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; ERNESTO A. AIELLO

HYPERTENSION

Año: 2006 vol. 47 p. 727 - 734

0194-911X

Many effects believed to be due to angiotensin II (Ang II) are due to the action of endothelin-1 (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 (SS) 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 min. This low concentration of Ang II increases SS by 29.2±3.7 % (p<0.05). This PIE was abrogated by Na+/H+ exchanger (NHE) or Na+/Ca2+ exchanger (NCX) reverse mode inhibition. The production of ROS increased in response to Ang II treatment (DROS respect to control: 68±15 fluorescence units, p<0.05). The Ang II-induced PIE and in ROS production were blocked by the AT1 receptor blocker losartan, the non-selective ET-1 receptor blocker TAK044, the selective ETA receptor blocker BQ-123 or the ROS scavenger MPG. 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 following exposure to 1 nmol/L Ang II is due to endogenous ET-1 acting through the ETA receptor and triggering ROS production, NHE stimulation and NCX reverse mode activation.