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RhoA kinase and protein kinase C participate in regulation of rabbit stomach fundus smooth muscle contraction
Author(s) -
Ratz Paul H,
Meehl Joel T,
Eddinger Thomas J
Publication year - 2002
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 - 10.1038/sj.bjp.0704952
Subject(s) - carbachol , endocrinology , muscarinic acetylcholine receptor , medicine , agonist , phenylephrine , protein kinase c , contraction (grammar) , muscle contraction , rhoa , chemistry , biology , receptor , kinase , signal transduction , biochemistry , blood pressure
The degree to which the RhoA kinase (ROK) blockers, Y‐27632 (1 μ M ) and HA‐1077 (10 μ M ), and the PKC blocker, GF‐109203X (1 μ M ), reduced force produced by carbachol, a muscarinic receptor agonist, and phenylephrine, an α‐adrenoceptor agonist, was examined in rabbit stomach fundus smooth muscle. When examining the effect on cumulative carbachol concentration‐response curves (CRCs), ROK and PKC blockers shifted the potency (EC 50 ) to the right but did not reduce the maximum response. In a single‐dose carbachol protocol using moderate (∼EC 50 ) and maximum carbachol concentrations, Y‐27632 and HA‐1077 reduced peak force, but GF‐109203X had no effect. By contrast, all three agents inhibited the carbachol contractions of rabbit bladder (detrusor) smooth muscle. Compared to carbachol, phenylephrine produced a weaker maximum response that was not inhibited by phentolamine, atropine nor capsaicin but was inhibited by Y‐27632, HA‐1077 and GF‐109203X. In detrusor, classical down‐regulation occurred, but in fundus, up‐regulation of responsiveness occurred. This up‐regulation in fundus may have been a post‐receptor event, because a KCl‐induced contraction produced after a carbachol CRC was stronger than one produced before the carbachol stimulus. In conclusion, these data suggest that ROK plays a critical role in the regulation of rabbit fundus smooth muscle contraction, which is distinct from chicken gizzard smooth muscle, where ROK is reported to exist but to not play a role in muscarinic receptor‐induced contraction. Additional unique findings are that PKC participates in phenylephrine‐ but not carbachol‐induced contraction in fundus, that carbachol does not activate identical subcellular signalling systems in fundus and detrusor, and that fundus, unlike detrusor, responds to carbachol stimulation with post‐receptor up‐regulation of contraction.British Journal of Pharmacology (2002) 137 , 983–992. doi: 10.1038/sj.bjp.0704952