Pharmacological profile of the new inotropic agent AT-11.
Although there are many classes of drugs, including cardiac glycosides, sympathomimetic inotropes, beta-adrenergic antagonists, angiotensin-converting enzyme inhibitors (ACE inhibitors) and spironolactone etc. used for the treatment of heart failure, the morbidity and mortality rates of patients after these treatments are not ameliorated. Chronic administration of Sympathomimetic inotropes also increased the arrhythmogenic effects. Consequently, improvement of treatment for heart failure remains a major medical challenge for the coming years. In this present experiment, the novel Na(+)-K(+) ATPase inhibitor AT-11 was characterized for its inotropic and toxic properties. Comparing AT-11 with ouabain, we found that AT-11 concentration-dependently increased contractility in guinea pig heart preparations, and the safety index of AT-11 was better than ouabain in vitro. In the in vivo study, AT-11 was also safer than ouabain at the equieffective dose. Moreover, AT-11 slowed heart rate more than ouabain did. This may be due to a larger AT-11-induced increase in vagal reflex than with ouabain and an indirect decrease in sympathetic tone to prevent Ca(2+) overload.
Lee
An-Sheng
AS
Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan, ROC.
Wu
Tian-Shung
TS
Su
Ming-Jai
MJ
D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects; D007783:Lactones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010042:Ouabain / Q000494:pharmacology; D011083:Polycyclic Compounds / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors*; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D014630:Vagus Nerve / Q000187:drug effects / Q000378:metabolism
C528443:AT-11 compound; D002316:Cardiotonic Agents; D007783:Lactones; D011083:Polycyclic Compounds; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase