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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Calcium Sensitization in Human Esophageal Muscle: Role for RhoA Kinase in Maintenance of Lower Esophageal Sphincter Tone

Departments of Physiology and Pharmacology (S.M.S., T.C., H.G.P.) and Medicine (H.G.P.), Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada

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.

Address correspondence to: Dr. Stephen M. Sims, Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1. E-mail: stephen.sims{at}schulich.uwo.ca