Document Detail

Leucine-enkephalin interrupts sympathetically mediated tachycardia prejunctionally in the canine sinoatrial node.
MedLine Citation:
PMID:  12968061     Owner:  NLM     Status:  MEDLINE    
This study examined the role of leucine-enkephalin (LE) in the sympathetic regulation of the cardiac pacemaker. LE was administered by microdialysis into the interstitium of the canine sinoatrial node during either sympathetic nerve stimulation or norepinephrine infusion. In study one, the right cardiac sympathetic nerves were isolated as they exit the stellate ganglion and were stimulated to produce graded (low, 20-30 bpm; high 40-50 bpm) increases in heart rate (HR). LE (1.5 nmoles/min) was added to the dialysis inflow and the sympathetic stimulations were repeated after 5 and 20 min of LE infusion. After 5 min, LE reduced the tachycardia during sympathetic stimulation at both low (18.2 +/- 1.3 bpm to 11.4 +/- 1.4 bpm) and high (45 +/- 1.5 bpm to 22.8 +/- 1.5 bpm) frequency stimulations. The inhibition was maintained during 20 min of continuous LE exposure with no evidence of opioid desensitization. The delta-opioid antagonist, naltrindole (1.1 nmoles/min), restored only 30% of the sympathetic tachycardia. Nodal delta-receptors are vagolytic and vagal stimulations were included in the protocol as positive controls. LE reduced vagal bradycardia by 50% and naltrindole completely restored the vagal bradycardia. In Study 2, additional opioid antagonists were used to determine if alternative opioid receptors might be implicated in the sympatholytic response. Increasing doses of the kappa-antagonist, norbinaltorphimine (norBNI), were combined with LE during sympathetic stimulation. NorBNI completely restored the sympathetic tachycardia with an ED50 of 0.01 nmoles/min. A single dose of the micro -antagonist, CTAP (1.0 nmoles/min), failed to alter the sympatholytic effect of LE. Study 3 was conducted to determine if the sympatholytic effect was prejunctional or postjunctional in character. Norepinephrine was added to the dialysis inflow at a rate (30-45 pmoles/min) sufficient to produce intermediate increases (35.2 +/- 1.8 bpm) in HR. LE was then combined with norepinephrine and responses were recorded at 5-min intervals for 20 min. The tachycardia mediated by added norepinephrine was unaltered by LE or LE plus naltrindole. At the same 5-min intervals, LE reduced vagal bradycardia by more than 50%. This vagolytic effect was again completely reversed by naltrindole. Collectively, these observations support the hypothesis that the local nodal sympatholytic effect of LE was mediated by kappa-opioid receptors that reduced the effective interstitial concentration of norepinephrine and not the result of a postjunctional interaction between LE and norepinephrine.
Amber A Stanfill; Keith Jackson; Martin Farias; Matthew Barlow; Shekhar Deo; Shavsha Johnson; James L Caffrey
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Experimental biology and medicine (Maywood, N.J.)     Volume:  228     ISSN:  1535-3702     ISO Abbreviation:  Exp. Biol. Med. (Maywood)     Publication Date:  2003 Sep 
Date Detail:
Created Date:  2003-09-11     Completed Date:  2003-10-23     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  100973463     Medline TA:  Exp Biol Med (Maywood)     Country:  United States    
Other Details:
Languages:  eng     Pagination:  898-906     Citation Subset:  IM    
Department of Integrative Physiology and The Cardiovascular Research Institute, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA.
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MeSH Terms
Adrenergic alpha-Agonists / pharmacology
Blood Pressure / drug effects
Bradycardia / drug therapy
Enkephalin, Leucine / administration & dosage,  metabolism*
Heart Rate / drug effects,  physiology*
Naltrexone / analogs & derivatives*,  pharmacology
Narcotic Antagonists / pharmacology
Norepinephrine / pharmacology
Receptors, Opioid / antagonists & inhibitors,  metabolism
Sinoatrial Node / drug effects*,  physiology
Sympathetic Nervous System / physiology*
Tachycardia / drug therapy
Vagus Nerve / physiology
Grant Support
1-F32-HL7133401/HL/NHLBI NIH HHS
Reg. No./Substance:
0/Adrenergic alpha-Agonists; 0/Narcotic Antagonists; 0/Receptors, Opioid; 111555-53-4/naltrindole; 16590-41-3/Naltrexone; 51-41-2/Norepinephrine; 58822-25-6/Enkephalin, Leucine

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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