digitoxigenin and Ventricular-Fibrillation

In anesthetized dogs, structure activity relationships among three cardiotonic compounds were determined by comparing the cardiovascular effects of digotoxigenin (the genin) to digitoxigenin-galactose (a genin-neutral sugar combination) and to digitoxigenin-aminogalactose (ASI-222, a genin-aminosugar combination) using either bolus i.v. injections or constant i.v. infusions. We recorded the effects of these drugs upon cardiac rate, mean blood pressure, left ventricular dP/dt, cardiac index, systolic time intervals, tension-time index, therapeutic index, ventricular excitability and the ventricular refractory period. The addition of an aminosugar group to digitoxigenin or an amine group to galactose-digitoxigenin results in an agent with greater ability to reduce heart rate and to increase cardiac contractility and cardiac index without affecting the tension-time index. Moreover, the addition of an amino group significantly increased the therapeutic index and ventricular refractory period but reduced the toxic index (lethal dose/toxic dose) when compared to the neutral-sugar cardenolide and genin. Our data indicate that such a substitution confers greater potency, prolongs the duration of activity and results in a compound with a greater therapeutic index.

Topics: Amino Sugars; Animals; Blood Pressure; Digitoxigenin; Dogs; Heart Rate; Structure-Activity Relationship; Ventricular Fibrillation