Korean J Nephrol.  1999 Sep;18(5):683-691.

Cyclosporine-induced Vascular Endothelial Dysfunction in Rats

• Hoh SY
• Lee JU

Abstract

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.

MeSH Terms

Acetylcholine
Animals
Aorta, Thoracic
Arginine
Blotting, Western
Calcium
Diazoxide
Endothelium
Endothelium, Vascular
Hand
Protein Isoforms
Rats*
Relaxation
RNA, Messenger
Acetylcholine
Arginine
Calcium
Diazoxide
Protein Isoforms
RNA, Messenger