EFFECTS OF BETA-ADRENOCEPTOR AGONISTS AND ANTAGONISTS ON HEART-RATE-VARIABILITY IN NORMAL SUBJECTS ASSESSED USING SUMMARY STATISTICS AND NONLINEAR PROCEDURES

The influence of celiprolol (beta(1)- and beta(2)-adrenoceptor partial agonist), propranolol (beta(1)- and beta(2)-adrenoceptor antagonist), and atenolol (beta(1)-adrenoceptor antagonist) on heart-rate variabil ity (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 c onditions (Latin-square design), subjects received placebo, celiprolol (200 and 800 mg), propranolol (160 mg), atenolol (50 mg), and combina tions of these agents. Single oral doses of medication (at weekly inte rvals) were administered at 22:30 h with sleeping heart rates (HRs) re corded overnight. Compared with placebo, celiprolol (200 and 800 mg) i ncreased the sleeping HR; the HR effect of celiprolol was different fr om the bradycardia after propranolol, 160 mg, and atenolol, 50 mg. Dos e-response effects on HR with celiprolol were evident in the presence of atenolol, unlike those with propranolol that abolished the HR incre ase between celiprolol, 200 mg and 800 mg. These data were consistent with beta(1)-selective adrenoceptor agonism with 200 mg but agonism at both the beta(1)- and beta(2)-adrenoceptor with celiprolol, 800 mg. T he action of the drugs on short-term HRV indices (rMSSD and pNN(50)) c losely followed their effects on HR. The longer-term HRV indices (glob al SD, SDANN) were reduced by celiprolol but increased by propranolol and atenolol. At a fixed HR, the data dispersion (SDNN5) was higher wi th propranolol compared with celiprolol; however, the dispersion was n ot merely an HR-dependent phenomenon. A novel nonlinear approach (quad rant analysis) revealed the sequencing of cardiac accelerations and de celerations after the high correlation between adjacent intervals had been removed. Celiprolol increased the frequency of consecutive cardia c accelerations; the duration between and variance of these beat-to-be at differences shortened after celiprolol but lengthened with increase d 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 i ndices and parasympathetic dominance after the beta-adrenoceptor antag onists propranolol and atenolol. The implications of these findings fo r the treatment of patients with cardiovascular disease warrant furthe r study.