istaroxime has been researched along with Arrhythmias--Cardiac* in 2 studies
2 other study(ies) available for istaroxime and Arrhythmias--Cardiac
| Article | Year |
|---|---|
Diverse toxicity associated with cardiac Na+/K+ pump inhibition: evaluation of electrophysiological mechanisms.
(E,Z)-3-((2-Aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744) is a novel Na(+)/K(+) pump inhibitor with positive inotropic effects. Compared with digoxin in various experimental models, PST2744 was consistently found to be less arrhythmogenic, thus resulting in a significantly higher therapeutic index. The present work compares the electrophysiological effects of PST2744 and digoxin in guinea pig ventricular myocytes, with the aim to identify a mechanism for their different toxicity. The work showed that 1) the action potential was transiently prolonged and then similarly shortened by both agents; 2) the ratio between Na(+)/K(+) pump inhibition and inotropy was somewhat larger for PST2744 than for digoxin; 3) both agents accelerated inactivation of high-threshold Ca(2+) current (I(CaL)), without affecting its peak amplitude; 4) the transient inward current (I(TI)) induced by a Ca(2+) transient in the presence of complete Na(+)/K(+) pump blockade was inhibited (-43%) by PST2744 but not by digoxin; 5) the conductance of Na(+)/Ca(2+) exchanger current (I(NaCa)), recorded under Na(+)/K(+) pump blockade, was only slightly inhibited by PST2744 (-14%) and unaffected by digoxin; and 6) both agents inhibited delayed rectifier current I(Ks) ( Topics: Animals; Arrhythmias, Cardiac; Calcium Channels; Cardiotonic Agents; Cell Separation; Digoxin; Dose-Response Relationship, Drug; Electrophysiology; Enzyme Inhibitors; Etiocholanolone; Female; Guinea Pigs; Heart Diseases; In Vitro Techniques; Membrane Potentials; Myocardium; Potassium Channels, Inwardly Rectifying; Sodium-Potassium-Exchanging ATPase | 2003 |
Structure-based design and synthesis of novel potent Na+,K+ -ATPase inhibitors derived from a 5alpha,14alpha-androstane scaffold as positive inotropic compounds.
The design, synthesis, and biological properties of novel inhibitors of the Na(+),K(+)-ATPase as potential positive inotropic compounds are reported. Following our model of superposition between cassaine and digitoxigenin, digitalis-like activity has been elicited from a non-digitalis steroidal structure by suitable modifications of the 5alpha,14alpha-androstane skeleton. The strong hydrophobic interaction of the digitalis or cassaine polycyclic cores can be effectively obtained with the androstane skeleton taken in a reversed orientation. Thus, oxidation of C-6 and introduction in the C-3 position of the potent pharmacophoric group recently introduced by us, in the 17 position of the digitalis skeleton, namely, O-(omega-aminoalkyl)oxime, led to a series of substituted androstanes able to inhibit the Na(+),K(+)-ATPase, most of them with an IC(50) in the low micromolar level, and to induce a positive inotropic effect in guinea pig. Within this series, androstane-3,6,17-trione (E,Z)-3-(2-aminoethyl)oxime (22b, PST 2744) induced a strong positive inotropic effect while being less arrhythmogenic than digoxin, when the two compounds were compared at equiinotropic doses. Topics: Androstanes; Animals; Arrhythmias, Cardiac; Dogs; Enzyme Inhibitors; Etiocholanolone; Guinea Pigs; Models, Molecular; Myocardial Contraction; Sodium-Potassium-Exchanging ATPase; Stereoisomerism; Stimulation, Chemical; Structure-Activity Relationship | 2003 |