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Vascul Pharmacol. 2014 Mar;60(3):95-101. doi: 10.1016/j.vph.2014.01.004. Epub 2014 Jan 25.

PKA and Epac activation mediates cAMP-induced vasorelaxation by increasing endothelial NO production.

Author information

1
Farmacología Cardiovascular y Plaquetaria, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain.
2
Farmacología Cardiovascular y Plaquetaria, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain. Electronic address: manuel.campos@usc.es.

Abstract

Vascular relaxation induced by 3',5'-cyclic adenosine monophosphate (cAMP) is both endothelium-dependent and endothelium-independent, although the underlying signaling pathways are not fully understood. Aiming to uncover potential mechanisms, we performed contraction-relaxation experiments on endothelium-denuded and intact rat aorta rings and measured NO levels in isolated human endothelial cells using single cell fluorescence imaging. The vasorelaxant effect of forskolin, an adenylyl cyclase activator, was decreased after selective inhibitor of protein kinase A (PKA), a cAMP-activated kinase, or L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor, only in intact aortic rings. Both selective activation of PKA with 6-Bnz-cAMP and exchange protein directly activated by cAMP (Epac) with 8-pCPT-2'-O-Me-cAMP significantly relaxed phenylephrine-induced contractions. The vasorelaxant effect of the Epac activator, but not that of the PKA activator, was reduced by endothelium removal. Forskolin, dibutyryl cAMP (a cAMP analogue), 6-Bnz-cAMP and 8-pCPT-2'-O-Me-cAMP increased NO levels in endothelial cells and the forskolin effect was significantly inhibited by inactivation of both Epac and PKA, and eNOS inhibition. Our results indicate that the endothelium-dependent component of forskolin/cAMP-induced vasorelaxation is partially mediated by an increase in endothelial NO release due to an enhanced eNOS activity through PKA and Epac activation in endothelial cells.

KEYWORDS:

Cyclic AMP; Endothelium; Epac proteins; Protein kinase A; eNOS

PMID:
24469067
DOI:
10.1016/j.vph.2014.01.004
[Indexed for MEDLINE]

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