Efficacy and safety of the novel Na+,K(+)-ATPase inhibitor 20R 14 beta-amino 3 beta-rhamnosyl 5 beta-pregnan 20 beta-ol in a dog model of heart failure.
20R 14 beta-amino 3 beta-rhamnosyl 5 beta-pregnan 20 beta-ol (LND 623, CAS 90520-42-6) was investigated and compared to digoxin in anesthetized dogs. The hemodynamic profiles showed: a) a pure positive inotropic action of LND-623; b) its potency was four-fold higher than that of digoxin and more marked in heart failure; c) its duration of action was maintained for at least 6 h. The onset and reversal of the inotropic effects of a single dose (3.3 nmol.kg-1.min-1) were faster with LND-623 than those of digoxin. This reversal is consistent with the faster dissociation profile observed at the level of the high affinity cardiac Na+,K(+)-ATPase receptor form. The advantage of LND-623 over digoxin resides in its larger therapeutic index (ratio of arrhythmogenic to inotropic responses) in anesthetized dogs with propranolol-induced heart failure. This index was 6 for LND-623 and 2 for digoxin.
Maixent
J M
JM
Laboratoire Nativelle, Longjumeau, France.
Berrebi Bertrand
I
I
Lelièvre
L G
LG
Fénard
S
S
D000758:Anesthesia; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D004077:Digoxin / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008362:Mannosides / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects; D011278:Pregnanes / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*
D002316:Cardiotonic Agents; D008362:Mannosides; D011278:Pregnanes; D004077:Digoxin; C045251:LND 623; D011433:Propranolol; D000254:Sodium-Potassium-Exchanging ATPase