Ivabradine reduces baseline and stress-induced increase of heart rate and blood pressure and modulates neuroendocrine stress response in rats depending on stressor intensity

Abstract

Ivabradine, a selective inhibitor of the sinoatrial pacemaker, is used in clinical practice to reduce heart rate. However, its potential effect on the neuroendocrine stress response has not been investigated. Therefore, we determined the effect of administering ivabradine to rats on cardiovascular parameters and plasma levels of epinephrine, norepinephrine, and corticosterone. Ivabradine was administered intraperitoneally 30 min before exposing animals to either handling, restraint, or immobilization stress. Heart rate and blood pressure were monitored telemetrically. Blood samples were collected before, during, and after stressor exposure to determine the extent of the neuroendocrine stress response as reflected by plasma epinephrine, norepinephrine, and corticosterone levels. In animals pretreated with ivabradine, significantly lower values of heart rate and blood pressure were found during both the baseline period and during exposure to stressors, as well as during the rest period following stressor exposure. Ivabradine also significantly reduced handling-induced epinephrine and norepinephrine release into the bloodstream. However, ivabradine significantly potentiated restraint-and immobilization-induced increases of plasma epinephrine levels, whereas stress-induced changes in plasma norepinephrine and corticosterone levels were ambiguous. Our data shows that ivabradine significantly reduces blood pressure in rats during both baseline and stressful conditions, and also affects the neuroendocrine stress response. These findings show that viscerosensory signaling from the cardiovascular system may significantly modulate the neuroendocrine stress response.

The Arousal-motor Hypothesis of Dopamine Function: Evidence that Dopamine Facilitates Reward Seeking in Part by Maintaining Arousal

“…The brain states corresponding to different arousal levels are set by the activity of cholinergic and monoaminergic neural populations (Lee and Dan, 2012). Most importantly for our study, elevating arousal in rats by handling them was found to increase the release of acetylcholine, norepinephrine, serotonin, histamine, and dopamine, in multiple brain regions and in the periphery (Enrico et al, 1998;Inglis and Fibiger, 1995;Inglis and Moghaddam, 1999;Kalen et al, 1989;Kawahara et al, 1999;Ondicova et al, 2019;Westerink et al, 2002). While all these neuromodulatory systems participate in the natural arousal response, that does not mean that they play the same role.…”

“…Both procedures involved handling, which by itself provides a powerful arousing stimulus with a broad impact on brain activity. Handling rats triggers epinephrine and norepinephrine release into the bloodstream (Ondicova et al, 2019), increases hippocampal and cortical acetylcholine (Inglis and Fibiger, 1995), hippocampal norepinephrine and serotonin (Kalen et al, 1989), cortical histamine (Westerink et al, 2002) and stimulates the release of norepinephrine in the locus ceruleus and both norepinephrine and dopamine in the medial prefrontal cortex (Kawahara et al, 1999). Finally, handling rats was found to increase dopamine levels in multiple dopamine terminal regions, including the basolateral amygdala, the prefrontal cortex, and the NAc (Inglis and Moghaddam, 1999).…”

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin–Angiotensin–Aldosterone System

“…Second, ivabradine may provide a benefit via its presumable pleiotropic sympatholytic effect. Indeed, the pre-treatment of rats exposed to handling stress with ivabradine was associated with a reduced release of adrenaline and noradrenaline into the blood stream [ 49 ], and changes to heart rate variability (HRV) in a rat model of doxorubicin-induced HF indicated an improved autonomic imbalance by ivabradine [ 50 ]. The HRV analysis in a SHIFT Holter sub-study showed an ivabradine-mediated shift toward a more prominent parasympathetic tone [ 51 ].…”