ELECTROPHYSIOLOGICAL EFFECTS OF S-16257, A NOVEL SINOATRIAL NODE MODULATOR, ON RABBIT AND GUINEA-PIG CARDIAC PREPARATIONS - COMPARISON WITHUL-FS-49

1 S 16257 is a new bradycardic agent. Its electropharmacological profi le has been compared to that of the known bradycardic compound UL-FS 4 9 (Zatebradine). Intracellular recordings of action potentials (APs) w ere performed with conventional glass microelectrodes. 2 In the rabbit isolated sino-atrial node (SAN) tissue, S 16257 and UL-FS 49 (1 mu M, 3 mu M and 10 mu M) were equipotent in slowing spontaneous APs firing predominantly by decreasing the rate of diastolic depolarization (at 3 mu M, - 23.8 +/- 3.9% and - 27.9 +/- 2.6%, respectively). For the tw o compounds a maximal effect was obtained at 3 mu M. In these preparat ions, action potential duration at 50% of total repolarization (APD(50 )) was more affected by UL-FS 49 than S 16257 at any concentration tes ted (at 3 mu M, + 8.9 +/- 2.9% and + 29.1 +/- 3.7% for S 16257 and UL- FS 49, respectively; P less than or equal to 0.01). 3 To estimate the direct effects on AP duration, driven cardiac preparations were expose d to these agents. In guinea-pig papillary muscles, paced at a frequen cy of 1 Hz, increasing concentrations of S 16257 or UL-FS 49 (0.1 to 1 0 mu M, 30 min exposure for each concentration) slightly prolonged AP repolarization. This prolongation was more marked for UL-FS 49 (at 1 m u M, + 6.1 +/- 0.6% and + 11.2 +/- 1.3% elevation of APD(50), for S 16 257 and UL-FS 49, respectively). 4 Application of UL-FS 49 (3 mu M) to rabbit Purkinje fibres, triggered at a frequency of 0.25 Hz, induced a marked prolongation of APD(50) and APD(90) (+ 149.4 +/- 51.2% and 86.0 +/- 15.4%, respectively). S 16257 (3 mu M) induced only a weak pr olongation of AP (+ 14.1 +/- 5.0% and + 14.8 +/- 3.3% for APD(50) and APD(90), respectively) significantly smaller than in the case of UL-FS 49. 5 These results show that S 16257 slows the rate of spontaneous A P firing in isolated SAN mainly by a reduction of the diastolic depola rization of the cells, which suggests an inhibition of the pace-maker current (I-f). S 16257 and UL-FS 49 are equipotent in their bradycardi c effect but S 16257 is more specific as it induces less increase in m yocardial repolarization time.