Use of opposing reflex stimuli and heart rate variability to examine the effects of lipophilic and hydrophilic β-blockers on human cardiac vagal control

Abstract

Evidence from animal studies suggests that beta-blockers can act within the central nervous system to increase cardiac vagal motoneuron activity. We have attempted to determine whether such an effect is evident in healthy humans, by examining the effects of lipophilic and hydrophilic agents on heart rate variability and cardiac vagal reflexes. A total of 20 healthy volunteers took part in the study. Autonomic studies were performed after 72 h of treatment with placebo, atenolol or metoprolol in a blinded cross-over design. ECG recordings were taken at rest and during mental and orthostatic stress. Heart rate variability was measured in the time and frequency domains. The effects on heart rate of two opposing cardiac vagal reflexes were examined. Trigeminal stimulation causing vagal stimulation, and isometric forearm muscle contraction ('muscle heart reflex') causing vagal inhibition, were performed alone and simultaneously. At rest, during mental stress and during trigeminal stimulation, beta-blocker therapy was associated with significantly increased high-frequency beat-to-beat heart rate variability when compared with placebo. There were no significant differences in effects on heart rate or heart rate variability between atenolol and metoprolol. Analysis of the muscle heart reflex, alone and with simultaneous trigeminal stimulation, showed that the magnitude of the R-R interval response was significantly greater after beta-blocker therapy compared with placebo, but the effects of atenolol and metoprolol were equivalent. beta-Blocker therapy increased cardiac vagal activity, as shown by measures of high-frequency heart rate variability and reflex studies. Lipophilic and hydrophilic beta-blockers appeared to be equally efficacious in increasing the cardiac vagal modulation of heart rate.

Limited Effect of Systemic β-Blockade on Sympathetic Outflow

“…However, in another study lipophilic and hydrophilic ␤-blockers had similar effects on responses to cardiovascular reflex testing and heart rate variability. 10 This finding is not consistent with an important effect of central ␤-adrenoreceptors on autonomic regulation because lipophilic agents cross the blood-brain barrier, whereas hydrophilic ␤-blockers mainly act in peripheral tissues. We tested the hypothesis that central nervous ␤-adrenoreceptors have a tonic stimulatory effect on the sympathetic nervous system and that this effect can be attenuated by systemic ␤-blockade.…”

Comparação entre métodos de avaliação da modulação vagal autonômica

“…In that context, it is unlikely that the use of beta-blockers has influenced only the results obtained with the HRV. There is consistent evidence that beta-blockers increase CVM through both a direct effect on the central nervous system 3 and a peripheral effect, due to a reduction in heart rate, which increases the probability that acetylcholine acts on the slow diastolic depolarization of sinoatrial node cells 4 , and due to a reduction in the pre-synaptic inhibition of the release of acetylcholine mediated by sympathetic activity 5 .…”

“…; B) the use of beta-blockers was observed in 100% of the patients with coronary heart disease, as expected, considering the current guidelines, and in 0% of the healthy group. Autonomic modulation depends on a complex regulatory mechanism involving interaction between the sympathetic and parasympathetic pathways 3,4 . However, after beta-blockade, the "modulatory" behavior of the vagus nerve is no longer spontaneous.…”

Antiarrhythmic effects of omega-3 fatty acids: from epidemiology to bedside

“…It has been suggested that a rate-independent effect of a drug on heart rate variability can be established by demonstrating an effect on heart rate variability normalized for the heart rate (eg, expressing the standard deviation of the R-R intervals as a percent of the mean R-R interval, ie, its coefficient of variation). 86 Such correc-tions have not yet been clearly reported in the setting of omega-3 FA, and further research is warranted.…”

“…[82][83][84][85][86] In a highly consistent series of studies, Christensen et al have shown an effect of omega-3 FA on heart rate variability in humans. First, in 55 postmyocardial infarction patients with left ventricular dysfunction, these authors documented a direct relationship between habits of fish consumption (and corresponding omega-3 FA levels in platelet membranes) and heart rate variability, expressed as the standard deviation of the R-R interval on 24-hour Holter monitoring.…”