The effects of carbenoxolone on human myocardial conduction: a tool to investigate the role of gap junctional uncoupling in human arrhythmogenesis.
OBJECTIVE
This study assessed the effects of carbenoxolone on human myocardial conduction and refractoriness.


BACKGROUND
Carbenoxolone, an antipeptic ulcer drug, has been shown to reduce gap junctional coupling without affecting cellular ion channels. Gap junctions (GJ) are considered to be determinants of cardiac action potential propagation. The effects of GJ uncoupling in the human heart are unknown.


METHODS
Right atrial (RA) and ventricular (RV) activation mapping (Carto, Biosense Webster Inc., Diamond Bar, California) was performed during sinus rhythm. Right atrial and RV wavefront propagation velocity (WPV), specifically in the direction of propagation, was determined from these maps using a triangulation method. Refractoriness at multiple RA and RV sites, sinus rhythm cycle length, and AH, PR, QRS, and QT intervals were measured. The protocol was repeated 1 h after oral administration of 100 mg of carbenoxolone.


RESULTS
In 11 patients, WPV was reduced from 79.6 +/- 13.3 cm/s to 57.2 +/- 9.1 cm/s (-27.1 +/- 12.8%, p < 0.001) in RA and from 98.7 +/- 19.8 cm/s to 76.5 +/- 21.7 cm/s (-22.7 +/- 14.1%, p < 0.01) in RV after carbenoxolone. Conduction slowing was more marked in 6 older patients with ischemic heart disease compared with younger subjects with normal hearts (RA -35.1 +/- 5.5% vs. -17.5 +/- 12.7%, p = 0.03; RV -33.8 +/- 5.1% vs. -9.3 +/- 7.7%, p < 0.001). Refractoriness and electrocardiogram parameters remained unchanged.


CONCLUSIONS
Carbenoxolone causes a 27% reduction in human RA WPV and 23% in the RV without affecting refractoriness. The slowing of myocardial conduction by carbenoxolone demonstrates the significance of GJ in regulating human myocardial conduction and provides a tool for investigating the effects of GJ uncoupling on human arrhythmogenesis.
Kojodjojo
Pipin
P
St. Mary's Hospital, Imperial College, London, United Kingdom.
Kanagaratnam
Prapa
P
Segal
Oliver R
OR
Hussain
Wajid
W
Peters
Nicholas S
NS
D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000150:complications / Q000209:etiology* / Q000503:physiopathology; D002229:Carbenoxolone / Q000494:pharmacology*; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D017629:Gap Junctions / Q000187:drug effects*; D006321:Heart / Q000502:physiology / Q000503:physiopathology; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications / Q000503:physiopathology*; D011930:Reaction Time / Q000187:drug effects; D012032:Refractory Period, Electrophysiological / Q000187:drug effects
D002229:Carbenoxolone