test; RPPI was considered an index of coronary flow reserve. Measurements of LVA and RPPI were made in wash-out at the start of the study (delta LVA 1 and delta RPPI 1) and after 1 week of treatment (delta LVA 2 and delta RPPI 2). The mean values of the differences were then evaluated and compared using Student's "t" test.

In Group 1 patients delta LVA 2 and delta RPPI 2 showed values which were similar to delta LVA 1 and delta RPPI 1 (mean value delta LVA 2 47 vs mean delta LVA 1 48.2 pixels, p = ns; mean value delta RPPI 2 5264 vs mean delta RPPI 1 5536 bpm x mmHg, p = ns). These results suggest that Group 1 patients did not develop tolerance either at the coronary or at the venous level. In Group 2 patients, delta LVA 2 was significantly lower than delta LVA 1 (mean delta LVA 2 18.4 vs mean delta LVA 1 54 pixels, p < 0.01). This finding indicated tolerance to nitrates at the venous level. On the other hand, in all Group 2 patients, values of delta RPPI 2, though lower than delta RPPI 1 (mean delta RPPI 2 3095 vs mean delta RPPI 1 6083 bpm x mmHg, p < 0.01) were still higher than 2500 bpm x mmHg, indicating that the effect of nitrates at the coronary level was preserved. These data suggest that in patients treated with high doses of nitrates, the effect of these drugs at the coronary level is still present when tolerance has already developed at the venous level.