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(Circulation Research. 1995;77:927.)
© 1995 American Heart Association, Inc.

Articles

Endoplasmic Reticulum Ca²⁺ Depletion Unmasks a Caffeine-Induced Ca²⁺ Influx in Human Aortic Endothelial Cells

Stefano Corda, Harold A. Spurgeon, Edward G. Lakatta, Maurizio C. Capogrossi, Roy C. Ziegelstein

From the Laboratory of Cardiovascular Science (S.C., H.A.S., E.G.L., M.C.C.), Gerontology Research Center, National Institute on Aging, National Institutes of Health, and the Department of Medicine (M.C.C., R.C.Z.), Division of Cardiology, Johns Hopkins University, Baltimore, MD.

Correspondence to Roy C. Ziegelstein, MD, Johns Hopkins Bayview Medical Center, Cardiology B-1 South, 4940 Eastern Ave, Baltimore, MD 21224. E-mail rziegels@welchlink.welch.jhu.edu.

Abstract Intracellular Ca²⁺ pools contribute to changes in cytosolic [Ca²⁺] ([Ca²⁺]_i), which play an important role in endothelial cell signaling. Recently, endothelial ryanodine-sensitive Ca²⁺ stores were shown to regulate agonist-sensitive intracellular Ca²⁺ pools. Since caffeine binds the ryanodine Ca²⁺ release channel on the endoplasmic reticulum in a variety of cell types, we examined the effect of caffeine on [Ca²⁺]_i in human aortic endothelial cell monolayers loaded with the fluorescent probe indo 1. Under baseline conditions, 10 mmol/L caffeine induced a small increase in [Ca²⁺]_i from 86±10 to 115±17 nmol/L (mean±SEM); this effect was similar to that of 5 µmol/L ryanodine and was unaffected by buffer Ca²⁺ removal. After depletion of an intracellular Ca²⁺ store by the irreversible endoplasmic reticulum Ca²⁺-ATPase inhibitor thapsigargin (1 µmol/L), ryanodine did not affect [Ca²⁺]_i. In contrast, caffeine induced a large rapid increase in [Ca²⁺]_i (176±19 to 338±35 nmol/L, P<.001) after thapsigargin exposure; this effect of caffeine was only observed when extracellular Ca²⁺ was present. A similar increase in [Ca²⁺]_i was induced by caffeine after depletion of ryanodine- and histamine-sensitive Ca²⁺ stores or after pretreatment with the endoplasmic reticulum Ca²⁺-ATPase inhibitor cyclopiazonic acid (10 µmol/L). Thus, under baseline conditions the effect of caffeine on [Ca²⁺]_i is similar to that of ryanodine and appears to be due to the release of an intracellular store. However, after depletion of an endoplasmic reticulum Ca²⁺ store, caffeine, but not ryanodine, stimulates Ca²⁺ influx, resulting in a large increase in [Ca²⁺]_i. The data suggest that caffeine-induced Ca²⁺ influx is controlled by the status of Ca²⁺ loading of intracellular Ca²⁺ stores in human aortic endothelial cells.

Key Words: cell calcium • endothelium • caffeine • thapsigargin • indo 1

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