The positive inotropic effect of angiotensin II: role of endothelin-1 and reactive oxygen species.
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.
Cingolani
Horacio E
HE
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata, Argentina. cimes@infovia.com.ar
Villa-Abrille
María C
MC
Cornelli
Mariana
M
Nolly
Alejandro
A
Ennis
Irene L
IL
Garciarena
Carolina
C
Suburo
Angela M
AM
Torbidoni
Vanesa
V
Correa
María V
MV
Camiliónde Hurtado
María C
MC
Aiello
Ernesto A
EA
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
D002316:Cardiotonic Agents; D019332:Endothelin-1; D017382:Reactive Oxygen Species; D044022:Receptor, Endothelin A; D017923:Sodium-Hydrogen Exchangers; D000804:Angiotensin II