Positive inotropic effect of Angiotensin II. Increases in intracellular Ca 2+ or changes in myofilament Ca 2+ responsiveness?

Abstract

Although it is well known that Angiotensin II (Ang II) has a direct positive inotropic effect in several species, the mechanisms of this action are still poorly understood. The aim of this review is to analyze the possible subcellular mechanisms underlying Ang II-induced positive inotropic action. The binding of Ang II to its receptor triggers a complex signal transduction cascade that stimulates the intracellular formation of two second messengers, inositol 1,4,5-triphosphate (IP 3), and 1,2, diacylglycerol (DAG). IP 3 triggers the release of Ca 2+ from intracellular stores in several cell types and has been shown to increase myofilament Ca 2+ sensitivity. DAG activates protein kinase C (PKC), an enzyme that catalyzes the phosphorylation of different cellular proteins, including several proteins of the myofibrils. Distinct ionic transporters, like the Na + H + antiporter and the Na +-independent Cl − HCO 3 − exchanger, implicated in the regulation of intracellular pH, and the Na + Ca 2+ exchanger which contribute to the intracellular Ca 2+ homeostasis, have been shown to be activated by a PKC-dependent mechanism. Thus, either one of the Ang II-induced second messengers, that is, IP 3 and DAG, has the potential to affect myocardial contractility by modifying either intracellular Ca 2+, myofilament Ca 2+ responsiveness, or both. As described herein, the available data do not allow a definitive single model to explain the mechanism of the Ang II-induced positive inotropic effect. Moreover, it is possible that the final action of Ang II on myocardial inotropism is the end product of a complex interaction of several of the mechanisms triggered by the hormone.