title: The autocrine/paracrine loop after myocardial stretch: mineralocorticoid receptor activation.
abstract: The stretch of cardiac muscle increases developed force in two phases. The first phase, which occurs rapidly, constitutes the well-known Frank-Starling mechanism and it is generally attributed to enhanced myofilament responsiveness to Ca(2+). The second phase or slow force response (SFR) occurs gradually and is due to an increase in the calcium transient amplitude as a result of a stretch-triggered autocrine/paracrine mechanism. We previously showed that Ca(2+) entry through reverse Na(+)/Ca(2+) exchange underlies the SFR, as the final step of an autocrine/paracrine cascade involving release of angiotensin II/endothelin, and a Na(+)/H(+) exchanger (NHE-1) activation-mediated rise in Na+. In the present review we mainly focus on our three latest contributions to the understanding of this signalling pathway triggered by myocardial stretch: 1) The finding that an increased production of reactive oxygen species (ROS) from mitochondrial origin is critical in the activation of the NHE-1 and therefore in the genesis of the SFR; 2) the demonstration of a key role played by the transactivation of the epidermal growth factor receptor; and 3) the involvement of mineralocorticoid receptors (MR) activation in the stretch-triggered cascade leading to the SFR. Among these novel contributions, the critical role played by the MR is perhaps the most important one. This finding may conceivably provide a mechanistic explanation to the recently discovered strikingly beneficial effects of MR antagonism in humans with cardiac hypertrophy and failure.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Medicas, Universidad Nacional de La Plata, Argentina.
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ennis
authors.forename: Ernesto A
authors.initials: EA
authors.lastname: Aiello
authors.forename: Horacio E
authors.initials: HE
authors.lastname: Cingolani
authors.forename: Nestor G
authors.initials: NG
authors.lastname: Perez
mesh_terms: D000804:Angiotensin II / Q000378:metabolism / Q000502:physiology; D019898:Autocrine Communication / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism / Q000517:prevention & control; D006801:Humans; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism*; D019899:Paracrine Communication / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013963:Thyroid Hormones / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D018161:Receptors, Mineralocorticoid; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D013963:Thyroid Hormones; C069139:growth factor-activatable Na-H exchanger NHE-1; D000804:Angiotensin II; D002118:Calcium
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