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Differences in sensitivity to the specific protein kinase C inhibitor Ro31‐8220 between small and large bronchioles of the rat
Author(s) -
Chopra L.C.,
Twort C.H.C.,
Ward J.P.T.
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17130.x
Subject(s) - carbachol , protein kinase c , medicine , chemistry , phorbol , endocrinology , biochemistry , biology , kinase , receptor
1 The involvement of protein kinase C (PKC) in constriction of small bronchioles has never been investigated. In this study we have examined the effects of the specific PKC inhibitors Ro31‐8220 and Ro31‐7549 and the non‐specific inhibitor H7 on carbachol‐, 5‐hydroxytryptamine (5‐HT)‐ and 4β‐phorbol dibutyrate (4β‐PDBu)‐induced contractions in large and small bronchioles. 2 The study was performed on isolated bronchioles of the rat with internal diameters of 574 μm ± 11 (small, n= 128), and 1475 μm ± 32 (large, n = 93), using a Mulvaney‐Halpen small vessel myograph. 3 In these preparations 4β‐PDBu had no effect if added on its own. However, after precontracting with 30 m m K + , 0.5 μ m 4β‐PDBu caused a contractile response of 110.4 ± 7.0% T K ( T K = maximum response to 75 m m K + in small and 69.3 ± 6.5% T K in large bronchioles. Ro31‐8220, Ro31‐7549 and H7 all showed concentration‐dependent inhibition of this response. 4 In small bronchioles 10 μ m Ro31‐8220 shifted both the carbachol and 5‐HT concentration‐ response curves to the right, and reduced the maximum response. In contrast, 10 μ m Ro31‐8220 had no significant effect on the EC 50 to carbachol of larger bronchioles, although the maximum response was reduced, and had no significant effect on the 5‐HT concentration‐ response curve. 200 μ m H7 shifted the carbachol concentration‐ response curve to the right as well as reducing the maximal response in both small and large bronchioles. 5 Large bronchioles exhibited a greater rate of decay of carbachol‐induced contraction than did small bronchioles. Pretreatment with Ro31‐8220 accelerated the rate of decay. 6 Pretreatment with IOIIM Ro31‐8220 caused a small reduction in the response to 75 m m K + in both small and large bronchioles (small: to 87.8 ± 3.0% T K ; large: to 94.1 ± 0.8% T K ) . H7 at 200 μ m caused a much larger reduction in both preparations (small: to 75.1 ± 3.0% T K ) ; large: to 82.7 ± 0.6% T K ) . 7 Small bronchioles were more sensitive than larger bronchioles to agonists and phorbol ester. The protein kinase inhibitor Ro31‐8220 could reduce agonist‐induced constriction in small and large bronchioles, as well as reducing or abolishing phorbol ester‐induced contractions. Small bronchioles were more sensitive than large bronchioles to Ro31–8220. These results suggest that there is a significant PKC involvement in constriction of bronchioles to carbachol and 5‐HT, and that the proportion of the contractile response that can be attributed to PKC is greater in smaller than larger bronchioles.