Published Online
on February 27, 2006

A more recent version of this article appeared on April 1, 2006

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Submitted on December 7, 2005
Revised on December 16, 2005

The Positive Inotropic Effect of Angiotensin II. Role of Endothelin-1 and Reactive Oxygen Species

Horacio E. Cingolani^*; María C. Villa-Abrille; Mariana Cornelli; Alejandro Nolly; Irene L. Ennis; Carolina Garciarena; Angela M. Suburo; Vanesa Torbidoni; María V. Correa; María C. Camilión de Hurtado; and Ernesto A. Aiello

From the Centro de Investigaciones Cardiovasculares (H.E.C., M.C.V.-A., M.C., A.N., I.L.E., C.G., M.V.C., M.C.C.d.H., E.A.A.), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, La Plata; and Facultad de Ciencias Biomédicas (A.M.S., V.T.), Universidad Austral, Pilar, Buenos Aires, Argentina.

^* To whom correspondence should be addressed. E-mail: cimes{at}infovia.com.ar.

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 (ROS 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 ET_A 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 ET_A receptor and triggering ROS production, Na⁺/H⁺ exchanger stimulation, and Na⁺/Ca²⁺ exchanger reverse mode activation.

Key words: membranes • ion channels • oxidative stress • receptors, angiotensin

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