title: The positive inotropic effect of angiotensin II: role of endothelin-1 and reactive oxygen species.
abstract: Many effects believed to be because of angiotensin II (Ang II) are attributable to the action of endothelin (ET)-1, which is released/produced by Ang II. We investigated whether Ang II elicits its positive inotropic effect (PIE) by the action of endogenous ET-1, in addition to the role played by reactive oxygen species (ROS) in this mechanism. Cat cardiomyocytes were used for: (1) sarcomere shortening measurements; (2) ROS measurements by epifluorescence; (3) immunohistochemical staining for preproET-1, BigET-1, and ET-1; and (4) measurement of preproET-1 mRNA by RT-PCR. Cells were exposed to 1 nmol/L Ang II for 15 minutes. This low concentration of Ang II increases sarcomere shortening by 29.2+/-3.7% (P<0.05). This PIE was abrogated by Na+/H+ exchanger or Na+/Ca2+ exchanger reverse mode inhibition. The production of ROS increased in response to Ang II treatment (DeltaROS respect to control: 68+/-15 fluorescence units; P<0.05). The Ang II-induced PIE and ROS production were blocked by the Ang II type 1 receptor blocker losartan, the nonselective ET-1 receptor blocker TAK044, the selective ETA receptor blocker BQ-123, or the ROS scavenger N-(2-mercapto-propionyl)glycine. Exogenous ET-1 (0.4 nmol/L) induced a similar PIE and increase in ROS production to those caused by Ang II. Immunostaining for preproET-1, BigET-1, and ET-1 was positive in cardiomyocytes. The preproET-1 mRNA abundance increased from 100+/-4.6% in control to 241.9+/-39.9% in Ang II-treated cells (P<0.05). We conclude that the PIE after exposure to 1 nmol/L Ang II is due to endogenous ET-1 acting through the ETA receptor and triggering ROS production, Na+/H+ exchanger stimulation, and Na+/Ca2+ exchanger reverse mode activation.
authors.affiliation: Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina. cimes@infovia.com.ar
authors.forename: Horacio E
authors.initials: HE
authors.lastname: Cingolani
authors.forename: María C
authors.initials: MC
authors.lastname: Villa-Abrille
authors.forename: Mariana
authors.initials: M
authors.lastname: Cornelli
authors.forename: Alejandro
authors.initials: A
authors.lastname: Nolly
authors.forename: Irene L
authors.initials: IL
authors.lastname: Ennis
authors.forename: Carolina
authors.initials: C
authors.lastname: Garciarena
authors.forename: Angela M
authors.initials: AM
authors.lastname: Suburo
authors.forename: Vanesa
authors.initials: V
authors.lastname: Torbidoni
authors.forename: María V
authors.initials: MV
authors.lastname: Correa
authors.forename: María C
authors.initials: MC
authors.lastname: Camiliónde Hurtado
authors.forename: Ernesto A
authors.initials: EA
authors.lastname: Aiello
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002415:Cats; D019332:Endothelin-1 / Q000378:metabolism*; D007150:Immunohistochemistry / Q000379:methods; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism; D013194:Staining and Labeling
chemical_list: D002316:Cardiotonic Agents; D019332:Endothelin-1; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II