Myocardial contractile behavior of a new sotalol derivative.
The effects of E4031, a new class III antiarrhythmic agent similar to sotalol, were tested in isometrically contracting rabbit papillary muscles and in anesthetized, open-chest dogs. In papillary muscles, E4031 caused a modest dose-dependent increase of 26 +/- 8% in developed tension and 38 +/- 8% in its maximal rate of rise. Since there was no significant change in the maximal rate of relaxation, the ratio between both maximal velocities increased from 0.92 +/- 0.03 to 1.19 +/- 0.10. Time to peak tension did not change significantly, whereas time to half relaxation increased from 72 +/- 3 to 85 +/- 4 ms. The effective refractory period in the rabbit papillary muscles increased from 179 +/- 10 to 414 +/- 45 ms. In the open-chest dog, the i.v. administration of E4031 did not induce significant changes in heart rate, mean arterial pressure, or left ventricular end diastolic pressure. +dP/dt increased from 1,839 +/- 162 to 2,470 +/- 247 mm Hg/s with no significant change in -dP/dt after 100 micrograms/kg of E4031. Consequently, (+dP/dt)/(-dP/dt) increased from 0.97 +/- 0.07 to 1.18 +/- 0.08. To further evaluate the effects of E4031 on myocardial relaxation, the time constant of isovolumic left ventricular pressure decay was measured by two different methods (tau 1 and tau 2) before and after administering 10 micrograms/kg E4031. Tau 1 increased from 27 +/- 1.8 to 33 +/- 1.6 ms and tau 2 increased from 30 +/- 2.3 to 41 +/- 3.3 ms.(ABSTRACT TRUNCATED AT 250 WORDS)
Cingolani
H E
HE
Merck Sharp & Dohme Research Laboratories, West Point, Pennsylvania.
Wiedmann
R T
RT
Lynch
J J
JJ
Baskin
E P
EP
Stein
R B
RB
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D003864:Depression, Chemical; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D010210:Papillary Muscles / Q000187:drug effects / Q000502:physiology; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011817:Rabbits; D013015:Sotalol / Q000031:analogs & derivatives*
D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D010880:Piperidines; D011725:Pyridines; C063968:E 4031; D013015:Sotalol