Effects of β-Adrenoceptor Agonists and Antagonists on Heart-Rate Variability in Normal Subjects Assessed Using Summary Statistics and Nonlinear Procedures

Abstract

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 potential cardiotoxicity of antipsychotic drugs as assessed by heart rate variability

“…We have developed a computer method to provide quantitative analysis of scatterplots; the major dimensions of length, area and width together with a density function can be rapidly and accurately determined. We have demonstrated that this methodology can differentiate between low and high autonomic states (Silke and Riddell, 1997). This is important because, when the autonomic state is attenuated, there is usually an improved patient survival, following myocardial infarction (Norwegian Multicentre Study Group, 1981;β-blocker Heart Attack Research Group, 1982) and in heart failure (Lechat et al, 1998).…”

“…HRV has been altered by drug therapy [e.g. beta-adrenoceptor antagonists increased variability (Brouwer et al, 1995;Pousset et al, 1996)], unlike partial agonists of the betaadrenoceptor, that impaired HRV (Silke and Riddell, 1997). As far as psychotropic medication is concerned, both tricyclic antidepressants (Walsh et al, 1994;Rechlin, 1995a,b;Tulen et al, 1996;Mezzacappa et al, 1998;Walsh et al, 1999) and clozapine (Rechlin, 1995a,b;Agelink et al, 1998) have been found to decrease HRV, which has been attributed to their anticholinergic properties and the consequent decreased parasympathetic regulation of cardiac function.…”

Evaluation of the effect on heart rate variability of a β2‐adrenoceptor agonist and antagonist using non‐linear scatterplot and sequence methods

“…Another selective β 2 ‐adrenoceptor agonist, terbutaline, also decreased the RR interval variability indices related to vagal tone; the parasympathetic nervous reactivity decreased [ 42]. Celiprolol (dose‐dependent β 2 ‐adrenoceptor partial agonist [ 43]) reduced short and long‐term time domain statistics together with scatterplot length, area and width [ 11]. In addition sequence analysis demonstrated an increased frequency of acceleration episodes, in accord with the hypothesis of a shift from balanced autonomic control to sympathetic dominance.…”

“…In addition sequence analysis demonstrated an increased frequency of acceleration episodes, in accord with the hypothesis of a shift from balanced autonomic control to sympathetic dominance. These effects of celiprolol (800 mg), in reducing HRV indices, were attenuated by β 1 ‐ and β 2 ‐adrenoceptor blockade with propranolol 160 mg but not by β 1 ‐adrenoceptor blockade with 50 mg atenolol [ 11]. Therefore one can conclude that agonism at the β 2 ‐adrenoceptor reduces HRV in contrast to antagonism at the β 1 ‐adrenoceptor, when HRV indices are increased.…”

“…The relationship between the ancillary pharmacological properties of a β‐adrenoceptor drug [ 10] and HRV is a neglected area. We have demonstrated that the partial β‐adrenoceptor agonist celiprolol reduced time‐domain and non‐linear measures of heart rate variability; a component of the reduced variability appeared mediated through the β 2 ‐adrenoceptor [ 11]. We therefore sought to extend these observations on HRV effects of agonism and antagonism at the β 2 ‐adrenoceptor in normal volunteers under randomised, double‐blind and placebo controlled conditions.…”