GPR55 ligands promote receptor coupling to multiple signalling pathways |
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Authors: | A Sánchez C Contreras N Villalba P Martínez AC Martínez A Bríones M Salaíces A García-Sacristán M Hernández D Prieto |
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Affiliation: | 1.Departamento de Fisiología, Facultad de Farmacia, Universidad Complutense, Madrid, Spain;2.Departamento de Anatomía y Anatomía Patológica Comparadas, Facultad de Veterinaria, Universidad Complutense, Madrid, Spain;3.Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma, Madrid, Spain |
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Abstract: |
Background and purpose:The aim of the current study was to investigate the role of arachidonic acid (AA) metabolism via cyclooxygenase (COX) in the endothelial dysfunction of penile arteries from pre-diabetic, obese Zucker rats (OZR).Experimental approach:Penile arteries from OZR and from lean Zucker rats (LZR) were mounted in microvascular myographs to assess vascular function and COX expression was determined by immunohistochemistry.Key results:Acetylcholine (ACh) and AA elicited relaxations that were impaired in arteries from OZR. Inhibition of both COX-1 and COX-2 reduced the relaxant effects of ACh and AA in LZR but not in OZR. Inhibitors of COX-1 and of the TXA2/PGH2 (TP) receptor enhanced the relaxations induced by AA in both LZR and OZR, whereas COX-2 inhibition enhanced these responses only in OZR. TP receptor blockade did not restore ACh relaxant responses in arteries from OZR. Inhibition of COX-1 increased basal tension in OZR and this contraction was blunted by TP receptor blockade. The vasoconstrictor responses to noradrenaline were augmented by indomethacin and by COX-2 inhibition in LZR but not in OZR. Immunohistochemical staining showed that both COX-1 and COX-2 are expressed in the endothelium of penile arteries from both LZR and OZR.Conclusions and implications:Vasoactive prostanoids were formed via constitutively active COX-1 and COX-2 pathways in normal rat penile arteries. Under conditions of insulin resistance, the release and/or effects of vasodilator prostanoids were impaired, contributing to the blunted endothelium-dependent vasodilatation and to the enhanced vasoconstriction. |
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Keywords: | insulin resistance penile arteries endothelial dysfunction arachidonic acid COX-1 constitutive COX-2 obese Zucker rat |
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