thapsigargin and 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine

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 A2. We used rat aortic rings to investigate the role of protein kinase C (PKC) in CsA-induced contractions and secondary prostacyclin (PGI2) release. CsA (10(-9) M) produced a sustained contraction in rat aortic rings. Both CsA-induced contractions and PGI2 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 PGI2 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 PGI2 release in rat aortic rings.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Animals; Aorta; Calcium Channel Blockers; Cell Membrane; Cyclosporine; Cytosol; Diltiazem; Enzyme Inhibitors; Epoprostenol; In Vitro Techniques; Male; Muscle Contraction; Muscle, Smooth, Vascular; Phorbol 12,13-Dibutyrate; Protein Kinase C; Rats; Staurosporine; Thapsigargin