Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49.
1. S 16257 is a new bradycardic agent. Its electropharmacological profile has been compared to that of the known bradycardic compound UL-FS 49 (Zatebradine). Intracellular recordings of action potentials (APs) were performed with conventional glass microelectrodes. 2. In the rabbit isolated sino-atrial node (SAN) tissue, S 16257 and UL-FS 49 (1 microM, 3 microM and 10 microM) were equipotent in slowing spontaneous APs firing predominantly by decreasing the rate of diastolic depolarization (at 3 microM, -23.8 +/- 3.9% and -27.9 +/- 2.6%, respectively). For the two compounds a maximal effect was obtained at 3 microM. In these preparations, action potential duration at 50% of total repolarization (APD50) was more affected by UL-FS 49 than S 16257 at any concentration tested (at 3 microM, +8.9 +/- 2.9% and +29.1 +/- 3.7% for S 16257 and UL-FS 49, respectively; P < or = 0.01). 3. To estimate the direct effects on AP duration, driven cardiac preparations were exposed to these agents. In guinea-pig papillary muscles, paced at a frequency of 1 Hz, increasing concentrations of S 16257 or UL-FS 49 (0.1 to 10 microM, 30 min exposure for each concentration) slightly prolonged AP repolarization. This prolongation was more marked for UL-FS 49 (at 1 microM, +6.1 +/- 0.6% and +11.2 +/- 1.3% elevation of APD50, for S 16257 and UL-FS 49, respectively). 4. Application of UL-FS 49 (3 microM) to rabbit Purkinje fibres, triggered at a frequency of 0.25 Hz, induced a marked prolongation of APD50 and APD90 (+149.4 +/- 51.2% and +86.0 +/- 15.4%, respectively). S 16257 (3 MicroM) induced only a weak prolongation of AP (+ 14.1 +/- 5.0% and + 14.8 +/- 3.3% for APD50 and APD90, respectively) significantly smaller than in the case of UL-FS 49.5. These results show that S 16257 slows the rate of spontaneous AP firing in isolated SAN mainly by a reduction of the diastolic depolarization of the cells, which suggests an inhibition of the pace-maker current (If). S 16257 and UL-FS 49 are equipotent in their bradycardic effect but S 16257 is more specific as it induces less increase in myocardial repolarization time.
Thollon
C
C
Division Pathologies Cardiaques et Vasculaires, Institut de Recherches Servier, Suresnes, France.
Cambarrat
C
C
Vian
J
J
Prost
J F
JF
Peglion
J L
JL
Vilaine
J P
JP
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000494:pharmacology*; D004594:Electrophysiology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000294:innervation; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D000077550:Ivabradine; D008297:Male; D010210:Papillary Muscles / Q000187:drug effects; D011690:Purkinje Fibers / Q000187:drug effects; D011817:Rabbits; D012849:Sinoatrial Node / Q000187:drug effects* / Q000502:physiology
D001552:Benzazepines; D002316:Cardiotonic Agents; D002317:Cardiovascular Agents; D000077550:Ivabradine; C043636:zatebradine