Korean J Nephrol.
1999 Sep;18(5):683-691.
Cyclosporine-induced Vascular Endothelial Dysfunction in Rats
Abstract
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Cyclosporine(CsA) has been known to cause an endothelial dysfunction following its use as
an immunosuppressive agent. On the other hand, the vascular endothelium has been recognized
as an endocrine organ in its own right, i.e., it releases vasoactive factors such as nitric
oxide(NO) and hyperpolarizing factor(EDHF). NO is synthesized by at least three isoforms
of NO synthases(NOS), among which ecNOS is constitutively expressed in the endothelium.
The principle of EDHF has not been determined. The present study was aimed at further
investigating the mechanisms underlying the CsA-induced vasculopathy. Rats were treated
with CsA (25mg/kg/day, subcutaneous) for one week and their thoracic aortae were isolated.
Their changes of iso-metric tension in responses to acetylcholine, diazoxide, and high
concentrations of calcium were recorded. The expression of ecNOS mRNA and protein was
determined by reverse transcription-polymerase reaction and Western blot analysis, respectively.
The acetylcholine-induced relaxation of the aortic rings was significantly diminished
follawing the CsA-treatment, which was prevented by L-arginine supplemented along with
the CsA-treatment. The relaxation of the thoracic aorta in response to either diazoxide
or high concentrations of extracellular calcium was not affected by CsA-treatrnent.
The vascular tissue contents of NO metabolites were significantly decreased following
the CsA-treatment, which was also prevented by L-arginine-supple-mentation. Neither
ecNOS mRNA nor protein expression was significantly altered following the CsA-treatment.
It is suggested that CsA induces an endothelial dysfunction, which cannot be attributed to
an altered role of EDHF, but to an impairment in L-arginine/NO pathway at the steps beyond
NOS protein expression.