Intracellular actions of angiotensin II in vascular smooth muscle cells.
Angiotensin II (AngII) is present inside vascular smooth muscle cells (VSMC); however, its intracellular functions, if any, are unknown. AngII was administered by microinjection. AngII was identified in endosomes and in the nucleus. Microinjection of AngII (10(-10) M) led to a rapid increase in the intracellular Ca2+ concentration ([Ca2+]i) in the cytosol and in the nucleus. The [Ca2+]i increase was the result of an influx of extracellular Ca2+ ions. The intracellular AngII effect was totally inhibited by concomitant injection of the AngII type 1 receptor blocker candesartan. Desensitization of extracellular AngII receptors, on the other hand, did not influence the intracellular effects, and neither did extracellular candesartan. The increase in [Ca2+]i was observed not only in the microinjected cell but also in directly adjacent VSMC. In contrast to the microinjected cells, the [Ca2+]i increase in the adjacent cells was mostly the result of Ca2+ release from intracellular stores. Pretreatment with thapsigargin, which interferes with Ca2+ release from intracellular stores, abolished the AngII response in adjacent cells. Microinjection of inositol trisphosphate induced a [Ca2+]i response in adjacent cells that was similar to the AngII-induced effects. Preincubation of VSMC with uncoupling substances did not decrease the AngII response but prevented a [Ca2+]i surge in adjacent cells. Tyrosine phosphorylation was next examined. Phosphorylation was detected in the injected cells, primarily in the cytoskeleton. It can be concluded that intracellular AngII binds to intracellular AngII receptors and elicits increased [Ca2+]i in the injected cell and then in cells in the immediate neighborhood. Cell-cell contact is necessary for the AngII-mediated effects. These data suggest that intracellular AngII may stimulate a cluster of VSMC from a single cell, via the release of second messengers.
Haller
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Franz Volhard Clinic and the Max Delbrück Center for Molecular Medicine, Humboldt University of Berlin, Germany.
Lindschau
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C
Quass
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Luft
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FC
D000804:Angiotensin II / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D007295:Inositol Phosphates / Q000378:metabolism / Q000494:pharmacology; D008845:Microinjections; D018613:Microscopy, Confocal; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D009568:Nitrendipine / Q000494:pharmacology; D051381:Rats
D002121:Calcium Channel Blockers; D007295:Inositol Phosphates; D000804:Angiotensin II; D009568:Nitrendipine; D002118:Calcium