THE DOSE-DEPENDENCY OF THE ALPHA-ADRENOCEPTOR AND BETA-ADRENOCEPTOR ANTAGONIST ACTIVITY OF CARVEDILOL IN MAN

1 The alpha- and beta-adrenoceptor antagonist activity of carvedilol, a beta-adrenoceptor antagonist with vasodilating properties, and labet alol were investigated in 10 healthy male subjects. They received infu sions with serially increasing concentrations of isoprenaline and phen ylephrine before and after single oral doses of carvedilol 6.25, 12.5 and 25 mg, labetalol 400 mg and placebo at weekly intervals in a doubl e-blind randomised manner. An exercise step test was performed at the end of the infusions. 2 The dose of isoprenaline required to increase heart rate by 25 beats min(-1) (I-25) and the dose of phenylephrine re quired to increase systolic and diastolic blood pressure by 20 mm Hg ( PS20 and PD20) were calculated using a quadratic fit to individual dos e-response curves. Comparisons were made with placebo and P < 0.05 was considered significant. 3 The I-25 was increased by carvedilol 25 mg and labetalol 400 mg (P < 0.05). The dose ratios at I-25 were: carvedi lol 6.25 mg 2.1 +/- 1.6, carvedilol 12.5 mg 3.1 +/- 1.9, carvedilol 25 mg 6.4 +/- 4.9 and labetalol 400 mg 8.8 +/- 4.4.4. The PS20 was incre ased by labetalol 400 mg (P < 0.05). The dose ratios at PS20 were: car vedilol 6.25 mg 1.1 +/- 0.3; 12.5 mg, 1.2 +/- 0.2; 25 mg, 1.3 +/- 0.4 and labetalol 400 mg 2.2 +/- 0.8. 5 The PD20 was increased by labetalo l 400 mg (P < 0.05). The dose ratios at PD20 were: carvedilol 6.25 mg 1.1 +/- 0.3; 12.5 mg, 1.3 +/- 0.3; carvedilol 25 mg 1.3 +/- 0.4 and la betalol 400 mg 2.1 +/- 0.8. 6 Exercise heart rate was reduced by carve dilol 6.25, 12.5 and 25 mg and labetalol 400 mg (152.9 +/- 13.4, 151.4 +/- 9.0, 144.1 +/- 10.5, 144.8 +/- 11.0 beats min(-1) respectively vs 161.8 +/- 14.1 beats min(-1) after placebo; P < 0.05). 7 In conclusio n, carvedilol 6.25, 12.5 and 25 mg demonstrated beta-adrenoceptor anta gonist activity with some evidence for alpha-adrenoceptor antagonist a ctivity with the 25 mg dose. Labetalol 400 mg showed both beta- and al pha-adrenoceptor antagonist activity with a beta- to alpha-adrenocepto r antagonist ratio of approximately 4 to 1.