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(Circulation Research. 2007;101:1194.)
© 2007 American Heart Association, Inc.

Integrative Physiology

Role of Ca²⁺-Independent Phospholipase A₂ and Store-Operated Pathway in Urocortin-Induced Vasodilatation of Rat Coronary Artery

Tarik Smani, Alejandro Domínguez-Rodríguez, Abdelkrim Hmadcha, Eva Calderón-Sánchez, Angélica Horrillo-Ledesma, Antonio Ordóñez

From the Laboratorio de Investigación Cardiovascular (T.S., A.D.-R., E.C.-S., A.O.), Hospital Universitario Virgen del Roció, Universidad de Sevilla, and Centro Andaluz de Biología Molecular & Medicina Regenerativa (A.H., A.H.-L.), Sevilla, Spain.

Correspondence to Tarik Smani, PhD, Laboratorio de Investigación Cardiovascular, Quirófanos Experimentales, Hospital General Universitario Virgen del Rocío, Avenida Manuel Siurot s/n, E-41013 Sevilla, Spain. E-mail tasmani{at}us.es

Urocortin has been shown to produce vasodilatation in several arteries, but the precise mechanism of its action is still poorly understood. Here we demonstrate the role of store operated Ca²⁺ entry (SOCE) regulated by Ca²⁺-independent phospholipase A₂ (iPLA₂) in phenylephrine hydrochloride (PE)-induced vasoconstriction, and we present the first evidence that urocortin induces relaxation by the modulation of SOCE and iPLA₂ in rat coronary artery. Urocortin produces an endothelium independent relaxation, and its effect is concentration-dependent (IC₅₀4.5 nmol/L). We show in coronary smooth muscle cells (SMCs) that urocortin inhibits iPLA₂ activation, a crucial step for SOC channel activation, and prevents Ca²⁺ influx evoked by the emptying of the stores via a cAMP and protein kinase A (PKA)–dependent mechanism. Lysophophatidylcholine and lysophosphatidylinositol, products of iPLA₂, exactly mimic the effect of the depletion of the stores in presence of urocortin. Furthermore, we report that long treatment with urocortin downregulates iPLA₂ mRNA and proteins expression in rat coronary smooth muscle cells. In summary, we propose a new mechanism of vasodilatation by urocortin which involves the regulation of iPLA₂ and SOCE via the stimulation of a cAMP/PKA-dependent signal transduction cascade in rat coronary artery.

Key Words: urocortin • iPLA₂ • vasoconstriction • store operated Ca²⁺ entry • cAMP-PKA

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