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Cardiovascular Research Advance Access first published online on May 21, 2009
This version [Corrected Proof] published online on June 13, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp161
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Urocortin induces positive inotropic effect in rat heart

Eva Calderón-Sanchez1, Carmen Delgado2, Gema Ruiz-Hurtado3, Alejandro Domínguez-Rodríguez1, Victoria Cachofeiro2, María Rodríguez-Moyano1, Ana María Gomez3, Antonio Ordóñez1 and Tarik Smani1,*

1 Laboratorio de Investigación Cardiovascular, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla 41013, Spain
2 Departamentos de Farmacología y Fisiología, Facultad de Medicina, Universidad Complutense y Centro de Investigaciones Biológicas (CSIC), Madrid 28040, Spain
3 Inserm, U637, Universités de Montpellier 1 and 2, Montpellier, France

* Corresponding author. Tel: +34 955 01 36 54; fax: +34 955 01 32 92. E-mail address: tasmani{at}us.es

Aims: The aim of this study is to evaluate the positive inotropic effect of urocortin (Ucn) and to characterize its signalling pathways.

Methods and results: Contractility was measured in ex vivo Langendorff-perfused hearts isolated from Wistar rats. Isolated ventricular cardiomyocytes were used to analyse intracellular calcium ([Ca2+]i) transients evoked by electrical stimulation and L-type Ca2+ current by confocal microscopy and whole-cell patch-clamping, respectively. The application of Ucn to perfused hearts induced progressive, sustained, and potent inotropic and lusitropic effects that were dose-dependent with an EC50 of approximately 8 nM. Ucn effects were independent of protein kinase A (PKA) activation but were significantly reduced by protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) inhibitors and by brefeldin A, an antagonist of guanine nucleotide exchange factor, suggested to be an inhibitor of exchange protein activated by cAMP (Epac). These whole-organ effects were correlated with the inotropic effects observed in isolated cells: Ucn increased ICaL density, [Ca2+]i transients, cell shortening and Ca2+ content of sarcoplasmic reticulum.

Conclusion: Our results show that Ucn evokes potent positive inotropic and lusitropic effects mediated, at least in part, by an increase in ICaL and [Ca2+]i transient amplitude. These effects may involve the activation of Epac, PKC, and MAPK signalling pathways.

KEYWORDS Urocortin; Inotropic; PKC; ERK1/2; Epac; Ca2+

Time for primary review: 20 days


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