科研之友
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摘要
Regulation of myocardial contractility by cardiotonic agents is achieved by an increase in intracellular Ca(2+) mobilization (upstream mechanism), an increase in Ca(2+) binding affinity to troponin C (central mechanism), or facilitation of the process subsequent to Ca(2+) binding to troponin C (downstream mechanism). cAMP mediates the regulation induced by Ca(2+) 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 Ca(2+) 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 Ca(2+) sensitizers, such as levosimendan, OR-1896, and UD-CG 212 Cl, require the cAMP-mediated signaling for induction of Ca(2+) sensitizing effect. These agents shift the [Ca(2+)](i)-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 Ca(2+) sensitivity by cross-talk with the action of individual cardiotonic agents. No clinically available cardiotonic agents act primarily via Ca(2+) sensitization, but the PIE of pimobendan and levosimendan is partly mediated by an increase in myofilament Ca(2+) sensitivity. Evidence is accumulating that cardiotonic agents with Ca(2+) 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 Ca(2+) sensitizers in long-term therapy for congestive heart failure patients.
- 出版日期2002-9
