Involvement of rho-kinase in contraction of guinea-pig aorta induced by prostanoid eP3 receptor agonists

Shum, W.W.C. and Le, G.Y. and Jones, R.L. and Gurney, A.M. and Sasaki, Y. (2003) Involvement of rho-kinase in contraction of guinea-pig aorta induced by prostanoid eP3 receptor agonists. British Journal of Pharmacology, 139 (8). pp. 1449-1461. ISSN 1476-5381 (https://doi.org/10.1038/sj.bjp.0705393)

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Abstract

The mechanism of contraction of guinea-pig isolated aorta induced by the prostanoid EP3 receptor agonist sulprostone (0.1–300 nm) has been investigated. In 60% of the experiments, the sulprostone log concentration–response curve (maximum=15–40% of 100 nm U-46619 response; low-responders) was unaffected by the removal of extracellular Ca2+, blockade of L-type Ca2+ channels with nifedipine and depletion of internal Ca2+ stores. In the remaining preparations (35–65% of 100 nm U-46619 response; high-responders), contractions to higher sulprostone concentrations showed a nifedipine-sensitive component, which was enhanced by charybdotoxin. In Ca2+-free Krebs solution, established contractions to 300 nm sulprostone were abolished by the Rho-kinase inhibitors H-1152, Y-27632 and HA-1077 (IC50 values=190, 770 and 2030 nm). The PKA/Rho-kinase inhibitor H-89 (10 nm–10 μm) caused enhancement progressing to inhibition. The selective PKC inhibitor Ro 32-0432 (3 μm) had no effect, while staurosporine, recently shown to be a potent Rho-kinase inhibitor, abolished sulprostone responses (IC50 ∼47 nm), but its action was slow. The MAP kinase inhibitors SB 202190, SB 203580 and PD 80958 produced little inhibition. In normal Krebs solution, H-1152 and Y-27632 abolished established contractions to 300 nm sulprostone and 1 μm phenylephrine, and partially inhibited 10 μm phenylephrine and 50 mm K+ responses. The results are discussed in relation to the reported potencies of the protein kinase inhibitors in enzyme assays. Activation of the Rho-kinase pathway appears to be a primary mechanism of contraction induced by EP3 receptor agonists in guinea-pig aorta.

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