Dose-dependent inhibition of stretch-induced arrhythmias by gadolinium in isolated canine ventricles. Evidence for a unique mode of antiarrhythmic action.
Transient diastolic dilatation of the isolated canine left ventricle predictably elicits arrhythmias. To test the hypothesis that such arrhythmias may be mediated by sarcolemmal stretch-activated channels, we attempted to inhibit stretch-induced arrhythmias with gadolinium (Gd3+), a potent stretch-activated channel blocker. In experiments with six isolated canine hearts, left ventricular volume was increased for 50 msec during early diastole and then returned to initial volume by a computerized servopump. The stretch volume was adjusted to yield a probability of eliciting a stretch-induced arrhythmia of 95 +/- 2% before treatment with Gd3+. When Gd3+ (1-10 microM) was administered, dose-dependent suppression of stretch-induced arrhythmias was observed. The probability of a stretch-induced arrhythmia was reduced to 13 +/- 10% (p less than 0.05) with 10 microM Gd3+. Washout of Gd3+ completely reversed this effect. Since Gd3+ is known to be a calcium channel antagonist, we compared the effect of Gd3+ on stretch-induced arrhythmias with that of verapamil and nifedipine. These calcium channel blockers produced no demonstrable inhibition of stretch-induced arrhythmias when administered at concentrations (1 microM) that substantially depressed left ventricular pressure development. Thus, our results indirectly implicate stretch-activated channels in the genesis of stretch-induced arrhythmias and provide preliminary evidence for a potential new mode of antiarrhythmic drug action--blockade of stretch-activated channels.
Hansen
D E
DE
Division of Cardiology, Vanderbilt University School of Medicine, Nashville, TN 37232.
Borganelli
M
M
Stacy
G P
GP
Taylor
L K
LK
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D003971:Diastole; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000008:administration & dosage / Q000494:pharmacology*; D006321:Heart / Q000502:physiology*; D066298:In Vitro Techniques; D009200:Myocardial Contraction; D009543:Nifedipine / Q000494:pharmacology; D010477:Perfusion; D014700:Verapamil / Q000494:pharmacology
D000889:Anti-Arrhythmia Agents; D005682:Gadolinium; D014700:Verapamil; D009543:Nifedipine