CYCLOSPORINE-A POTENTIATES RECEPTOR-ACTIVATED [CA2+](C) INCREASE

The use of the immunosuppressant cyclosporin A (CsA) is frequently ass ociated with hypertension. Drug-induced local vasoconstriction appears to be responsible for this effect. Using fura-2 and Ca-45(2+) efflux techniques, we have examined variations in the cytosolic calcium conce ntration ([Ca2+](c)) in rat aortic smooth muscle cells and have shown that increases in [Ca2+](c) after [Arg(8)]vasopressin, serotonin, endo thelin-l or angiotensin II stimulation were potentiated after preincub ation of cells with CsA. This effect was independent of cyclophilin or calcineurin inhibition by CsA. Measurements of inositol phosphates (I nsP(n)) after agonist stimulation showed that CsA also potentiated the ir formation. As for Ca-45(2+) efflux this effect was not related to c yclophilin or calcineurin inhibition Direct stimulation of G proteins with aluminium tetrafluoride induced an increase in InsP, formation an d Ca-45(2+) efflux Neither of these responses was potentiated by CsA T hese results indicate that CsA acts on a target upstream of G protein activation, possibly at the receptor level, resulting in a potentiatio n of InsP(n) formation and subsequent calcium increase.