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

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Abstract
Aims To examine the impact on heart rate variability (HRV), of agonism or antagonism at the cardiac β2-adrenoceptor in healthy volunteers, using standard time-domain summary statistics and non-linear methods (scatterplot and quadrant analysis). Methods Under double-blind and randomised conditions (Latin square design), 17 normal volunteers received placebo, salbutamol (β2-adrenoceptor partial agonist), ICI 118,551 (specific β2-adrenoceptor antagonist), or salbutamol plus ICI 118,551. Single oral doses of medication (at weekly intervals) were administered at 22.30 h, with HRV assessed from the sleeping heart rates. Results Salbutamol reduced the long-term (SDNN: 135 ms [120, 156], SDANN: 107 ms [89, 124]) time-domain indicators of HRV compared with placebo (SDNN: 39 [24, 55], SDANN 42 [29, 56], {mean difference [95% confidence intervals of difference]}). Alone, ICI 118,551 did not effect HRV, but in combination blocked the actions of salbutamol. Scatterplot length (944 ms [869, 1019]) and area (222*103 ms2 [191, 253]) were reduced by salbutamol compared with placebo; (length difference (164 [98, 230]) and area difference 59 [36, 83]). Scatterplot width (dispersion) was lower at both low (width RR-1 25% salbutamol 277 ms [261, 293]: salbutamol minus placebo 14 ms [0, 28]) and high (width 75% salbutamol 417 [391, 443]: salbutamol minus placebo 41 [20, 62]) heart rates. ICI 118,551 alone did not alter scatterplot parameters but in combination blocked the effect of salbutamol. Cardiac acceleration episodes (i.e. consecutive ΔRR and ΔRRn+1 shorten) were increased following salbutamol 7288 [6089, 8486] compared with placebo −1890 [−2600, −1179]; the beat-to beat difference (ΔRRn+1 ) was reduced after salbutamol compared with the other treatments. ICI 118,551 did not effect acceleration episodes but reduced the effect of salbutamol when used in combination. Conclusions Agonism at the cardiac β2-adrenoceptor in healthy volunteers with salbutamol altered autonomic balance towards sympathetic dominance; this re-balancing was blocked by ICI 118,551 given in combination with salbutamol. However antagonism at the β2-adrenoceptor with ICI 118,551 alone did not significantly alter the HRV. The β2-adrenoceptor modulates HRV in healthy volunteers; the implications of agonism and antagonism at the β2-adrenoceptor in cardiovascular disease states warrants further investigation.

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