Cyclosporin and oxidized low density lipoproteins synergistically potentiate vasoconstriction: influence of the endothelium.

Abstract

Cyclosporin (CyA) and oxidatively modified low density lipoproteins (Ox-LDL) are known to cause vasoconstriction, observations of possible clinical significance because lipid disorders favouring the formation of Ox-LDL are common in patients under CyA treatment. We hypothesized that co-incubation of isolated arteries with Ox-LDL and CyA might enhance their respective influence on vascular tone. We investigated vascular reactivity of isolated intact rabbit renal arteries pre-incubated with CyA in the presence of native and Ox-LDL. Following pre-incubation of the arteries with CyA (10 micrograms.ml-1, 90 min), both unstimulated vascular tone as well as norepinephrine-induced vasoconstrictions remained unchanged compared to controls preincubated with the CyA-vehicle di-methyl-sulfoxide. Ox-LDL (100 micrograms.ml-1) in the absence of CyA significantly enhanced vasoconstrictions to threshold concentrations of norepinephrine (78 +/- 10 microns at 30 nM). However, following CyA treatment, the Ox-LDL-induced potentiation of contractile responses to norepinephrine was further enhanced (157 +/- 19 vs 71 +/- 11 microns). Native LDL had no influence on vascular tone. Potentiation of norepinephrine-induced vasoconstriction by Ox-LDL took place in either endothelium-denuded or endothelium-intact arteries, whereas the further enhancement of vascular tone following CyA treatment was seen only in endothelium-intact segments. Endothelium-dependent dilations to acetylcholine were fully preserved following Ox-LDL and CyA treatment. Indomethacin, saralasin, and the thromboxane A2 antagonist daltroban had no influence, whereas the Ca2+ antagonists nitrendipine and verapamil prevented the potentiation of vasoconstrictions by CyA and Ox-LDL.(ABSTRACT TRUNCATED AT 250 WORDS)