title: Positive inotropic effect of angiotensin II. Increases in intracellular Ca2+ or changes in myofilament Ca2+ 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 (IP3), and 1,2, diacylglycerol (DAG). IP3 triggers the release of Ca2+ from intracellular stores in several cell types and has been shown to increase myofilament Ca2+ 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-/HCO3- exchanger, implicated in the regulation of intracellular pH, and the Na+/Ca2+ exchanger which contribute to the intracellular Ca2+ homeostasis, have been shown to be activated by a PKC-dependent mechanism. Thus, either one of the Ang II-induced second messengers, that is, IP3 and DAG, has the potential to affect myocardial contractility by modifying either intracellular Ca2+, myofilament Ca2+ 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.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Medicina, La Plata, Argentina.
authors.forename: A
authors.initials: A
authors.lastname: Mattiazzi
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism*; D004075:Diglycerides / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D007382:Intermediate Filaments / Q000187:drug effects / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism* / Q000648:ultrastructure; D009210:Myofibrils / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D017923:Sodium-Hydrogen Exchangers / Q000494:pharmacology; D013045:Species Specificity
chemical_list: D004075:Diglycerides; D011945:Receptors, Angiotensin; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II; D015544:Inositol 1,4,5-Trisphosphate; D011493:Protein Kinase C; D000251:Adenosine Triphosphatases; C034688:sodium calcium ATPase; D002118:Calcium