Endothelin-1 Stimulates the Na + /Ca 2+ Exchanger Reverse Mode Through Intracellular Na + (Na + i )–Dependent and Na + i -Independent Pathways

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 45; no. 2; pp. 288 - 293
• Main Authors: Aiello, Ernesto Alejandro, Villa-Abrille, María Celeste, Dulce, Raúl Ariel, Cingolani, Horacio Eugenio, Pérez, Néstor Gustavo
• Format: Journal Article
• Language: English
• Published: 01-02-2005
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.HYP.0000152700.58940.b2

This study aimed to explore the signaling pathways involved in the positive inotropic effect (PIE) of low doses of endothelin-1 (ET-1). Cat papillary muscles were used for force and intracellular Na
+
concentration (Na
+
i
) measurements, and isolated cat ventricular myocytes for patch-clamp experiments. ET-1 (5 nmol/L) induced a PIE and an associated increase in Na
+
i
that were abolished by Na
+
/H
+
exchanger (NHE) inhibition with HOE642. Reverse-mode Na
+
/Ca
2+
exchanger (NCX) blockade with KB-R7943 reversed the ET-1–induced PIE. These results suggest that the ET-1–induced PIE is totally attributable to the NHE-mediated Na
+
i
increase. However, an additional direct stimulating effect of ET-1 on NCX after the necessary increase in Na
+
i
could occur. Thus, the ET-1–induced increase in Na
+
i
and contractility was compared with that induced by partial inhibition of the Na
+
/K
+
ATPase by lowering extracellular K
+
(K
+
o
)
.
For a given Na
+
i
, ET-1 induced a greater PIE than low K
+
o
. In the presence of HOE642 and after increasing contractility and Na
+
i
by low K
+
o
, ET-1 induced an additional PIE that was reversed by KB-R7943 or the protein kinase C (PKC) inhibitor chelerythrine. ET-1 increased the NCX current and negatively shifted the NCX reversal potential (E
NCX
). HOE642 attenuated the increase in NCX outward current and abolished the E
NCX
shift. These results indicate that whereas the NHE-mediated ET-1–induced increase in Na
+
i
seems to be mandatory to drive NCX in reverse and enhance contractility, Na
+
i
-independent and PKC-dependent NCX stimulation appears to additionally contribute to the PIE. However, it is important to stress that the latter can only occur after the primary participation of the former.