Cardiac α1-Adrenoceptors and Inotropy: Myofilament Ca2+ Sensitivity, Intracellular Ca2+ Mobilization, Signaling Pathway, and Pathophysiological Relevance.

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Cardiac α1-adrenoceptor stimulation elicits a positive inotropic effect because of myofilament Ca2+ sensitization with a small increase in Ca2+ transients predominantly mediated by α1B-adrenoceptors via the intracellular alkalinization and potential myosin light chain 2 phosphorylation. However, the α1-adrenoceptor–mediated inotropy exhibits a wide range of species-dependent variation. In addition, it displays remarkable regional and subtype-dependent variations among species. The signaling pathway for α1-adrenoceptor–mediated regulation is vulnerable being markedly influenced by experimental and pathophysiological conditions. Cardiac α1-adrenoceptors may have clinical relevance in that sympathomimetic amines including norepinephrine possess higher affinity to α1-adrenoceptors than β-adrenoceptors, and α1-adrenoceptors play a compensatory role in patients with heart failure. Modulation of cardiac α1-adrenoceptor–mediated signaling pathway could provide potential targets for the development of novel therapeutic strategy. The role of cardiac α1-adrenoceptors in regulation of myocardial contractility, including mechanism of action, signaling pathway, and pathophysiological and clinical significance, has been less clarified compared with the well-established β-adrenoceptor–mediated regulation. In this viewpoint, I will focus on the state-of-the-art of cardiac α1-adrenoceptor–mediated basic mechanism and its pathophysiological relevance in relation to clinical implications. The regulation of myocardial contractility by Ca2+ is achieved by either alteration of peak Ca2+ transients (CaT) that reflect the intracellular Ca2+ ([Ca2+]i) mobilization during twitch contraction (upstream mechanism), myofilament Ca2+ sensitivity (central or downstream mechanism) or combination of both, in which the binding of Ca2+ to troponin C plays a central role (central mechanism) in cardiac EC coupling. Cardiac α1-adrenoceptor stimulation elicits a moderate increase in peak CaT (20% of the maximum of β-adrenoceptor–mediated increase), whereas it induces the maximum positive inotropic effect (PIE) in an amount of 60% of the β-adrenoceptor–mediated maximum …