MRI of the ankle influences clinicians' diagnoses and management plans.

1 The a-and ,B-adrenoceptor antagonist activity of carvedilol, a 3-adrenoceptor antagonist with vasodilating properties, and labetalol were investigated in 10 healthy male subjects. They received infusions with serially increasing concentrations of isoprenaline and phenylephrine 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 double-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 (I25) and the dose of phenylephrine required to increase systolic and diastolic blood pressure by 20 mm Hg (PS20 and PD20) were calculated using a quadratic fit to individual dose-response curves. Comparisons were made with placebo and P < 0.05 was considered significant.3 The I25 was increased by carvedilol 25 mg and labetalol 400 mg (P < 0.05). The dose ratios at I25 were: carvedilol 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 increased by labetalol 400 mg (P < 0.05). The dose ratios at PS20 were: carvedilol 6.25 mg 1.0 ± 0.2; 12.5 mg, 1.2 ± 0.2; 25 mg, 1.3 ± 0.4 and labetalol 400 mg 2.2 ± 0.8. 5The PD20 was increased by labetalol 400 mg (P < 0.05). The dose ratios at PD20were: carvedilol 6.25 mg 1.1 ± 0.3; 12.5 mg, 1.3 ± 0.3; carvedilol 25 mg 1.3 ± 0.4 and labetalol 400 mg 2.1 ± 0.8. 6 Exercise heart rate was reduced by carvedilol 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-I respectively vs 161.8 ± 14.1 beats min-1 after placebo; P < 0.05). 7 In conclusion, carvedilol 6.25, 12.5 and 25 mg demonstrated ,-adrenoceptor antagonist activity with some evidence for a-adrenoceptor antagonist activity with the 25 mg dose. Labetalol 400 mg showed both ,B-and a-adrenoceptor antagonist activity with a IP-to a-adrenoceptor antagonist ratio of approximately 4 to 1.

The influence of celiprolol (beta1- and beta2-adrenoceptor partial agonist), propranolol (beta1- and beta2-adrenoceptor antagonist), and atenolol (beta1-adrenoceptor antagonist) on heart-rate variability (HRV) was assessed from Holter records in 12 normal volunteers. A combination of summary statistics and nonlinear procedures was used to assess HRV and autonomic balance. Under double-blind and randomised conditions (Latin-square design), subjects received placebo, celiprolol (200 and 800 mg), propranolol (160 mg), atenolol (50 mg), and combinations of these agents. Single oral doses of medication (at weekly intervals) were administered at 22:30 h with sleeping heart rates (HRs) recorded overnight. Compared with placebo, celiprolol (200 and 800 mg) increased the sleeping HR, the HR effect of celiprolol was different from the bradycardia after propranolol, 160 mg, and atenolol, 50 mg. Dose-response effects on HR with celiprolol were evident in the presence of atenolol, unlike those with propranolol that abolished the HR increase between celiprolol, 200 mg and 800 mg. These data were consistent with beta1-selective adrenoceptor agonism with 200 mg but agonism at both the beta1- and beta2-adrenoceptor with celiprolol, 800 mg. The action of the drugs on short-term HRV indices (rMSSD and pNN50) closely followed their effects on HR. The longer-term HRV indices (global SD, SDANN) were reduced by celiprolol but increased by propranolol and atenolol. At a fixed HR, the data dispersion (SDNN5) was higher with propranolol compared with celiprolol; however, the dispersion was not merely an HR-dependent phenomenon. A novel nonlinear approach (quadrant analysis) revealed the sequencing of cardiac accelerations and decelerations after the high correlation between adjacent intervals had been removed. Celiprolol increased the frequency of consecutive cardiac accelerations; the duration between and variance of these beat-to-beat differences shortened after celiprolol but lengthened with increased variance after propranolol and atenolol. These results demonstrated reduced HRV indices and a shift toward sympathetic dominance after the beta-adrenoceptor agonist celiprolol contrasting with increased HRV indices and parasympathetic dominance after the beta-adrenoceptor antagonists propranolol and atenolol. The implications of these findings for the treatment of patients with cardiovascular disease warrant further study.

The variability in the pressor effects of the alpha 1-adrenoceptor agonist phenylephrine was observed under placebo conditions in ten healthy subjects in a double blind randomized study. Phenylephrine infusions were administered before administration of placebo (baseline) and 2, 4, 8, 12, 24 and 48 h later. The doses of phenylephrine required to increase systolic blood pressure by 20 mmHg after 8 and 12 h (5.30 and 9.30 pm, 81.4 +/- 15.3 and 71.1 +/- 16.0 micrograms min-1, respectively) were significantly (P < 0.01) less than the baseline values (8.30 am, 108.0 +/- 27.6 g min-1). These results might indicate a circadian variation in the phenylephrine-induced alpha-adrenoceptor-mediated vascular response in healthy subjects. These observations lend further insight into circadian variations of vascular tone that might contribute to circadian rhythms in cardiovascular disease.

1 The a-adrenoceptor antagonist, P,-adrenoceptor antagonist and ,82-partial agonist activity of dilevalol, a ,3-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-').