Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node

Farias, Martin; Jackson, Keith E.; Johnson, Michael W.; Caffrey, James L.

doi:10.1152/ajpheart.00275.2003

Cited by 13 publications

(7 citation statements)

References 29 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, stimulation of ORs has been shown to be cardioprotective against myocardial infarction and may trigger processes similar to ischemic preconditioning (Schultz and Gross, 2001; Gross, 2003). Activation of ORs is associated with a modulation of vagal transmission in the sinoatrial node and atria (Starke et al, 1985; Farias et al, 2003; Deo et al, 2008). Recently, after the cloning of opioid receptors, Bell et al (2000) identified the mRNA of all three opioid receptor subtypes [μ (M), δ (D), and κ (K)] within human myocardium by using RT‐PCR.…”

mentioning

confidence: 99%

Identification of μ‐ and κ‐opioid receptors as potential targets to regulate parasympathetic, sympathetic, and sensory neurons within rat intracardiac ganglia

Mousa

Shaqura

Schäper

et al. 2010

J of Comparative Neurology

View full text Add to dashboard Cite

Recent interest has been focused on the opioid regulation of heart performance; however, specific allocation of opioid receptors to the parasympathetic, sympathetic, and sensory innervations of the heart is scarce. Therefore, the present study aimed to characterize such specific target sites for opioids in intracardiac ganglia, which act as a complex network for the integration of the heart's neuronal in- and output. Tissue samples from rat heart atria were subjected to RT-PCR, Western blot, radioligand-binding, and double immunofluorescence confocal analysis of mu (M)- and kappa (K)-opioid receptors (ORs) with the neuronal markers vesicular acetylcholine transporter (VAChT), tyrosine hydroxylase (TH), calcitonin gene-related peptide (CGRP), and substance P (SP). Our results demonstrated MOR- and KOR-specific mRNA, receptor protein, and selective membrane ligand binding. By using immunofluorescence confocal microscopy, MOR and KOR immunoreactivity were colocalized with VAChT in large-diameter parasympathetic principal neurons, with TH-immunoreactive small intensely fluorescent (SIF) cells, and on nearby TH-IR varicose terminals. In addition, MOR and KOR immunoreactivity were identified on CGRP- and SP-IR sensory neurons throughout intracardiac ganglia and atrial myocardium. Our findings show that MOR and KOR are expressed as mRNA and translated into specific receptor proteins on cardiac parasympathetic, sympathetic, and sensory neurons as potential binding sites for opioids. Thus, they may well play a role within the complex network for the integration of the heart's neuronal in- and output.

show abstract

mentioning

confidence: 99%

Identification of μ‐ and κ‐opioid receptors as potential targets to regulate parasympathetic, sympathetic, and sensory neurons within rat intracardiac ganglia

Mousa

Shaqura

Schäper

et al. 2010

J of Comparative Neurology

View full text Add to dashboard Cite

show abstract

“…In addition to direct innervation, multiple factors within the node modify both spontaneous activity and neurotransmitter release. Among these moderators, cardiac opioids appear to be potentially important neuromodulators (3,9,10).…”

mentioning

confidence: 99%

“…ME, leucine-enkephalin (LE), and MEAP have all been demonstrated to alter vagally induced bradycardia when introduced into the SA node by microdialysis (9 -11, 13). The opioids identified in the heart alter heart rate by binding to specific opiate receptors, which are probably located prejunctionally on sympathetic and parasympathetic nerve terminals (10,27).…”

mentioning

confidence: 99%

“…In the heart, ␦-receptor stimulation produced a bimodal response during vagal stimulation (11,13). Lower doses (10 Ϫ15 mol/min) of enkephalin enhanced vagal transmission (vagotonic), while higher doses (10 Ϫ12 mol/min) suppressed vagal transmission (vagolytic) (11). The two opposing effects appeared to have been mediated by phenotypes of the ␦-opioid receptor because each effect was blocked by subtype-specific antagonists.…”

mentioning

confidence: 99%

See 1 more Smart Citation

The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of δ₂-opioid receptor stimulation

Davis

Deo²,

Barlow³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

Self Cite

View full text Add to dashboard Cite

. The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of ␦ 2-opioid receptor stimulation. Am J Physiol Heart Circ Physiol 291: H2318 -H2326, 2006. First published June 30, 2006 doi:10.1152/ajpheart.00455.2006.-The cardiac enkephalin, methionine-enkephalin-arginine-phenylalanine (MEAP), alters vagally induced bradycardia when introduced by microdialysis into the sinoatrial (SA) node. The responses to MEAP are bimodal; lower doses enhance bradycardia and higher doses suppress bradycardia. The opposing vagotonic and vagolytic effects are mediated, respectively, by ␦1 and ␦2 phenotypes of the same receptor. Stimulation of the ␦1 receptor reduced the subsequent ␦2 responses. Experiments were conducted to test the hypothesis that the ␦-receptor interactions were mediated by the monosialosyl ganglioside GM-1. When the mixed agonist MEAP was evaluated after nodal GM-1 treatment, ␦1-mediated vagotonic responses were enhanced, and ␦2-mediated vagolytic responses were reduced. Prior treatment with the ␦ 1-selective antagonist 7-benzylidenaltrexone (BNTX) failed to prevent attrition of the ␦ 2-vagolytic response or restore it when added afterward. Thus the GM-1-mediated attrition was not mediated by ␦ 1 receptors or increased competition from ␦1-mediated vagotonic responses. When GM-1 was omitted, deltorphin produced a similar but less robust loss in the vagolytic response. In contrast, however, to GM-1, the deltorphin-mediated attrition was prevented by pretreatment with BNTX, indicating that the decline in response after deltorphin alone was mediated by ␦ 1 receptors and that GM-1 effectively bypassed the receptor. Whether deltorphin has intrinsic ␦ 1 activity or causes the release of an endogenous ␦ 1-agonist is unclear. When both GM-1 and deltorphin were omitted, the subsequent vagolytic response was more intense. Thus GM-1, deltorphin, and time all interact to modify subsequent ␦ 2-mediated vagolytic responses. The data support the hypothesis that ␦ 1-receptor stimulation may reduce ␦2-vagolytic responses by stimulating the GM-1 synthesis. bradycardia; deltorphin; heart rate THE SINOATRIAL (SA) node or cardiac pacemaker is densely innervated by sympathetic and parasympathetic nerve fibers that moderate automaticity through the local nodal release of norepinephrine and acetylcholine. In addition to direct innervation, multiple factors within the node modify both spontaneous activity and neurotransmitter release. Among these moderators, cardiac opioids appear to be potentially important neuromodulators (3, 9, 10).Proenkephalin mRNA is more abundant in the heart than most other tissues, including the brain (12). Enkephalins are found in the heart, and despite the stoichiometric advantage afforded met-enkephalin (ME), ME-arginine-phenylalanine (MEAP) concentrations are higher in the heart than any of the other three enkephalins (2, 19, 29). ME, leucine-enkephalin (LE), and MEAP have all been demonstrated to alter vagally induced bradycardia when introduced into the SA node by microdialysis (9 -11, 13). The op...

show abstract

“…12 This effect would be functionally similar to the vagolytic effect of DOR-2 activation in the SA node. 13,14,17,18 Although the sympathotonic effect of lower dose enkephalin is more difficult to demonstrate, a small progressive increase baseline vascular resistance and subsequent arterial pressure occurred as the dose of ME was increased. DOR-1 blockade eliminated this initial hypertensive response, produced an acute increase in baseline femoral vascular conductance and a small though not significant increase in enkephalin-mediated vascular conductance.…”

Section: Discussionmentioning

confidence: 99%

Sympatholytic delta-2 opioid receptors moderate ganglionic vasomotor control

Barlow

Deo

Caffrey

2011

Exp Biol Med (Maywood)

View full text Add to dashboard Cite

This study tested the hypothesis that enkephalin increases femoral vascular conductance via the delta-2 phenotype of the opioid receptor (DOR-2) within peripheral sympathetic ganglia. Graded pulses of methionine-enkephalin (ME) were administered (0.03-10 μg/kg) into the terminal aorta of anesthetized dogs proximal to lumbar arteries that perfuse vasomotor ganglia regulating femoral blood flow. Femoral vascular conductance increased sharply (ED50 = 2.6 × 10(-9) mol/kg) accompanied by declines in arterial pressure and femoral vascular resistance. A dose-related increase in arterial pressure preceded each subsequent fall in pressure. The DOR-2 antagonist, naltriben (NTB), abrogated the hyperemic effect of ME (ID50 = 1.4 × 10(-9) mol/kg). DOR-1 blockade (BNTX) was five-fold less effective. The hyperemic effect of ME was also enhanced when sympathetic activity was reflexly increased by bilateral carotid occlusion. The DOR-2 agonist, deltorphin II, produced exaggerated increases in conductance compared with ME that were also reduced by DOR-2 blockade. DOR-1 blockade eliminated the initial pressor responses, exaggerated the subsequent depressor response, increased baseline femoral conductance 10-fold and shifted the ME-mediated hyperemic threshold one dose lower from 0.3 to 0.1 μg/kg, providing indirect support for a competing DOR-1-mediated constriction. Extended exposure to DOR-1 blockade lowered the maximal ME increase in conductance by 30%, suggesting that BNTX reduces the available pool of DOR receptors. In summary, enkephalin mediates a robust hyperemic effect through sympatholytic ganglionic DOR-2 receptors and DOR-1 antagonist studies provide indirect evidence for constituent opposition from a proposed DOR-1-mediated sympathotonic constrictor pathway.

show abstract

Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node

Cited by 13 publications

References 29 publications

Identification of μ‐ and κ‐opioid receptors as potential targets to regulate parasympathetic, sympathetic, and sensory neurons within rat intracardiac ganglia

Identification of μ‐ and κ‐opioid receptors as potential targets to regulate parasympathetic, sympathetic, and sensory neurons within rat intracardiac ganglia

The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of δ₂-opioid receptor stimulation

Sympatholytic delta-2 opioid receptors moderate ganglionic vasomotor control

Contact Info

Product

Resources

About

Cardiac enkephalins attenuate vagal bradycardia: interactions with NOS-1-cGMP systems in canine sinoatrial node

Cited by 13 publications

References 29 publications

Identification of μ‐ and κ‐opioid receptors as potential targets to regulate parasympathetic, sympathetic, and sensory neurons within rat intracardiac ganglia

Identification of μ‐ and κ‐opioid receptors as potential targets to regulate parasympathetic, sympathetic, and sensory neurons within rat intracardiac ganglia

The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of δ2-opioid receptor stimulation

Sympatholytic delta-2 opioid receptors moderate ganglionic vasomotor control

Contact Info

Product

Resources

About

The monosialosyl ganglioside GM-1 reduces the vagolytic efficacy of δ₂-opioid receptor stimulation