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Role of Ca 2+ mobilization and Ca 2+ sensitization in 8‐iso‐PGF 2α ‐induced contraction in airway smooth muscle
Author(s) -
Shiraki A.,
Kume H.,
Oguma T.,
Makino Y.,
Ito S.,
Shimokata K.,
Honjo H.,
Kamiya K.
Publication year - 2009
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.2008.03164.x
Subject(s) - chemistry , antagonist , phospholipase c , medicine , endocrinology , thromboxane a2 , phosphatidylinositol , receptor antagonist , oxidative stress , contraction (grammar) , receptor , biochemistry , signal transduction
Summary Background Isoprostanes are prostaglandin (PG)‐like compounds synthesized by oxidative stress, not by cyclooxygenase, and increase in bronchoalveolar lavage fluid of patients with asthma. The airway inflammation implicated in this disease may be amplified by oxidants. Although isoprostanes are useful biomarkers for oxidative stress, the action of these agents on airways has not been fully elucidated. Objective This study was designed to determine the intracellular mechanisms underlying the effects of oxidative stress on airway smooth muscle, focused on Ca 2+ signalling pathways involved in the effect of 8‐iso‐PGF 2α . Methods Using simultaneous recording of isometric tension and F 340 /F 380 (an indicator of intracellular concentrations of Ca 2+ , [Ca 2+ ] i ), we examined the correlation between tension and [Ca 2+ ] i in response to 8‐iso‐PGF 2α in the fura‐2 loaded tracheal smooth muscle. Results Augmented tension and F 340 /F 380 by 8‐iso‐PGF 2α were attenuated by ICI‐192605, an antagonist of thromboxane A 2 receptors (TP receptors). Moreover, D609, an antagonist of phosphatidylcholine‐specific phospholipase C, markedly reduced both the tension and F 340 /F 380 induced by 8‐iso‐PGF 2α , whereas U73122, an antagonist of phosphatidylinositol‐specific phospholipase C, modestly inhibited them by 8‐iso‐PGF 2α . SKF96365, a non‐selective antagonist of Ca 2+ channels, markedly reduced both tension and F 340 /F 380 by 8‐iso‐PGF 2α . However, diltiazem and verapamil, voltage‐dependent Ca 2+ channel inhibitors, modestly attenuated tension although their reduction of F 340 /F 380 was not different from that by SKF96365. Y‐27632, an inhibitor of Rho‐kinase, significantly attenuated contraction induced by 8‐iso‐PGF 2α without reducing F 340 /F 380 , whereas GF109203X and Go6983, protein kinase C inhibitors, did not markedly antagonize them although reducing F 340 /F 380 with a potency similar to Y‐27632. Conclusion 8‐iso‐PGF 2α causes airway smooth muscle contraction via activation of TP receptors. Ca 2+ mobilization by SKF96365‐ and D609‐sensitive Ca 2+ influx and Ca 2+ sensitization by Rho‐kinase contribute to the intracellular mechanisms underlying the action of 8‐iso‐PGF 2α . Rho‐kinase may be a therapeutic target for the physiologic abnormalities induced by oxidative stress in airways.