© 2003 by European Society of Cardiology
Copyright © 2003, European Society of Cardiology
A low dose of angiotensin II increases inotropism through activation of reverse Na+/Ca2+ exchange by endothelin release
Centro de Investigaciones Cardiovasculares, Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Calle 60 y 120, 1900 La Plata, Argentina
*Corresponding author. Tel.: +54-221-483-4833; fax: +54-221-425-5861. Email address: gperez{at}atlas.med.unlp.edu.ar
Objective: This work was aimed to prove that release/formation of endogenous endothelin acting in an autocrine/paracrine fashion contributes to the increase in contractility promoted by a low dose of angiotensin II. Methods: Isolated cat papillary muscles were used for force, pHi, [Na+]i and [Ca2+]i measurements and isolated cat myocytes for patch-clamp experiments. Results: In papillary muscles, 1.0 nmol/l angiotensin II increased force by 23±2% (n = 4, P<0.05), [Na+]i by 2.2±0.2 mmol/l (n = 4, P<0.05), and peak (but not diastolic) Ca2+ from 0.674±0.11 to 0.768±0.13 µmol/l (n = 4, P<0.05), without affecting pHi. Force and [Na+]i increase were abolished by inhibition of the Na+/H+ exchanger (NHE) with the inhibitor HOE642, blockade of endothelin receptors with the nonselective antagonist TAK044 and by inhibition of the endothelin-converting enzyme with phosphoramidon. Force but not [Na+]i increase was abolished by inhibition of reverse Na+/Ca2+ exchange (NCX) with the inhibitor KB-R7943. Similar increase in force (21±2%, n = 4, P<0.05) and in [Na+]i (2.4±0.4 mmol/l, n = 4, P<0.05) that were also suppressed by TAK044 and HOE642 were induced by exogenous 5.0 nmol/l endothelin-1. KB-R7943 reverted the endothelin-1 effect on force but not on [Na+]i. In isolated myocytes, exogenous endothelin-1 dose-dependently increased the NCX current and shifted the NCX reversal potential (ENCX) to a more negative value (
ENCX: –10±3 and –17±5 mV, with 1 and 10 nmol/l endothelin-1, respectively, n = 12). The latter effect was prevented by HOE642. Conclusion: Taken together, the results indicate that a low dose of angiotensin II induces release of endothelin, which, in autocrine/paracrine fashion activates the Na+/H+ exchanger, increases [Na+]i and changes ENCX, promoting the influx of Ca2+ that leads to a positive inotropic effect (PIE).
KEYWORDS Angiotensin; Endothelins; Ion transport; Na/Ca-exchanger; Na/H-exchanger; Cat papillary muscles; Isolated cat myocytes; E–C coupling
1 Established Investigators of Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina.
2 Fellow of Comisión de Investigaciones Científicas (CIC) de la Provincia de Buenos Aires, Argentina.
Time for primary review 22 days
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