Mechanisms of action of novel cardiotonic agents.
Regulation of myocardial contractility by cardiotonic agents is achieved by an increase in intracellular Ca2+ mobilization (upstream mechanism), an increase in Ca2+ binding affinity to troponin C (central mechanism), or facilitation of the process subsequent to Ca2+ binding to troponin C (downstream mechanism). cAMP mediates the regulation induced by Ca2+ mobilizers such as beta-adrenoceptor agonists and selective phosphodiesterase III inhibitors acting through the upstream mechanism. These agents act likewise on the central mechanism to decrease Ca2+ sensitivity of troponin C in association with the cAMP-mediated phosphorylation of troponin I. In addition to such a well-known action of cAMP, recent experimental findings have revealed that Ca2+ sensitizers, such as levosimendan, OR-1896, and UD-CG 212 Cl, require the cAMP-mediated signaling for induction of Ca2+ sensitizing effect. These agents shift the [Ca2+] -force relationship to the left, but their positive inotropic effect (PIE) is inhibited by carbachol, which suppresses selectively the cAMP-mediated PIE. These findings imply that cAMP may play a crucial role in increasing the myofilament Ca2+ sensitivity by cross-talk with the action of individual cardiotonic agents. No clinically available cardiotonic agents act primarily via Ca2+ sensitization, but the PIE of pimobendan and levosimendan is partly mediated by an increase in myofilament Ca2+ sensitivity. Evidence is accumulating that cardiotonic agents with Ca2+ sensitizing action are more effective than agents that act purely via the upstream mechanism in clinical settings. Further clinical trials are required to establish the effectiveness of Ca2+ sensitizers in long-term therapy for congestive heart failure patients.
Department of Pharmacology, Yamagata University School of Medicine, Japan. mendou@med.id.yamagata-u.ac.jp
Masao
M
Endoh
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000145:classification / Q000494:pharmacology* / Q000627:therapeutic use; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000378:metabolism; D006801:Humans
D002316:Cardiotonic Agents; D002118:Calcium