ON THE POSITIVE INOTROPIC ACTION OF ALKYLATING BROMOACETATES OF STROPHANTHIDIN AND STROPHANTHIDOL-[19-H³]

¹ Department of Pharmacology, Northwestern University Medical School, Chicago, Illinois

Strophanthidin- 3-bromoacetate (SinBA) and strophanthidol-3-bromoacetate-[19-H³] (SolBA-H³) were prepared, and the relationship between drug half-life and half-life of the positive inotropic effect was investigated. Contracting left atria were exposed for three hours to 6 x 10^-6M SolBA-H³. Subsequent washing and contraction in drug-free buffer resulted in complete loss of the inotropic effect within 30 to 45 minutes (T_1/2 = 7 minutes). At the end of the three-hour exposure plus six washes, the atria had accumulated 10 times the concentration of the buffer media, and this radioactivity disappeared with a half-life of 240 minutes. The presence of drug with no manifestation of pharmacologic effect was investigated further. A cumulative dose-response curve of ouabain was established after a three-hour exposure to SinBA and a one-hour washout to assure removal of all inotropic effect due to SinBA. No change in effectiveness of ouabain was noted as compared to control hearts. In addition, isolated rabbit hearts were perfused with 1 x 10^-5 M SinBA for three hours; adenosine triphosphatase (ATPase) was isolated and the enzyme was assayed for Na⁺, K⁺-stimulated activity. No difference was observed in the activity of ATPase isolated from SinBA- perfused hearts in comparison to solvent-perfused hearts or untreated controls. It is believed that this lack of demonstration of ATPase inhibition is due to rupture of the SinBA-enzyme bond during the extraction of the enzyme in a high ionic environment.