Effects of AL 107, a novel semisynthetic cardiac glycoside, on the cardiovascular system in anaesthetized beagle dogs with pentobarbital-induced cardiac insufficiency.
The inotropic efficacy, arrhythmogenicity and cardiohaemodynamic properties of AL 107 (3-alpha-methyl-digitoxigenin glucoside, CAS 62190-59-4), a novel cardiac glycoside, were studied in anaesthetized dogs with pentobarbital-induced acute cardiac insufficiency. Three groups of dogs received AL 107, ouabain or verhicle. The cardiac glycosides were infused intravenously in eight increasing dose levels which where given cumulatively. Slope of left ventricular pressure rise (LVdp/dtmax) increased in the AL 107- and ouabain-treated groups. At the end of the 6th dose level ouabain caused a significantly higher LVdp/dtmax (137 +/- 15% of the baseline value taken before induction of insufficiency) than AL 107 (94 +/- 9%). Further increase of the dose resulted in a reduction of LVdp/dtmax in ouabain-treated dogs, whereas AL 107 continuously increased LVdp/dtmax up to the highest dose infused, where 130 +/- 16% of the baseline value was reached. In ouabain-treated dogs, ECG abnormalities accompanied the decrease of LVdp/dtmax whereas ECG-changes did not interfere with the development of left ventricular contractility in AL 107-treated dogs. The 6th dose of ouabain provoked a maximal increase of cardiac output (CO) (up to 107 +/- 8% of baseline values) and stroke volume (SV) (up to 122 +/- 6% of baseline values) which decreased upon further dose elevation. In the dose-range studied AL-107 induced a continuous increase of both parameters which, however, hardly reached the baseline values. ECG abnormalities occurred in both substance-treated groups and showed quantitative but not qualitative differences. The ECG showed rapid recovery after cessation of AL 107 infusion but did not normalize during a postinfusional recovery period of 1 h after treatment with ouabain. In conclusion, AL 107 increased cardiac performance in an acute canine model of cardiac insufficiency. It was slightly less active than ouabain. However, the ECG disorders were more moderate in AL 107--than in ouabain-treated dogs, a difference which was most pronounced with respect to reversibility in the postinfusional period.
Kögel
B
B
Centre of Research, Grünenthal GmbH, Aachen, Germany.
Schneider
J
J
Gleitz
J
J
Wilffert
B
B
Peters
T
T
D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002301:Cardiac Glycosides / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D002303:Cardiac Output, Low / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002496:Central Venous Pressure / Q000187:drug effects; D004073:Digitoxigenin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006439:Hemodynamics / Q000187:drug effects*; D006993:Hypnotics and Sedatives; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects; D010424:Pentobarbital / Q000494:pharmacology*; D013318:Stroke Volume / Q000187:drug effects
D002301:Cardiac Glycosides; D002316:Cardiotonic Agents; D006993:Hypnotics and Sedatives; D004073:Digitoxigenin; C035601:3 alpha-methyldigitoxigenin glucoside; D010424:Pentobarbital