Rilmenidine elevates cytosolic free calcium concentration in suspended cerebral astrocytes.
Rilmenidine, a ligand for imidazoline and alpha2-adrenergic receptors, is neuroprotective following focal cerebral ischemia. We investigated the effects of rilmenidine on cytosolic free Ca2+ concentration ([Ca2+]i) in rat astrocytes. Rilmenidine caused concentration-dependent elevation of [Ca2+]i, consisting of a transient increase (1-100 microM rilmenidine) or a transient increase followed by sustained elevation above basal levels (1-10 mM rilmenidine). A similar elevation in [Ca2+]i was induced by the imidazoline ligand cirazoline. The transient response to rilmenidine was observed in Ca2+-free medium, indicating that rilmenidine evokes release of Ca2+ from intracellular stores. However, the sustained elevation of Ca2+ was completely dependent on extracellular Ca2+, consistent with rilmenidine activating Ca2+ influx. Pretreatment with thapsigargin, an inhibitor of the endoplasmic reticulum Ca2+-ATPase, abolished the response to rilmenidine, confirming the involvement of intracellular stores and suggesting that rilmenidine and thapsigargin activate a common Ca2+ influx pathway. The alpha2-adrenergic antagonist rauwolscine attenuated the increase in [Ca2+]i induced by clonidine (a selective alpha2 agonist), but not the response to rilmenidine. These results indicate that rilmenidine stimulates both Ca2+ release from intracellular stores and Ca2+ influx by a mechanism independent of alpha2-adrenergic receptors. In vivo, rilmenidine may enhance uptake of Ca2+ from the extracellular fluid by astrocytes, a process that may contribute to the neuroprotective effects of this agent.
Ozog
M A
MA
Department of Anatomy, Faculty of Medicine and Dentistry, University of Western Ontario, London, Canada.
Wilson
J X
JX
Dixon
S J
SJ
Cechetto
D F
DF
D000255:Adenosine Triphosphate / Q000494:pharmacology; D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism*; D003600:Cytosol / Q000187:drug effects* / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology*; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D000077769:Rilmenidine
D058669:Adrenergic alpha-2 Receptor Antagonists; D000316:Adrenergic alpha-Agonists; D007093:Imidazoles; D010080:Oxazoles; D018341:Receptors, Adrenergic, alpha-2; D000255:Adenosine Triphosphate; D000077769:Rilmenidine; C014282:cirazoline; D002118:Calcium