Effects of new and potent methanesulfonanilide class III antiarrhythmic agents on myocardial refractoriness and contractility in isolated cardiac muscle.
The effects of the new and potent methanesulfonanilide class III antiarrhythmic agents (E-4031, UK-66,914, and UK-68,798) on myocardial refractoriness and contractility were compared to those of d-sotalol in ferret isometrically contracting right ventricular papillary muscle preparations. During 1 Hz pacing at 37 degrees C, the four class III agents elicited concentration-dependent increases in ventricular effective refractory period (ERP), with a relative order of potency of UK-68,798 greater than E-4031 greater than UK-66,914 much greater than d-sotalol. EC25 values (effective concentration required to increase ERP 25% above baseline) were (in microM) UK-68,798, 0.018; E-4031, 0.058; UK-66,914, 0.501; and d-sotalol, 43.76. Maximal increases in ERP relative to baseline (% of baseline value) for the class III agents at 37 degrees C (range of 44.5 +/- 4.5 to 63.0 +/- 3.1%) were greater than the maximal increases observed at 27 degrees C (range of 15.0 +/- 3.3 to 31.2 +/- 4.8%), whereas the maximal absolute (ms) increases in ERP above baseline were comparable for the class III agents at both temperatures. Increases in ERP produced by the four class III agents at 37 degrees C were significantly greater at a pacing frequency of 1 Hz (range of 70.0 +/- 7.6 to 102.0 +/- 2.3 ms) than at 3 Hz (range of 18.3 +/- 4.4 to 31.BBB/- 4.8 ms). During a temporary period of hypoxic perfusion at 37 degrees C, increases in ERP produced by the four class III agents were reversed, such that "hypoxic" ERP values approximated pretreatment, baseline values.(ABSTRACT TRUNCATED AT 250 WORDS)
Baskin
E P
EP
Department of Pharmacology, Merck Sharp & Dohme Research Laboratories, West Point, PA 19486.
Serik
C M
CM
Wallace
A A
AA
Brookes
L M
LM
Selnick
H G
HG
Claremon
D A
DA
Lynch
J J
JJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D005289:Ferrets; D006321:Heart / Q000187:drug effects*; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D010627:Phenethylamines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012032:Refractory Period, Electrophysiological / Q000187:drug effects*; D013015:Sotalol / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D013696:Temperature
D000889:Anti-Arrhythmia Agents; D010627:Phenethylamines; D010880:Piperidines; D011719:Pyrazines; D011725:Pyridines; D013449:Sulfonamides; C069454:UK 66914; C063968:E 4031; D013015:Sotalol; C063533:dofetilide