Modulation of drug effects by regional sympathetic denervation and supersensitivity.
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.


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 less than 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 less than 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.
Krannert Institute of Cardiology, Department of Medicine, Indiana University School of Medicine, Indianapolis 46202.
M S
MS
Stanton
D P
DP
Zipes
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology; D002586:Cesium / Q000494:pharmacology*; D002712:Chlorides; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D006329:Heart Conduction System / Q000503:physiopathology*; D008297:Male; D009203:Myocardial Infarction / Q000503:physiopathology*; D009638:Norepinephrine / Q000494:pharmacology; D019800:Phenol; D010636:Phenols; D013563:Sympathectomy, Chemical; D013564:Sympathetic Nervous System / Q000502:physiology*
D002712:Chlorides; D010636:Phenols; D002586:Cesium; D019800:Phenol; C028019:cesium chloride; D009638:Norepinephrine