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Bimodal delta-opioid receptors regulate vagal bradycardia in canine sinoatrial node

M Farias1, K Jackson, D Yoshishige

  • 1Department of Integrative Physiology, Cardiovascular Research Institute, University of North Texas Health Science Center, 3500 Camp Bowie Blvd., Fort Worth, TX 76107, USA.

American Journal of Physiology. Heart and Circulatory Physiology
|August 14, 2003
PubMed

Insights

Methionine-enkephalin-arginine-phenylalanine (MEAP) exhibits dual effects on vagal bradycardia in the SA node. Low doses enhance vagal responses via delta1-receptors, while high doses inhibit them through delta2-receptors.

Area of Science:

  • Cardiovascular Physiology
  • Neuropharmacology
  • Opioid Receptor Research

Background:

  • The sinoatrial (SA) node's response to vagal nerve stimulation is crucial for heart rate regulation.
  • Endogenous opioids, like methionine-enkephalin-arginine-phenylalanine (MEAP), are present in the SA node, but their precise role in vagal modulation is unclear.
  • Previous studies showed conflicting effects of MEAP on vagal bradycardia, suggesting a complex regulatory mechanism.

Purpose of the Study:

  • To investigate the hypothesis that intranodal enkephalin responses are bimodal, depending on dose and opioid receptor subtype.
  • To determine the specific opioid receptor subtypes (delta1 vs. delta2) mediating the dose-dependent effects of MEAP on vagal bradycardia.
  • To elucidate the mechanism by which endogenous MEAP influences vagal responses in the SA node.

Main Methods:

  • Microdialysis was used to introduce varying doses of MEAP into the canine SA node.
  • Vagal nerve stimulation at different frequencies (1, 2, 3 Hz) was performed to assess heart rate responses.
  • Selective opioid receptor antagonists, naltrindole (delta-selective), 7-benzylidenenaltrexone (BNTX, delta1-selective), and naltriben (delta2-selective), were used to block receptor activity.
  • SA node artery occlusion was employed to increase endogenous MEAP levels.

Main Results:

  • Ultralow doses of MEAP (fmol/min range) significantly increased vagal bradycardia (50-100% enhancement), acting via delta1-receptors as indicated by BNTX blockade.
  • Higher doses of MEAP (nmol/min range) induced a vagolytic (inhibitory) effect, which was not blocked by the delta2-selective antagonist naltriben.
  • The vagotonic effect of ultralow MEAP was reversed by naltrindole, while the vagolytic effect of higher MEAP doses was not specified in relation to receptor subtypes.
  • Increased endogenous MEAP (via artery occlusion) led to improved vagal bradycardia, which was blocked by the delta1-selective antagonist BNTX.

Conclusions:

  • Opioid signaling within the SA node exhibits a bimodal response pattern to MEAP.
  • Low doses of MEAP act as vagotonic agents, enhancing vagal bradycardia through activation of delta1-opioid receptors.
  • Higher doses of MEAP function as vagolytic agents, inhibiting vagal bradycardia, potentially through delta2-opioid receptors, although this requires further investigation.

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