Suppressive Effects of R 56865 on Triggered Propagated Contractions and Triggered Arrhythmias in Rat Cardiac Trabeculae

Abstract

Triggered arrhythmias in rat right ventricular trabeculae are induced by triggered propagated contractions (TPCs) that start in damaged regions of the muscle and propagate along the preparation. We analyzed the effects of the Na+/Ca2+ overload inhibiting agents R 56865 on both TPCs and triggered arrhythmias. This compound has been shown to prevent ultrastructural signs of intracellular calcium overload and arrhythmias caused by exposure to toxic concentrations of cardiac glycosides. TPCs were induced by trains of 15 stimuli (2 Hz, 15 s intervals) at 19-21 degrees C and a [Ca2+]o of 1.0-2.5 mM in the superfusate. Force was measured with a silicon strain gauge; length and shortening of sarcomeres were measured at two sites of the muscle using laser diffraction techniques. Exposure to 1.14 x 10(-7) M R 56865 for 30 min decreased the force of the last stimulated twitch (twitch force) to 89.7 +/- 4.7% (mean +/- SEM) of control, the force produced by TPCs to 39.4 +/- 9.8%, and the velocity of propagation of TPCs to 52.8 +/- 6.3%, while TPC latency increased not significantly to 104.7 +/- 2.8% of control. R 56865 suppressed TPC force, for the same small decrease in twitch force (10%), significantly more than 100 nM D-600 did (29.5 +/- 2.0 vs. 12.4 +/- 3.1%). Eventually, TPCs disappeared in 8 of 14 muscles, in 2 of them without any decrease in twitch force. At 5.7 x 10(-7) M, R 56865 abolished TPCs in five additional trabeculae. An increase in [Ca2+]o reintroduced TPCs. During stimulation of 0.5 Hz, 1.14 x 10(-7) M R 56865 increased the stimulus threshold by 21 +/- 4% in 6 of 14 muscles and decreased the twitch force by 26 +/- 3% in 7 of 14 trabeculae. Triggered arrhythmias were induced in six muscles with the use of 0.5 mM caffeine or 5 nM Bay K 8644; R 56865 rapidly terminated these arrhythmias in all muscles. Although the mechanism of the antiarrhythmic effects of R 56865 remains to be determined, we speculate that the drug raises the threshold for both generation of triggered action potentials and calcium-induced calcium release from the sarcoplasmic reticulum.