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Effects of -hydroxylase product on distal human pulmonary arteries

¹Le Bilarium, Department of Physiology and Biophysics, ²Service of Thoracic Surgery, and ³Department of Pathology, Université de Sherbrooke, Sherbrooke, Quebéc, Canada; and ⁴Laboratoire de Physiologie Cellulaire Respiratoire, Institut National de la Santé et de la Recherche Médicale U885, Université Bordeaux 2, Bordeaux, France

Submitted 25 September 2007 ; accepted in final form 7 January 2008

The aim of the present study was to provide a mechanistic insight into how 20-hydroxyeicosatetraenoic acid (20-HETE) relaxes distal human pulmonary arteries (HPAs). This compound is produced by -hydroxylase from free arachidonic acid. Tension measurements, performed on either fresh or 1 day-cultured pulmonary arteries, revealed that the contractile responses to 1 µM 5-hydroxytryptamine were largely relaxed by 20-HETE in a concentration-dependent manner (0.01–10 µM). Iberiotoxin pretreatments (10 nM) partially decreased 20-HETE-induced relaxations. However, 10 µM indomethacin and 3 µM SC-560 pretreatments significantly reduced the relaxations to 20-HETE in these tissues. The relaxing responses induced by the eicosanoid were likely related to a reduced Ca²⁺ sensitivity of the myofilaments since free Ca²⁺ concentration ([Ca²⁺])-response curves performed on β-escin-permeabilized cultured explants were shifted toward higher [Ca²⁺]. 20-HETE also abolished the tonic responses induced by phorbol-ester-dibutyrate (a PKC-sensitizing agent). Western blot analyses, using two specific primary antibodies against the PKC-potentiated inhibitory protein CPI-17 and its PKC-dependent phosphorylated isoform pCPI-17, confirmed that 20-HETE interferes with this intracellular process. We also investigated the effect of 20-HETE on the activation of Rho-kinase pathway-induced Ca²⁺ sensitivity. The data demonstrated that 20-HETE decreased U-46619-induced Ca²⁺ sensitivity on arteries. Hence, this observation was correlated with an increased staining of p116^Rip, a RhoA-binding protein. Together, these results strongly suggest that the 20-hydroxyarachidonic acid derivative is a potent modulator of tone in HPAs in vitro.

20-hydroxyeicosatetraenoic acid; calcium sensitivity; tension measurement

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