MECHANISM OF ENHANCED VASOCONSTRICTOR HORMONE ACTION IN VASCULAR SMOOTH-MUSCLE CELLS BY CYCLOSPORINE-A

1 The use of the immunosuppressive drug cyclosporin A (CsA) is limited by two major side effects, nephrotoxicity and hypertension, which are caused by drug-induced local vasoconstriction. We have recently shown that CsA potentiates the contraction of isolated resistance arteries to vasoconstrictor hormones and increases the calcium response to thes e agents in vascular smooth muscle cells (VSMC). The goal of the prese nt study was to investigate further the molecular mechanism(s) involve d in these effects. 2 Stimulation of VSMC with [Arg](8)vasopressin (AV P) induced a concentration-dependent increase in total inositol phosph ates (InsP) and cellular calcium response (as measured by Ca-45(2+) ef flux). Preincubation of VSMC with CsA increased both InsP formation an d Ca-45(2+) efflux. 3 The potentiating effect of CsA on AVF-elicited I nsP formation and Ca-45(2+) efflux was inhibited by coincubation with the protein synthesis inhibitors actinomycin D and cycloheximide, indi cating that CsA acted on gene expression. 4 Binding experiments with [ H-3]-AVP on VSMC showed that CsA increased the number of AVP receptors by about two fold without affecting receptor affinity. Actinomycin D completely blocked this increase. 5 These results demonstrate for the first: time that incubation of VSMC with CsA increases the expression of AVP receptors, resulting in a potentiation of InsP formation and ca lcium response upon stimulation with AVP. This effect of CsA is likely Co occur with other vasoconstrictor hormone receptors as well and cou ld be a key mechanism in the induction of vasoconstriction and subsequ ent drug-induced nephrotoxicity and hypertension.