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 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.
Oriji
G K
GK
Hypertension-Endocrine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Keiser
H R
HR
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001011:Aorta; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D003600:Cytosol / Q000378:metabolism; D004110:Diltiazem / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D019311:Staurosporine / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D015240:Phorbol 12,13-Dibutyrate; D019284:Thapsigargin; D016572:Cyclosporine; C052422:1-(5-isoquinolinesulfonyl)piperazine; C080501:1-(5-isoquinolinylsulfonyl)-3-methylpiperazine; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D011464:Epoprostenol; D011493:Protein Kinase C; D004110:Diltiazem; D019311:Staurosporine