Strategies to antagonise the cyclosporine A-induced proliferation of human pulmonary artery smooth muscle cells: anti-endothelin-1 antibodies, verapamil, and octreotide.
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-serine(8)-cyclosporine, SDZ IMM 125, was used for comparison. CsA-induced proliferation was determined by incorporation of [(3)H]thymidine ([(3)H]Thy). CsA in the concentration range between 0.1 nM and 0.1 microM 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.
Medina
J
J
Novartis Pharma AG, Preclinical Safety Department, CH-4002, Basel, Switzerland. jesus.edinaalonso@pharma.novartis.com
Wolf
A
A
D000906:Antibodies / Q000276:immunology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D019332:Endothelin-1 / Q000276:immunology / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D015282:Octreotide / Q000494:pharmacology; D011651:Pulmonary Artery; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D000906:Antibodies; D002121:Calcium Channel Blockers; D003524:Cyclosporins; D019332:Endothelin-1; D007166:Immunosuppressive Agents; D014662:Vasoconstrictor Agents; D016572:Cyclosporine; D014700:Verapamil; C075935:SDZ IMM 125; D015282:Octreotide