Cyclosporin A potentiates receptor-activated [Ca2+]c increase.
The use of the immunosuppressant cyclosporin A (CsA) is frequently associated with hypertension. Drug-induced local vasoconstriction appears to be responsible for this effect. Using fura-2 and 45Ca2+ efflux techniques, we have examined variations in the cytosolic calcium concentration ([Ca2+]c) in rat aortic smooth muscle cells and have shown that increases in [Ca2+]c after [Arg8]vasopressin, serotonin, endothelin-1 or angiotensin II stimulation were potentiated after preincubation of cells with CsA. This effect was independent of cyclophilin or calcineurin inhibition by CsA. Measurements of inositol phosphates (InsPn) after agonist stimulation showed that CsA also potentiated their formation. As for 45Ca2+ efflux this effect was not related to cyclophilin or calcineurin inhibition. Direct stimulation of G proteins with aluminium tetrafluoride induced an increase in InsPn formation and 45Ca2+ efflux. Neither of these responses was potentiated by CsA. These results indicate that CsA acts on a target upstream of G protein activation, possibly at the receptor level, resulting in a potentiation of InsPn formation and subsequent calcium increase.
Lo Russo
A
A
Pharmacology Group, School of Pharmacy University of Lausanne, Switzerland.
Passaquin
A C
AC
Cox
C
C
Rüegg
U T
UT
D017607:Aluminum Compounds / Q000494:pharmacology; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D004789:Enzyme Activation; D005459:Fluorides / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D016559:Tacrolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D017607:Aluminum Compounds; D007166:Immunosuppressive Agents; D014662:Vasoconstrictor Agents; D001127:Arginine Vasopressin; C050992:tetrafluoroaluminate; D016572:Cyclosporine; D015544:Inositol 1,4,5-Trisphosphate; C058028:immunomycin; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D005459:Fluorides; D002118:Calcium; D016559:Tacrolimus