The present study investigated the mechanisms mediating the actions of the immunosuppressive drug cyclosporine A (CsA) on human pulmonary artery smooth muscle cell (PASMC) proliferation. The new hydroxyethyl derivative of d-serine8-cyclosporine, SDZ IMM 125, was used for comparison. CsA-induced proliferation was determined by incorporation of [3H]thymidine ([3H]Thy). CsA in the concentration range between 0.1 nM and 0.1 μM induced a concentration-dependent increase in proliferation after 24, 48, and 72 hr of incubation. Higher CsA concentrations were cytotoxic. When proliferation experiments were performed in the presence of a monoclonal antibody against endothelin-1 (ET-1), CsA-induced proliferation was totally inhibited. No inhibition occurred in the presence of the same antibody when heat-inactivated or a non-specific monoclonal antibody. In parallel, CsA increased the production of ET-1, as determined by radioimmunoassay. Incubation of PASMCs with ET-1 at the concentration range at which the latter was released by CsA induced cell proliferation. The somatostatin derivative Sandostatin (SDT; octreotide), which is an inhibitor of the growth of smooth muscle cells as well as a potent inhibitor of ET-1 secretion, inhibited both the CsA-induced ET-1 release and the increase in [3H]Thy incorporation by PASMCs. A similar effect was observed for the calcium channel blocker verapamil (VP). SDZ IMM 125 induced weaker effects than CsA in terms of PASMC proliferation and ET-1 secretion. In conclusion, CsA increased the rate of proliferation of PASMCs, while SDZ IMM 125 induced a weaker effect. Anti-ET-1 antibody, VP, and SDT significantly inhibited CsA-induced PASMC proliferation.

The immunosuppressive drug, cyclosporin A (CsA), which is successfully used to prevent rejection in organ transplantation, induces renal side-effects as shown by a decrease in glomerular filtration rate and ultrafiltration coefficient regulated by the tone of mesangial cells.

BACKGROUNDOne adverse side-effect of the immunosuppressive drug cyclosporin A (CsA) is a decrease in glomerular filtration rate (GFR). This effect might be the result of increased glomerular contractions. The present study compared the contractile effects of CsA, cyclosporin G (CsG) and the novel cyclosporin derivative IMM 125 in isolated rat glomeruli and primary cultures of rat mesangial cells.METHODSInteractive image analysis was used to measure glomerular and mesangial cell contraction.RESULTSCsA, CsG, and IMM 125 at concentrations of 0, 10(-9), 10(-8), 10(-7), 10(-6) and 10(-5) M caused a time-dependent and a concentration-dependent contraction of isolated glomeruli and mesangial cells 30 min after incubation. In glomeruli, CsA was more potent than CsG and IMM 125. In mesangial cells, IMM 125 also exhibited the lowest contractile activity, while CsA and CsG were almost equally myoreactive. The absolute degree of the glomerular contraction was proportional to the number of contracting mesangial cells in one glomeruli. The number of responding cells after incubation with IMM 125 and CsG were lower compared to CsA, which might explain the different response with CsG and CsA in both models.CONCLUSIONSSince the concentrations used in these experiments were close to that reached in rat serum after treatment with CsA, the present results suggest that the contractile effects of IMM 125 and CsG in isolated glomeruli were clearly smaller compared to CsA, which might reflect the cyclosporins induced GFR changes in vivo.