Cyclosporine A-induced contraction of isolated rat aortic smooth muscle cells.
The mechanisms by which the immunosuppressive drug cyclosporine A (CsA) induces hypertension and nephrotoxicity are still not fully understood. Although smooth muscle cell (SMC) contraction is probably the mechanism of vasoconstriction, the direct contractive effect of CsA on SMCs has not yet been demonstrated. Thus, it was the purpose of this study to evaluate the direct effects of CsA in cultured SMCs through interactive image analysis. In aortic SMCs, CsA at the concentrations of 0.01, 0.1 and 1 microM, caused a concentration-dependent decrease of the planar cross-sectional area (PCSA) after 30 min and 60 min of treatment. The PCSA decreases were statistically significantly different from control at all concentrations. No cytotoxicity was observed under these conditions. Ten minutes preincubation of SMCs with a monoclonal antibody against endothelin-1 (ET-1) significantly prevented the CsA effects at 1 microM. When the same antibody was heat inactivated or an unspecific antibody (anti-desmin immunoglobulin G) was applied, the CsA-induced contractions were not affected. These data suggest that CsA can cause a direct contractive effect on vascular SMCs. This effect is partly mediated by ET-1.
Medina
J
J
Novartis Pharma Ltd., Toxicology/Pathology, Basel, Switzerland.
Cordier
A
A
Wolf
A
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D019332:Endothelin-1 / Q000276:immunology / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
D000911:Antibodies, Monoclonal; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D016572:Cyclosporine