Direct vasoconstrictor effects of sandimmune (cyclosporine A) are mediated by its vehicle cremophor EL: inhibition by the thromboxane A2/prostaglandin endoperoxide receptor antagonist ifetroban.
The use of cyclosporine A (CsA), a cyclic polypeptidic immunosuppressive agent, is associated with a number of cardiovascular problems. This study assessed the effects of CsA and its vehicle, cremophor EL (cremophor), on force development in isolated vascular tissue. CsA evoked a concentration-dependent increase in force (EC50 = 2.5 +/- 0.8 micrograms/ml) in the rabbit jugular vein. Cremophor alone also produced a concentration-dependent increase in force (EC50 = 39.5 +/- 10.9 micrograms/ml) that matched the CsA/cremophor response at equivalent cremophor concentrations. The cremophor-induced vasoconstriction was inhibited by the structurally distinct thromboxane A2 receptor antagonists ifetroban and glyburide, but not by indomethacin (10 microM). Ricinoleic acid also produced vasoconstriction (EC50 = 0.24 +/- 0.04 microgram/ml) that was sensitive to inhibition by ifetroban but not by indomethacin. CsA dissolved directly in ethanol produced a small increase in force that was indistinguishable from that evoked by ethanol alone. Cremophor (EC50 = 1.5 +/- 0.5 mg/ml) and ricinoleic acid (EC50 = 4.7 +/- 0.7 microgram/ml) also evoked force development in the rabbit aorta, responses that were antagonized by ifetroban. Thus, force development evoked by CsA in the rabbit jugular vein appears to be mediated primarily by its vehicle, cremophor. It is hypothesized that cremophor, by virtue of its ricinoleic acid component, evoked force development by acting as a weak thromboxane A2 agonist.
Lodge
N J
NJ
Bristol-Myers Squibb, Pharmaceutical Research Institute, Princeton, New Jersey.
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016572:Cyclosporine / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005905:Glyburide / Q000494:pharmacology; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010080:Oxazoles / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D011422:Propionates / Q000494:pharmacology*; D011817:Rabbits; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D012277:Ricinoleic Acids / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D010080:Oxazoles; D014677:Pharmaceutical Vehicles; D011422:Propionates; D017482:Receptors, Thromboxane; D012277:Ricinoleic Acids; D014662:Vasoconstrictor Agents; C000515:cremophor EL; D016572:Cyclosporine; C078904:ifetroban; C030521:ricinoleic acid; D005990:Glycerol; D005905:Glyburide