Long-term effects of hyperpolarization-activated inward current blockade on cardiac parasympathetic activity

EP Europace ◽  
2021 ◽  
Vol 23 (Supplement_3) ◽  
Author(s):  
A Scridon ◽  
VB Halatiu ◽  
AI Balan ◽  
DA Cozac ◽  
GV Moldovan ◽  
...  
Keyword(s):  
Heart Rate ◽  
Vagus Nerve ◽  
Vagal Stimulation ◽  
Sinus Node ◽  
Vagal Tone ◽  
Right Atrial ◽  
The Right

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by a grant of the Romanian Ministry of Education and Research, CNCS - UEFISCDI Background The autonomic control of the pacemaker current, If, and the molecular mechanisms underlying parasympathetic If modulation are well understood. Conversely, the effects of chronic If blockade on the parasympathetic nervous system and on the heart rate (HR) response to acute parasympathetic changes are still largely unknown. Such interactions could significantly influence the course of patients undergoing chronic therapy with the If blocker ivabradine. Purpose We aimed to assess the effects of long-term If blockade using ivabradine on cardiac autonomic modulation and on the cardiovascular response to acute in vivo and in vitro parasympathetic stimulation. Methods Radiotelemetry ECG transmitters were implanted in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day); sympathetic and parasympathetic heart rate variability parameters were assessed. At the end of the study, the right atrium was removed and right atrial HCN(1-4) RNA expression levels were analyzed. The HR and systolic blood pressure (SBP) responses to in vivo electrical stimulation of the right vagus nerve (2–20 Hz) and the spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10-9–10-6 mol/L) were assessed in 6 additional Control and 10 IVA rats. Results At the end of the study, mean 24-h HR was significantly lower in the IVA compared with the Control rats (301.3 ± 7.5 bpm vs. 341.5 ± 8.3 bpm; p< 0.01). Ivabradine administration led to a significant increase in vagal tone and shifted the sympatho-vagal balance towards vagal dominance (awake, asleep, and over 24-h; all p< 0.05). In the Control rats, in vivo vagus nerve stimulation induced a progressive decrease in both the SBP (p = 0.0001) and the HR (p< 0.0001). Meanwhile, in the IVA rats, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p< 0.05). Ivabradine-treated rats also presented a significantly lower SNDR drop in response to carbamylcholine (p< 0.01) and significantly higher HCN4 expression (p = 0.02). Conclusion Long-term If blockade using ivabradine caused a significant increase in vagal tone and shifted the autonomic balance towards vagal dominance in rats. Given the highly proarrhythmic effects of vagal activation at the atrial level, these findings could provide an explanation for the increased risk of atrial fibrillation associated with ivabradine use in clinical trials. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in vivo vagal stimulation, and led to significant sinus node HCN4 up-regulation. These data suggest that ivabradine-induced HCN4 and the consequent If up-regulation could render the sinus node less sensitive to acute vagal inputs and could thus protect against excessive bradycardia induced by acute vagal activation.

scholarly journals Long-Term Effects of Ivabradine on Cardiac Vagal Parasympathetic Function in Normal Rats

2021 ◽  
Vol 12 ◽  
Author(s):  
Alina Scridon ◽  
Vasile Bogdan Halaţiu ◽  
Alkora Ioana Balan ◽  
Dan Alexandru Cozac ◽  
Valeriu Moldovan ◽  
...  
Keyword(s):  
Heart Rate ◽  
Vagus Nerve ◽  
Parasympathetic Nervous System ◽  
Vagal Stimulation ◽  
Cardiovascular Response ◽  
Right Atrial ◽  
Vagal Modulation

Background: The complex interactions that exist between the pacemaker current, If, and the parasympathetic nervous system could significantly influence the course of patients undergoing chronic therapy with the If blocker ivabradine. We thus aimed to assess the effects of chronic ivabradine therapy on autonomic modulation and on the cardiovascular response to in situ and in vitro parasympathetic stimulation. The right atrial expression of HCN genes, encoding proteins for If, was also evaluated.Methods: Sympathetic and parasympathetic heart rate variability parameters and right atrial HCN(1-4) RNA levels were analyzed in 6 Control and 10 ivabradine-treated male Wistar rats (IVA; 3 weeks, 10 mg/kg/day). The heart rate (HR) and systolic blood pressure (SBP) responses to in situ electrical stimulation of the vagus nerve (2–20 Hz) were assessed in 6 additional Control and 10 IVA rats. The spontaneous sinus node discharge rate (SNDR) response to in vitro cholinergic receptors stimulation using carbamylcholine (10−9–10−6 mol/L) was also assessed in these later rats.Results: Ivabradine significantly increased vagal modulation and shifted the sympatho-vagal balance toward vagal dominance. In Control, in situ vagus nerve stimulation induced progressive decrease in both the SBP (p = 0.0001) and the HR (p< 0.0001). Meanwhile, in IVA, vagal stimulation had no effect on the HR (p = 0.16) and induced a significantly lower drop in SBP (p< 0.05). IVA also displayed a significantly lower SNDR drop in response to carbamylcholine (p< 0.01) and significantly higher right atrial HCN4 expression (p = 0.02).Conclusion: Chronic ivabradine administration enhanced vagal modulation in healthy rats. In addition, ivabradine reduced the HR response to direct muscarinic receptors stimulation, canceled the cardioinhibitory response and blunted the hemodynamic response to in situ vagal stimulation. These data bring new insights into the mechanisms of ivabradine-related atrial proarrhythmia and suggest that long-term If blockade may protect against excessive bradycardia induced by acute vagal activation.

scholarly journals Arylamine N-acetyltransferase 2 Expression in the Developing Heart

2005 ◽  
Vol 53 (5) ◽  
pp. 583-592 ◽  
Author(s):  
Larissa Wakefield ◽  
Valerie Cornish ◽  
Fiona Broackes-Carter ◽  
Edith Sim
Keyword(s):  
Cardiac Tissue ◽  
Cardiac Development ◽  
Sinus Node ◽  
Circulation Pattern ◽  
Right Atrial ◽  
Developing Heart ◽  
Right Atrial Appendage ◽  
The Right

Murine arylamine N-acetyltransferase 2 (NAT2) is expressed in the developing heart and in the neural tube at the time of closure. Classically described as a xenobiotic metabolizing enzyme, there is increasing evidence for a distinct biological role for murine NAT2. We have characterized the expression of arylamine N-acetyltransferase 2 during cardiogenesis, mapping its expression in vivo, using a lacZ insertion deletion, and also in vitro, by measuring NAT2 enzyme activity. These findings show that cardiac Nat2 expression is both temporally and spatially regulated during development. In neonatal mice, cardiac Nat2 expression is most extensive in the central fibrous body and is evident in the atrioventricular valves and the valves of the great vessels. Whereas Nat2 expression is not detected in ventricular myocardial cells, Nat2 is strongly expressed in scattered cells in the region of the sinus node, the epicardium of the right atrial appendage, and in the pulmonary artery. Expression of active NAT2 protein is maximal when the developing heart attains the adult circulation pattern and moves from metabolizing glucose to fatty acids. NAT2 acetylating activity in cardiac tissue from Nat2−/- and Nat2+/- mice indicates a lack of compensating acetylating activity either from other acetylating enzymes or by NAT2 encoded by the wild-type Nat2 allele in Nat2+/- heterozygotes. The temporal and spatial control of murine Nat2 expression points to an endogenous role distinct from xenobiotic metabolism and indicates that Nat2 expression may be useful as a marker in cardiac development.

Abstract 418: Caveolar Disruption of L-type Calcium Channel and Ryanodine Receptor Facilitates Atrial Ectopy and Arrhythmogenesis in Heart Failure Mice

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Di Lang ◽  
Lucas ratajczyk ◽  
Leonid Tyan ◽  
Daniel Turner ◽  
Francisco Alvarado ◽  
...  
Keyword(s):  
Heart Failure ◽  
Optical Mapping ◽  
Ryanodine Receptors ◽  
Tissue Level ◽  
Confocal Imaging ◽  
Right Atrial ◽  
Isolated Atria ◽  
The Right

Atrial fibrillation (AF) often occurs during heart failure (HF). Ectopic foci that trigger AF, are linked to discrete atrial regions that experience the highest remodeling and clinically used for AF ablation; however, mechanisms of their arrhythmogenic propensity remain elusive. We employed in vivo ECG telemetry, in vitro optical mapping and confocal imaging of Ca 2+ transients (CaT) from myocytes isolated from the right atrial appendage (RAA) and inter-caval region (ICR) of wild type (WT, n=10), caveolin-3 knockout (KO, n=6) and 8-weeks post-myocardial infarction HF (n=8) mice. HF and KO mice showed an increased susceptibility to pacing-induced AF and enhanced ectopy originated exclusively from ICR. Optical mapping in isolated atria showed prolongation of CaT rise up time (CaT-RT) in HF ICR, which suggested a remodeled coupling between L-type Ca 2+ channels (LTCCs) and ryanodine receptors (RyRs) in this specific region. In WT mice, RAA consists of structured myocytes with a prominent transverse-axial tubular system (TATS) while ICR myocytes don’t have TATS. In RAA, CaT-RT depends on LTCCs in TATS triggering RyR, while in ICR, all the LTCCs are localized in surface caveolae where they can activate subsarcolemmal RyRs and lead to a slow diffusion of Ca 2+ inside the cell interior. Downregulation of caveolae was observed specifically in HF ICR. To mimic this, we used cav3-KO mice. Triggered activities were observed in myocytes isolated from HF and KO ICR, which presumably underlie the ectopic activities in tissue level. These myocytes presented significantly unsynchronized sarcoplasmic reticulum (SR) Ca 2+ releases (synchronization index: 10.8±0.9 in WT vs 38.3±4.1 in HF vs 21.5±2.1 in KO, p <0.01 for HF and KO vs WT respectively) especially at the subsarcolemmal space that prolongs CaT-RT (62.2±4.1 ms in WT vs 122.5±12.8 ms in KO, p <0.01). In addition, failing ICR myocytes showed a higher occurrence and size of spontaneous Ca 2+ sparks which were linked to CaMKII activity and associated phosphorylation of RyR. Our findings demonstrate that in HF, caveolar disruption creates “hot spots” for arrhythmogenic ectopic activity emanated from discrete vulnerable regions of the right atrium which are associated with desynchronized SR Ca 2+ release and elevated fibrosis.

Effect of cervical vagal stimulation on chicken heart rate and atrioventricular conduction

1983 ◽  
Vol 244 (2) ◽  
pp. R235-R243
Author(s):  
J. M. Goldberg ◽  
M. H. Johnson ◽  
K. D. Whitelaw
Keyword(s):  
Heart Rate ◽  
Vagal Stimulation ◽  
Atrioventricular Conduction ◽  
Right Atrial ◽  
Atrial Pacing ◽  
Chicken Heart ◽  
Av Conduction ◽  
Supramaximal Stimulation ◽  
The Right ◽  
Stimulation Of

The effects of supramaximal stimulation of the right and left cervical vagi on heart rate, pacemaker localization, and atrioventricular (AV) conduction were investigated in 15 anesthetized open-chest chickens before and after atropine sulfate. Epicardial bipolar electrograms were recorded from selected atrial sites and right ventricle. A back lead electrocardiogram was also recorded. The effect of stimulation on atrioventricular conduction was evaluated during pacing from one of the right atrial recording sites. Supramaximal stimulation of either cervical vagus produced bradycardia but not cardiac arrest. Heart rate was reduced from an average spontaneous rate of 282 +/- 13 (SE)/min to 161 +/- 13/min with stimulation of the right and left cervical vagus. Pacemaker shifts occurred in over 50% of the vagal stimulations. The most frequent shift occurred to the lower AV node or ventricles. Pacemaker shifts to the AV junctional region producing almost simultaneous activation of the atria and ventricles were not observed. Vagal stimulation during atrial pacing produced minimal prolongation in AV conduction time [right vagus, 13 +/- 3 (SE) ms; left vagus, 8 +/- 2 ms]. Second and third degree heart blocks were not observed during pacing. Vagal stimulation after atropine indicates that the cervical vagi do not contain sympathetic fibers going to pacemaker or AV conduction tissues.

Extrinsic inputs to intrinsic neurons in the porcine heart in vitro

1999 ◽  
Vol 276 (2) ◽  
pp. R455-R467 ◽  
Author(s):  
F. M. Smith
Keyword(s):  
Vagus Nerve ◽  
Nerve Stimulation ◽  
Neural Control ◽  
Threshold Level ◽  
Vagal Nerve ◽  
Vagal Nerve Stimulation ◽  
Right Atrial ◽  
The Right ◽  
Β Adrenergic Receptors

Convergence of inputs from extrinsic cardiac nerves [vagus and cardiopulmonary (CPN)] on intrinsic cardiac neurons was investigated in the pig ( Sus scrofa). A segment of the right atrial wall containing epicardial neurons along with attached stumps of the right vagus nerve and CPN was maintained in vitro; intracellular recordings were made from 57 neurons. Three types of neuron were identified by their responses to long intracellular depolarizing current pulses: phasic [discharged 1 action potential (AP); 40%]; accommodating (discharged multiple APs decrementing in frequency during pulse; 33%); and tonic (discharged multiple APs at a high frequency; 27%). Sixty-six percent of the neurons responded with excitatory postsynaptic potentials (EPSP) to vagal nerve stimulation; two-thirds of these cells fired APs when EPSP amplitude exceeded threshold level. Postsynaptic responses to vagal nerve stimulation were mediated by nicotinic ion channels; responses were eliminated by hexamethonium. CPN stimulation produced EPSPs but no APs in 17% of the neurons. All neurons responding with postsynaptic depolarizations to CPN stimulation also received vagal inputs. Combined stimulation of the vagus nerve and CPN produced APs in all but one of these neurons. Timolol eliminated postsynaptic responses from CPN stimulation, indicating that these responses involved β-adrenergic receptors and likely resulted from activation of sympathetic postganglionic terminals. These results show that some intrinsic cardiac neurons receive convergent inputs from the CPN and vagus nerve. It is suggested that such neurons represent intraganglionic sites for sympathetic-parasympathetic interactions in neural control of the heart.

Modulation of electrophysiological properties of neonatal canine heart by tonic parasympathetic stimulation

1990 ◽  
Vol 258 (1) ◽  
pp. H38-H44 ◽  
Author(s):  
A. S. Pickoff ◽  
A. Stolfi
Keyword(s):  
Cycle Length ◽  
Parasympathetic Nervous System ◽  
Vagal Stimulation ◽  
Sinus Node ◽  
Right Atrial ◽  
Conduction Time ◽  
Canine Heart ◽  
Electrophysiological Properties ◽  
Refractory Periods ◽  
The Right

The effects of tonic right and left vagal stimulation (RVS and LVS) on electrophysiological properties of the immature myocardium and specialized conduction system were evaluated in 11 neonatal canines pretreated with propranolol (1 mg/kg iv). Electrophysiological studies were performed by recording intracardiac electrograms from multiple endocardial catheters during programmed electrical stimulation. Assessments were made of sinus node function, intra-atrial, atrioventricular (AV) nodal and His-Purkinje conduction, and atrial and ventricular refractoriness in the control state and during RVS and LVS at 4–12 Hz. Vagal stimulation prolonged the sinus cycle length; RVS produced a 38% increase and LVS a 25% increase at 8 Hz (P less than 0.01). There were no changes in the intra-atrial or His-Purkinje conduction times. Comparable increases occurred during RVS and LVS in the paced cycle length resulting in AV nodal Wenckebach, the AV nodal conduction time at a paced cycle length of 340 ms, and the effective and functional refractory periods of the AV node, suggesting symmetrical influences of the right and left vagus on neonatal AV nodal function. Right atrial effective and functional refractory periods shortened significantly during vagal stimulation (ERP, 36% RVS and 23% LVS; FRP, 27% RVS and 15% LVS), and in 5 of 11 neonates, a sustained regular atrial tachyarrhythmia was induced during atrial extra-stimulation. Small yet significant increases were observed in the right ventricular ERP and FRP during vagal stimulation. This study provides information regarding the functional integrity of the parasympathetic nervous system and its potential role as a modulator of the electrophysiological properties of the newborn heart.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhancement of cardiac vagal action during ischaemia of the sino-atrial node

1986 ◽  
Vol 71 (4) ◽  
pp. 449-451 ◽  
Author(s):  
Erica K. Potter ◽  
D. I. McCloskey ◽  
Gillian P. Courtice
Keyword(s):  
Heart Rate ◽  
Vagus Nerve ◽  
Sinoatrial Node ◽  
Vagal Stimulation ◽  
Arterial Supply ◽  
The Right

1. The effect of ischaemia of the sino-atrial node on cardiac vagal action was studied in anaesthetized dogs. 2. The cut, cardiac end of the right vagus nerve was stimulated with a standard supramaximal stimulus every 10 s. The arterial supply to the sinoatrial node was occluded for periods of 1–3 min during this intermittent vagal stimulation. 3. Vagal action on heart rate was potentiated during ischaemia of the sino-atrial node.

Electrophysiological-anatomic correlates of ATP-triggered vagal reflex in dogs

1993 ◽  
Vol 265 (2) ◽  
pp. H681-H690 ◽  
Author(s):  
A. Pelleg ◽  
C. M. Hurt ◽  
J. M. Soler-Baillo ◽  
M. Polansky
Keyword(s):  
Vagus Nerve ◽  
Sinus Node ◽  
Right Atrial ◽  
Pacemaker Activity ◽  
Dependent Manner ◽  
Vagus Nerves ◽  
Experimental Conditions ◽  
C Fiber ◽  
Vagal Reflex ◽  
The Right

To test the hypothesis that afferent traffic of the ATP-triggered vagal reflex travels mainly in the right vagus nerve, we quantitated the response of the sinus node pacemaker activity and atrioventricular (AV) nodal conduction to increasing doses of intra-atrial ATP under baseline conditions, in the presence of aminophylline, and subsequently after either right followed by left cervical vagotomy or vice versa. In addition, the effect of right vagal C-fiber afferent blockade on the action of ATP in the sinus node was also determined. Because vagal efferent traffic to the sinus and AV nodes travels mainly via the right and left vagus nerves, respectively, the working hypothesis predicted that left vagotomy would have a much smaller effect than right vagotomy on the negative chronotropic action of ATP in the sinus node and predicted similar effects of left vs. right vagotomy on the negative dromotropic action of ATP on AV nodal conduction. ATP suppressed sinus node automaticity and AV nodal conduction in a dose-dependent manner. The attenuation of the action of ATP on the sinus node by right vagotomy was much more pronounced than that caused by left vagotomy, while the negative dromotropic action of ATP in the AV node was similarly attenuated by right vs. left vagotomy. In addition, sinus node automaticity, which was only mildly attenuated by left vagotomy, was markedly suppressed by right vagal C-fiber afferent blockade. It was concluded that in the dog, afferent vagal traffic triggered by intra-right atrial ATP travels under these experimental conditions mainly via the right vagus nerve.

Dynamics of heart rate response to sympathetic nerve stimulation

1998 ◽  
Vol 275 (3) ◽  
pp. H995-H1001 ◽  
Author(s):  
Abdelkader Mokrane ◽  
Réginald Nadeau
Keyword(s):  
Heart Rate ◽  
Time Constant ◽  
Nerve Stimulation ◽  
Sympathetic Nerve ◽  
Neural Control ◽  
Sinus Node ◽  
Mean Delay ◽  
Norepinephrine Concentration ◽  
The Right

Electrical stimulation of the right cardiac sympathetic nerve was used to achieve a step increase of norepinephrine concentration at the sinus node. The heart rate (HR) response to sympathetic stimulation was characterized by a first-order process with a time delay. For moderate to high intensities of stimulation the mean delay and time constant were 0.7 and 2.1 s, respectively, and for low intensities of stimulation they were 0.4 and 1.1 s, respectively. From the analysis of the HR response to different patterns of nerve stimulation, in vivo neurotransmitter kinetics were estimated. The time constant of norepinephrine dissipation averaged ∼9 s. These results combined with computer simulations revealed two facets of sympathetic neural control of HR: 1) negligible role of the sympathetic system in beat-to-beat regulation of HR under stationary conditions and 2) ability of HR to react relatively quickly (within a few seconds) to sharp increases in sympathetic nerve traffic.

Determinants of atrial contractile force in the intact heart

1965 ◽  
Vol 209 (6) ◽  
pp. 1061-1068 ◽  
Author(s):  
John F. Williams ◽  
Edmund H. Sonnenblick ◽  
Eugene Braunwald
Keyword(s):  
Vagus Nerve ◽  
Vagal Stimulation ◽  
Contractile Force ◽  
Right Atrial ◽  
Direct Stimulation ◽  
Wide Range ◽  
Left And Right ◽  
The Right ◽  
Tension Curves ◽  
Intact Heart

Atrial contractile force was recorded in anesthetized open-chested dogs using a specially designed adjustable strain-gauge arch, linear over a wide range of forces. The shape of both resting and active atrial length-tension curves as well as the maximum force developed was similar to those described for the ventricle, after corrections for differences in muscle mass. Increasing heart rate by right atrial stimulation had no significant effect on atrial force. Isoproterenol, calcium, and acetylstrophanthidin each produced marked increases in the force of contraction. Sympathetic stimulation, produced by direct stellate stimulation or reflexly induced by carotid hypotension, increased atrial force, whereas direct vagal stimulation or vagal stimulation produced reflexly by balloon inflation in the thoracic aorta produced marked decreases in atrial force. Both atria were depressed more by direct stimulation of the right vagus nerve than of the left, and right atrial force was affected more than was left atrial force when either vagus nerve was stimulated.

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