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CARDIOVASCULAR

Cytosolic Ca²⁺ and Phosphoinositide Hydrolysis Linked to Constitutively Active _1D-Adrenoceptors in Vascular Smooth Muscle

Departamento de Farmacología, Facultad de Farmacia, Universitat de València, València, Spain (R.G., M.A.N., M.D.I., P.D.); and Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain (F.P-V., A.L.C., J.T.)

In the present study, we analyzed changes in intracellular Ca²⁺ levels and inositol phosphate accumulation related to a population of _1D-adrenoceptors in rat aorta resembling constitutively active receptors. Following intracellular Ca²⁺ store depletion by noradrenaline in Ca²⁺-free medium and removal of the agonist, restoration of extracellular Ca²⁺ induced four signals: a biphasic (transient and sustained) increase in [Ca²⁺]_i, inositol phosphate accumulation, and a contractile response in the aorta. The transient increase in Ca²⁺, the inositol phosphate accumulation, and the contractile response were not observed in aortae incubated with prazosin or BMY 7378 [8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione] (a selective _1D-adrenoceptor ligand), relating the three signals to _1D-adrenoceptor activity. In the presence of nimodipine, only the sustained increase in Ca²⁺ and the inositol phosphate accumulation were observed, relating both signals to calcium entry through L-channels. The four signals were abolished by Ni²⁺. In the rat tail artery, where _1D-adrenoceptors are not functionally active, restoration of extracellular Ca²⁺ after store depletion induced only a sustained increase in [Ca²⁺]_i without inositol phosphate accumulation nor contractile response. Taken together these results suggest that in the aorta, Ca²⁺ entry is required for the recovery of cytosolic calcium levels and the display of the membrane signals related to the constitutive activity of _1D-adrenoceptors, i.e., inositol phosphate formation and Ca²⁺ entry through L-type channels, which maintains a contractile response once the agonist has been removed.

Address correspondence to: Pilar D'Ocon Navaza, Departamento de Farmacología, Facultad de Farmacia, Universitat de Valencia, Avda, Vicent Andres Estelles s/n, Burjassot, Valencia 46100, Spain. E-mail: doconp{at}uv.es

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