Urocortin induces positive inotropic effect in rat heart.
OBJECTIVE
The aim of this study is to evaluate the positive inotropic effect of urocortin (Ucn) and to characterize its signalling pathways.


RESULTS
Contractility was measured in ex vivo Langendorff-perfused hearts isolated from Wistar rats. Isolated ventricular cardiomyocytes were used to analyse intracellular calcium ([Ca(2+)](i)) transients evoked by electrical stimulation and L-type Ca(2+) 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 EC(50) 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 I(CaL) density, [Ca(2+)](i) transients, cell shortening and Ca(2+) content of sarcoplasmic reticulum.


CONCLUSIONS
Our results show that Ucn evokes potent positive inotropic and lusitropic effects mediated, at least in part, by an increase in I(CaL) and [Ca(2+)](i) transient amplitude. These effects may involve the activation of Epac, PKC, and MAPK signalling pathways.
Calderón-Sanchez
Eva
E
Laboratorio de Investigación Cardiovascular, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla 41013, Spain.
Delgado
Carmen
C
Ruiz-Hurtado
Gema
G
Domínguez-Rodríguez
Alejandro
A
Cachofeiro
Victoria
V
Rodríguez-Moyano
María
M
Gomez
Ana María
AM
Ordóñez
Antonio
A
Smani
Tarik
T
D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055724:Electrophysiological Phenomena; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013268:Stimulation, Chemical; D054832:Urocortins / Q000494:pharmacology* / Q000502:physiology
D020746:Calcium Channels, L-Type; D020662:Guanine Nucleotide Exchange Factors; D047428:Protein Kinase Inhibitors; D054832:Urocortins; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C