Heart-rate variability effects of beta-adrenoceptor agonists (xamoterol, prenalterol, and salbutamol) assessed nonlinearly with scatterplots and sequence methods

Full antagonists of the cardiac beta-adrenoceptor improve heart-rate variab ility (HRV) in humans; however, partial agonism at the beta(2)-adrenoceptor has been suggested to decrease HRV. We therefore studied the HRV effects o f some partial agonists of the beta(1)- and beta(2)-adrenoceptors in normal volunteers. Under double-blind and randomised conditions (Latin square des ign), eight healthy volunteers received placebo; xamoterol, 200 mg (beta(1) -adrenoceptor partial agonist); prenalterol, 50 mg (beta(1)- and beta(2)-ad renoceptor partial agonist); salbutamol, 8 mg (beta(2)-adrenoceptor partial agonist); ICI 118,551, 25 mg (selective beta(2)-adrenoceptor antagonist); and combinations of each partial agonist with ICI 118,551. Single oral dose s of medication (at weekly intervals) were administered at 22:30 h with HRV assessed from the overnight sleeping heart rates. HRV was determined by us ing standard time-domain summary statistics and two nonlinear methods, the Poincare plot (scatterplot) and cardiac sequence analysis. On placebo, the sleeping heart rate decreased significantly, between 2 and 8 h after dosing . The heart rate with ICI 118,551 was unaltered. Xamoterol, prenalterol, an d salbutamol increased the sleeping heart rate. ICI 118,551 blocked the hea rt-rate effects of salbutamol, attenuated those of prenalterol, but did not influence the xamoterol heart rate. The scatterplot (Poincare) area was re duced by beta(1)-adrenoceptor (xamoterol), beta(2)-adrenoceptor (salbutamol ), and combined beta(1)- and beta(2)-adrenoceptor (prenalterol) agonism. A reduction in scatterplot length followed salbutamol, prenalterol alone, and prenalterol in combination with ICI 118,551. The geometric analysis of the scatterplots allowed width assessment (i.e., dispersion) at fixed RR inter vals. At higher heart rates (i.e., 25 and 50% of RR scatterplot length), di spersion was decreased after xamoterol, prenalterol, and prenalterol/ICI 11 8,551. Cardiac sequence analysis (differences between three adjacent beats; Delta RR vs. Delta RRn+1) assessed the short-term pat terns of cardiac acc eleration and deceleration; four patterns were identified: +/+ (a lengtheni ng sequencing), +/- or -/+ (balanced sequences), and finally -/- (a shorten ing sequence). Cardiac acceleration or deceleration episodes (i.e., number of times Delta RR and Delta RRn+1 were altered in the same direction) were increased after salbutamol and prenalterol. In conclusion, partial agonism at either the cardiac beta(1)-adrenoceptor (xamoterol), beta(2)-adrenocepto r (salbutamol), and beta(1)- plus beta(2)- adrenoceptors (prenalterol) alte red the autonomic balance toward sympathetic dominance in healthy volunteer s; blockade of the beta(2)-adrenoceptor with the highly selective beta(2)-a ntagonist ICI 118,551 prevented the effects of salbutamol on HRV, attenuate d the HRV effects of prenalterol, but had no effect on the actions of xamot erol. Agonism at both the beta(1)- and beta(2)-adrenoceptor reduced HRV in healthy subjects; the implications for the preventive use of the beta-adren oceptor compounds in cardiovascular disease warrant further investigation.