The therapeutic potential of novel cardiotonic agents.
During the course of treatment of heart failure patients, cardiotonic agents are inevitable for improvement of myocardial dysfunction. Clinically available agents, such as beta-adrenoceptor agonists and selective phosphodiesterase 3 inhibitors, act mainly via cyclic AMP/protein kinase A-mediated facilitation of Ca(2+) mobilisation (upstream mechanism). These agents are associated with the risk of Ca(2+) overload leading to arrhythmias, myocardial cell injury and premature cell death. In addition, they are energetically disadvantageous because of an increase in activation energy and metabolic effects. Cardiac glycosides act also via an upstream mechanism and readily elicit Ca(2+) overload with a narrow safety margin. No currently available agents act primarily via an increase in the myofilament sensitivity to Ca(2+) ions (central and/or downstream mechanisms). Novel Ca(2+) sensitisers under basic research may deserve clinical trials to examine the therapeutic potential to replace currently employed agents in acute and chronic heart failure patients. Molecular mechanisms of action of Ca(2+) sensitisers are divergent. In addition, they show a wide range of discrete pharmacological profiles due to additional actions associated with individual compounds. Therefore, the outcome of clinical trials has to be explained carefully based on these mechanisms of actions.
Department of Pharmacology, Yamagata University School of Medicine, 2-2-2 Iida-nishi, Yamagata, 990-9585 Japan. mendou@med.id.yamagata-u.ac.jp
Masao
M
Endoh
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D008841:Actin Cytoskeleton / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology / Q000627:therapeutic use; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use
D000318:Adrenergic beta-Agonists; D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D002118:Calcium