The dose dependency of the alpha‐adrenoceptor antagonist and beta‐ adrenoceptor partial agonist activity of dilevalol and labetalol in man.

1. The alpha‐adrenoceptor antagonist, beta 1‐adrenoceptor antagonist and beta 2‐partial agonist activity of dilevalol, a beta‐adrenoceptor antagonist with vasodilating properties and labetalol were investigated in two studies. 2. In the first study, six healthy male subjects received serially increasing concentrations phenylephrine after single oral doses of dilevalol 200 mg, labetalol 400 mg and placebo at weekly intervals in a randomised double‐blind manner. An exercise step test was performed at the end of the infusions. 3. The doses of phenylephrine required to increase systolic and diastolic blood pressures by 20 mmHg (PS20 and PD20 respectively) were increased by labetalol 400 mg (P < 0.05) but unchanged by dilevalol 200 mg. The dose ratios for PS20 (means +/‐ s.d.) were: dilevalol 200 mg 1.1 +/‐ 0.1, labetalol 400 mg 2.2 +/‐ 0.1. There was no difference in the percentage reduction in exercise tachycardia between dilevalol and labetalol. 4. In the second study, 10 healthy male subjects received infusions with serially increasing concentrations of phenylephrine and angiotensin II before and after single oral doses of dilevalol 200, 400 and 800 mg, labetalol 200 mg and placebo at weekly intervals in a double‐blind randomised manner. Finger tremor was measured (piezoelectric accelerometer) with each infusion. An exercise step test was performed at the end of the infusions. 5. The PS20 and PD20 of phenylephrine were increased by labetalol 200 mg and unchanged by dilevalol. The dose ratios for PS20 were: dilevalol 200 mg 1.1 +/‐ 0.2. dilevalol 400 mg 1.1 +/‐ 0.4, dilevalol 800 mg 1.4 +/‐ 0.4 and labetalol 200 mg 2.5 +/‐ 0.7. The dose ratios for PD20 were: dilevalol 200 mg 1.1 +/‐ 0.4, dilevalol 400 mg 0.9 +/‐ 0.3. dilevalol 800 mg 1.3 +/‐ 0.4 and labetalol 200 mg 2.3 +/‐ 0.9. 6. The PS20 and PD20 of angiotensin II were unchanged by any of the drugs. 7. Exercise heart rate was reduced by dilevalol 200 mg (130 +/‐ 13 beats min‐1), 400 mg (123 +/‐ 12 beats min‐1), 800 mg (125 +/‐ 9 beats min) and labetalol 200 mg (143 +/‐ 12 beats min‐1) vs placebo (161 +/‐ 17 beats min‐1). 8. Finger tremor was significantly increased by dilevalol 800 mg (13.17 +/‐ 10.51 vs 6.62 +/‐ 4.51 centivolts for placebo: P < 0.01). Neither phenylephrine nor angiotensin II had an effect on finger tremor. 9. In conclusion, dilevalol 200, 400 and 800 mg demonstrated beta 1‐adrenoceptor antagonist activity with no evidence of alpha 1‐adrenoceptor antagonist activity. Labetalol 200 and 400 mg showed both beta 1‐ and alpha 1‐ antagonist activity. Dilevalol 800 mg demonstrated significant partial beta 2‐adrenoceptor agonist activity by increasing finger tremor.