CYCLOSPORINE-A-INDUCED CONTRACTIONS AND PROSTACYCLIN RELEASE ARE MAINTAINED BY EXTRACELLULAR CALCIUM IN RAT AORTIC RINGS - ROLE OF PROTEIN-KINASE-C

Chronic treatment with the immunosuppressive drug, Cyclosporine A (CsA ), is associated with increased intracellular calcium in vascular smoo th muscle cells, which may cause vasoconstriction and/or activate phos pholipase A(2). We used rat aortic rings to investigate the role of pr otein kinase C (PKC) in CsA-induced contractions and secondary prostac yclin (PGI(2)) release. CsA (10(-9) M) produced a sustained contractio n in rat aortic rings. Both CsA-induced contractions and PGI(2) releas e were inhibited 84 to 89% by 10(-9) M, and 99 to 100% by 10(-6) M pre treatment doses of any of three different PKC inhibitors, i.e. 1-(5-is oquinolinesulfonylmethyl) piperazine (H7), staurosporine or 1-(5-isoqu inolinesulfonyl) piperazine. Pretreatment with (10(-9) M) of diltiazem (a voltage-sensitive L-type calcium channel blocker) completely inhib ited both CsA-induced contractions and PGI(2) release. Conversely, pre treatment with (10(-9) M) of thapsigargin (an intracellular calcium ch annel blocker) did not alter the action of CsA. These results strongly suggest that PKC, in association with an influx of extracellular calc ium mediates CsA-induced contractions and secondary PGI(2) release in rat aortic rings.