| Abstract: | Critical reassessment of established inotropic drugs such as the phosphodiesterase inhibitors and the digitalis glycosides has reaffirmed the need for novel cardiotonic agents that will not only beneficially affect the haemodynamic and functional impairment of patients with overt congestive heart failure, but also prevent its clinical manifestation and reduce the high mortality. None of the drugs examined in these directions - calcium sensitisers, β-receptor blockers, sodium channel modulators, digitalis derivatives - have been shown to achieve these goals. The research on endogenous digitalis did not, as was hoped, reveal a general strategy for improving the therapeutic index of cardiac glycosides. The proof that Na+/K+-transporting ATPase of cardiac muscle is the molecular point of attack (receptor) for the inotropic and toxic effects of digitalis-like acting C/D-cis and C/D-trans steroids revealed the cyclopentano-perhydrophenanthrene nucleus as their common pharmacophoric lead structure. This has opened a wide field for lead development in the direction of derivatives that favourably discriminate between the inotropy-linked α1-isoform and the toxicity-linked α3-isoform of Na+/K+-ATPase as the basis for the design of inotropic agents with high therapeutic margin. |
