Modulation of drug effects by regional sympathetic denervation and supersensitivity

Marshall S. Stanton, Douglas P. Zipes

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Background. Regional sympathetic denervation, such as that produced by a myocardial infarction, causes electrophysiological heterogeneity in the ventricles. The purpose of this study was to test the hypothesis that such denervation could cause drugs to exert heterogeneous myocardial effects. Methods and Results. Sympathetic stimulation increases the amplitude of cesium chloride-induced early afterdepolarizations (EADs). The amplitude of these induced EADs was used to determine whether drug responses were different in innervated versus denervated areas of the heart. A canine model of sympathetic denervation was created at the cardiac apex by either transmural myocardial infarction (n=19) or phenol application (n=11). Cesium chloride (84 mg/kg) was infused while monophasic action potential recordings were simultaneously obtained from the base and apex of the left ventricle using an epicardial contact electrode. We found that control (innervated) dogs (n=17) showed no difference in the EAD amplitude recorded from the apex compared with the base. In dogs with apical sympathetic denervation, the EAD amplitude was greater at the innervated base during ansae subclaviae stimulation than at the denervated apex (25.8±6.6% at base versus 18.8±6.7% at apex, p<0.001). However, during norepinephrine infusion, the EADs recorded from the denervated apex were greater than those recorded from the innervated base (23.3±7.6% at apex versus 20.6±6.0% at base, p<0.02) due to denervation supersensitivity. Conclusions. These data show that regional myocardial denervation creates autonomic and electrophysiological heterogeneity and the substrate for heterogeneous drug actions. This drug-induced electrophysiological heterogeneity may be another mechanism for proarrhythmia.

Original languageEnglish
Pages (from-to)1709-1714
Number of pages6
JournalCirculation
Volume84
Issue number4
StatePublished - Oct 1991

Fingerprint

Sympathectomy
Denervation
Pharmaceutical Preparations
Autonomic Denervation
Myocardial Infarction
Dogs
Phenol
Action Potentials
Heart Ventricles
Canidae
Norepinephrine
Electrodes
cesium chloride

Keywords

  • Arrhythmogenesis
  • Nervous system, autonomic
  • Proarrhythmia
  • Triggered activity

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Modulation of drug effects by regional sympathetic denervation and supersensitivity. / Stanton, Marshall S.; Zipes, Douglas P.

In: Circulation, Vol. 84, No. 4, 10.1991, p. 1709-1714.

Research output: Contribution to journalArticle

Stanton, MS & Zipes, DP 1991, 'Modulation of drug effects by regional sympathetic denervation and supersensitivity', Circulation, vol. 84, no. 4, pp. 1709-1714.
Stanton, Marshall S. ; Zipes, Douglas P. / Modulation of drug effects by regional sympathetic denervation and supersensitivity. In: Circulation. 1991 ; Vol. 84, No. 4. pp. 1709-1714.
@article{64a223e86b914d389e851eb53c9c46f7,
title = "Modulation of drug effects by regional sympathetic denervation and supersensitivity",
abstract = "Background. Regional sympathetic denervation, such as that produced by a myocardial infarction, causes electrophysiological heterogeneity in the ventricles. The purpose of this study was to test the hypothesis that such denervation could cause drugs to exert heterogeneous myocardial effects. Methods and Results. Sympathetic stimulation increases the amplitude of cesium chloride-induced early afterdepolarizations (EADs). The amplitude of these induced EADs was used to determine whether drug responses were different in innervated versus denervated areas of the heart. A canine model of sympathetic denervation was created at the cardiac apex by either transmural myocardial infarction (n=19) or phenol application (n=11). Cesium chloride (84 mg/kg) was infused while monophasic action potential recordings were simultaneously obtained from the base and apex of the left ventricle using an epicardial contact electrode. We found that control (innervated) dogs (n=17) showed no difference in the EAD amplitude recorded from the apex compared with the base. In dogs with apical sympathetic denervation, the EAD amplitude was greater at the innervated base during ansae subclaviae stimulation than at the denervated apex (25.8±6.6{\%} at base versus 18.8±6.7{\%} at apex, p<0.001). However, during norepinephrine infusion, the EADs recorded from the denervated apex were greater than those recorded from the innervated base (23.3±7.6{\%} at apex versus 20.6±6.0{\%} at base, p<0.02) due to denervation supersensitivity. Conclusions. These data show that regional myocardial denervation creates autonomic and electrophysiological heterogeneity and the substrate for heterogeneous drug actions. This drug-induced electrophysiological heterogeneity may be another mechanism for proarrhythmia.",
keywords = "Arrhythmogenesis, Nervous system, autonomic, Proarrhythmia, Triggered activity",
author = "Stanton, {Marshall S.} and Zipes, {Douglas P.}",
year = "1991",
month = "10",
language = "English",
volume = "84",
pages = "1709--1714",
journal = "Circulation",
issn = "0009-7322",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

TY - JOUR

T1 - Modulation of drug effects by regional sympathetic denervation and supersensitivity

AU - Stanton, Marshall S.

AU - Zipes, Douglas P.

PY - 1991/10

Y1 - 1991/10

N2 - Background. Regional sympathetic denervation, such as that produced by a myocardial infarction, causes electrophysiological heterogeneity in the ventricles. The purpose of this study was to test the hypothesis that such denervation could cause drugs to exert heterogeneous myocardial effects. Methods and Results. Sympathetic stimulation increases the amplitude of cesium chloride-induced early afterdepolarizations (EADs). The amplitude of these induced EADs was used to determine whether drug responses were different in innervated versus denervated areas of the heart. A canine model of sympathetic denervation was created at the cardiac apex by either transmural myocardial infarction (n=19) or phenol application (n=11). Cesium chloride (84 mg/kg) was infused while monophasic action potential recordings were simultaneously obtained from the base and apex of the left ventricle using an epicardial contact electrode. We found that control (innervated) dogs (n=17) showed no difference in the EAD amplitude recorded from the apex compared with the base. In dogs with apical sympathetic denervation, the EAD amplitude was greater at the innervated base during ansae subclaviae stimulation than at the denervated apex (25.8±6.6% at base versus 18.8±6.7% at apex, p<0.001). However, during norepinephrine infusion, the EADs recorded from the denervated apex were greater than those recorded from the innervated base (23.3±7.6% at apex versus 20.6±6.0% at base, p<0.02) due to denervation supersensitivity. Conclusions. These data show that regional myocardial denervation creates autonomic and electrophysiological heterogeneity and the substrate for heterogeneous drug actions. This drug-induced electrophysiological heterogeneity may be another mechanism for proarrhythmia.

AB - Background. Regional sympathetic denervation, such as that produced by a myocardial infarction, causes electrophysiological heterogeneity in the ventricles. The purpose of this study was to test the hypothesis that such denervation could cause drugs to exert heterogeneous myocardial effects. Methods and Results. Sympathetic stimulation increases the amplitude of cesium chloride-induced early afterdepolarizations (EADs). The amplitude of these induced EADs was used to determine whether drug responses were different in innervated versus denervated areas of the heart. A canine model of sympathetic denervation was created at the cardiac apex by either transmural myocardial infarction (n=19) or phenol application (n=11). Cesium chloride (84 mg/kg) was infused while monophasic action potential recordings were simultaneously obtained from the base and apex of the left ventricle using an epicardial contact electrode. We found that control (innervated) dogs (n=17) showed no difference in the EAD amplitude recorded from the apex compared with the base. In dogs with apical sympathetic denervation, the EAD amplitude was greater at the innervated base during ansae subclaviae stimulation than at the denervated apex (25.8±6.6% at base versus 18.8±6.7% at apex, p<0.001). However, during norepinephrine infusion, the EADs recorded from the denervated apex were greater than those recorded from the innervated base (23.3±7.6% at apex versus 20.6±6.0% at base, p<0.02) due to denervation supersensitivity. Conclusions. These data show that regional myocardial denervation creates autonomic and electrophysiological heterogeneity and the substrate for heterogeneous drug actions. This drug-induced electrophysiological heterogeneity may be another mechanism for proarrhythmia.

KW - Arrhythmogenesis

KW - Nervous system, autonomic

KW - Proarrhythmia

KW - Triggered activity

UR - http://www.scopus.com/inward/record.url?scp=0025945218&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0025945218&partnerID=8YFLogxK

M3 - Article

VL - 84

SP - 1709

EP - 1714

JO - Circulation

JF - Circulation

SN - 0009-7322

IS - 4

ER -