Mechanism of enhanced vasoconstrictor hormone action in vascular smooth muscle cells by cyclosporin 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 these agents in vascular smooth muscle cells (VSMC). The goal of the present study was to investigate further the molecular mechanism(s) involved in these effects. 2. Stimulation of VSMC with [Arg]8 vasopressin (AVP) induced a concentration-dependent increase in total inositol phosphates (InsP) and cellular calcium response (as measured by 45Ca2+ efflux). Preincubation of VSMC with CsA increased both InsP formation and 45Ca2+ efflux. 3. The potentiating effect of CsA on AVP-elicited InsP formation and 45Ca2+ efflux was inhibited by co-incubation with the protein synthesis inhibitors actinomycin D and cycloheximide, indicating that CsA acted on gene expression. 4. Binding experiments with [3H]-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 calcium response upon stimulation with AVP. This effect of CsA is likely to occur with other vasoconstrictor hormone receptors as well and could be a key mechanism in the induction of vasoconstriction, and subsequent drug-induced nephrotoxicity and hypertension.
Lo Russo
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A
Pharmacology Group, School of Pharmacy, University of Lausanne, Switzerland.
Passaquin
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AC
Rüegg
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UT
D000818:Animals; D001011:Aorta / Q000187:drug effects*; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D051381:Rats; D011921:Rats, Inbred WKY; D017483:Receptors, Vasopressin / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*; D014667:Vasopressins / Q000494:pharmacology*
D017483:Receptors, Vasopressin; D014667:Vasopressins; D016572:Cyclosporine