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To determine whether propranolol can be administered twice daily without any loss of antianginal effect, we studied nine men receiving long-term propranolol therapy for stable angina pectoris. Each patient performed bicycle exercise to the point of angina on two consecutive mornings. By means of double-blind placebo-propranolol administration before the test, the study created a situation whereby on one day the exercise took place 12 hours after the last dose of propranolol, and on the other day 1 1/2 hours after a dose. Despite markedly lower blood levels of propranolol on the day that exercise was performed 12 hours after the last dose, exercise time to angina was nearly identical on the 2 days. We conclude that long-term therapy with propranolol for angina pectoris can be administered on a twice daily basis with no loss of effectiveness.

Ten men with stable angina not completely relieved by full doses of propranolol (mean, 218 mg daily) were given double-blind, on alternate mornings, a placebo or an oral dose (5 to 30 mg) of isosorbide dinitrate (ISDN) previously titrated to lower sitting systolic blood pressure by 20 mm Hg. Patients had been trained in a protocol which precipitated angina after three to six minutes of bicycle exercise. On test days, with propranolol continued, bicycle exercise was performed until the appearance of angina before ISDN or placebo administration, and hourly thereafter for eight hours. Mean exercise duration was greater one hour after ISDN than after placebo by 182 sec (423 +/- 39 vs 241 +/- 13, p less than 0.001), and a difference of 63 sec was still present at six hours (p less than 0.002). At one hour, ISDN lowered resting systolic blood pressure by 26 mm Hg (from 114 +/- 5 mm Hg to 88 +/- 4 mm Hg; p less than .001) without appreciably changing heart rate. We conclude that ISDN is a very effective and reasonably long-acting antianginal supplement to propranolol.

Ten men with stable angina not completely relieved by full doses of propranolol (mean 218 mg/day) were administered an oral dose of 10 mg of nifedipine or placebo on alternate mornings in a double-blind fashion. Patients had been trained in a protocol that precipitated angina after 3-6 minutes of bicycle exercise. On test days, with propranolol continued, bicycle exercise to angina or fatigue was performed before nifedipine or placebo administration, and hourly thereafter for 8 hours. Mean exercise duration was greater 1 hour after nifedipine than after placebo by 123 seconds (372 +/- 21 vs 249 +/- 16 seconds, p less than 0.001). By the fifth hour, the increase in exercise time was reduced to 93 seconds (p less than 0.001), and a significant, though further diminished, difference of 57 seconds was still present at 8 hours (p less than 0.01). Nifedipine lowered resting systolic blood pressure by 20 mm Hg (p less than 0.001) without appreciably changing heart rate. We conclude that nifedipine is a very effective and reasonably long-acting antianginal supplement to propranolol.

Ten men with stable angina not fully relieved by optimal doses of propranolol were given on each of four mornings a single dose of 10 mg nifedipine, 120 mg verapamil, isosorbide dinitrate (5 to 30 mg, previously titrated to lower systolic blood pressure by 15 to 20 mm Hg), or placebo, in double-blind fashion. Bicycle exercise to angina was performed hourly for 8 hr thereafter. All three vasodilators increased exercise time by at least 50% by the first hour (p less than .001), with a gradually diminishing effect persisting for 6 to 8 hr (p less than .01). Although for the group there were no differences in magnitude and duration of effect among the three drugs, in five of the individual patients there were important differences in response favoring one or another vasodilator. We conclude that nifedipine, verapamil, and isosorbide dinitrate are equally effective and reasonably long-acting antianginal supplements to propranolol, although some patients may benefit more from one than another of the three.

Ten men with stable angina pectoris not fully relieved by optimal doses of propranolol (mean 218 mg daily) were given a single oral dose of 120 mg verapamil or a placebo on alternate mornings; the order of treatment was double blind. Patients had trained in a protocol that precipitated angina after three to six minutes of exercise on a bicycle ergometer. On test days, and with continued propranolol treatment, bicycle exercise was performed just before the administration of verapamil or placebo and hourly thereafter for eight hours. Mean exercise tolerance was 118 seconds greater one hour after verapamil than one hour after placebo (p <0.001), and a significant though somewhat diminished difference of 66 seconds was still present at six hours (p <0.01). Verapamil lowered resting systolic blood pressure by 12 mm Hg (p <0.01) without changing heart rate. None of the 10 patients showed adverse effects from the verapamil-propranolol combination.The results of this study suggest that verapamil is a highly effective antianginal supplement to propranolol.