Cyclosporine A-induced contractions and prostacyclin release are maintained by extracellular calcium in rat aortic rings: role of protein kinase C

Abstract

Chronic treatment with the immunosuppressive drug, Cyclosporine A (CsA), is associated with increased intracellular calcium in vascular smooth muscle cells, which may cause vasoconstriction and/or activate phospholipase A 2. We used rat aortic rings to investigate the role of protein kinase C (PKC) in CsA-induced contractions and secondary prostacyclin (PGI 2) release. CsA (10 −9 M) produced a sustained contraction in rat aortic rings. Both CsA-induced contractions and PGI 2 release were inhibited 84 to 89% by 10 −9 M, and 99 to 100% by 10 −6 M pretreatment doses of any of three different PKC inhibitors, i.e. 1-(5-isoquinolinesulfonylmethyl) piperazine (H7), staurosporine or 1-(5-isoquinolinesulfonyl) piperazine. Pretreatment with (10 −9 M) of diltiazem (a voltage-sensitive L-type calcium channel blocker) completely inhibited both CsA-induced contractions and PGI 2 release. Conversely, pretreatment with (10 −9 M) of thapsigargin (an intracellular calcium channel blocker) did not alter the action of CsA. These results strongly suggest that PKC, in association with an influx of extracellular calcium mediates CsA-induced contractions and secondary PGI 2 release in rat aortic rings.