title: Changes in cardiac glycoside activity produced by aminosugar addition.
abstract: 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.
mesh_terms: D000606:Amino Sugars / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004073:Digitoxigenin / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects*; D013329:Structure-Activity Relationship; D014693:Ventricular Fibrillation / Q000139:chemically induced
chemical_list: D000606:Amino Sugars; D004073:Digitoxigenin