RT Journal Article
SR Electronic
T1 Calcium Sensitization in Human Esophageal Muscle: Role for RhoA Kinase in Maintenance of Lower Esophageal Sphincter Tone
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 178
OP 186
DO 10.1124/jpet.108.140806
VO 327
IS 1
A1 Stephen M. Sims
A1 Tom Chrones
A1 Harold G. Preiksaitis
YR 2008
UL http://jpet.aspetjournals.org/content/327/1/178.abstract
AB A rise in intracellular-free calcium ([Ca2+]i) concentration is important for initiating contraction of smooth muscles, and Ca2+ sensitization involving RhoA kinase can sustain tension. We previously found that [Ca2+]i was comparable in cells from the esophageal body (EB) and lower esophageal sphincter (LES) muscles, despite the fact that the LES maintains resting tone. We hypothesized that Ca2+ sensitization contributes to contraction in human esophageal muscle. Tension and [Ca2+]i were measured simultaneously in intact human EB and LES muscles using the ratiometric Ca2+-sensitive dye fura-2. Spontaneous oscillations in EB muscle tension were associated with transient elevations of [Ca2+]i. Carbachol caused a large increase in tension, compared with spontaneous oscillations, although the rise of [Ca2+]i was similar, suggesting Ca2+ sensitization. The RhoA-kinase blockers (R)-(+)-trans-4-(1-aminoethyl)-N-(4-pyridyl) cyclohexanecarboxamide dihydrochloride monohydrate (Y-27632) and 1-(5-isoquinolinesulfonyl)-homopiperazine hydrochloride (HA-1077) reduced carbacholand nerve-evoked contraction of the EB, accompanied by smaller reduction in the rise of [Ca2+]i. Protein kinase C inhibitors reduced force to a lesser extent. RhoA-kinase blockers caused concentration-dependent reduction of tension in spontaneously contracted LES muscles. Moreover, RhoA-kinase blockers reduced intrinsic nerve-evoked and carbachol-evoked contraction. However, there was no effect on nerve- or nitric oxide-mediated relaxation of LES. Ca2+ sensitization mediated by the RhoA-kinase pathway has an important role in contraction of human EB muscles and LES tonic contraction, a feature not previously recognized. The American Society for Pharmacology and Experimental Therapeutics