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Cardiovascular Research Advance Access [Accepted Manuscript] published online on May 21, 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 de Rocío/CSIC/Universidad de Sevilla. Sevilla 41013
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&2. Montpellier, France

Corresponding Author: Tarik Smani, PhD, Instituto de Biomedicina de Sevilla/Hospital Universitario Virgen del Rocío, Quirófano Experimental/Laboratorio de Investigación Cardiovascular. Avenida Manuel Siurot s/n, Sevilla 41013, Spain. Phone: (+34) 955 01 36 54; Fax: (+34) 955 01 32 92. Email: 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: Contractility was measured in ex vivo Langendorff perfused hearts isolated from Wistar rats. Isolated ventricular cardiomyocytes were used to analyze intracellular calcium ([Ca2+]i) transients evoked by electrical stimulation and L-type Ca2+ current by confocal microscopy and whole-cell patch-clamping, respectively.

Results: The application of Ucn to perfused hearts induced progressive, sustained and potent inotropic and lusitropic effects that were dose dependent with an EC50 of ~8 nM. Ucn effects were independent of protein kinase A (PKA) activation but were significantly reduced by protein kinase C (PKC) and mitogens-activated protein kinase (MAPK) inhibitors and by brefeldin A (BFA), an antagonist of guanine nucleotide exchange factor (GEF), 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, cells shortening and sarcoplasmic reticulum Ca2+ content.

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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