Posttransplantation therapeutic rapamycin concentration protects nitric oxide-related vascular endothelial function: comparative effects in rat thoracic aorta and coronary endothelial cell culture.
OBJECTIVE
To investigate the potential effects of therapeutic dosages of the immunosuppression agent rapamycin on endothelial function with regard to nitric oxide (NO) synthesis in rat thoracic aorta in vivo and rat coronary endothelial cells in vitro.


METHODS
Male Wistar rats were injected with rapamycin, 1.5 mg/kg/d intraperitoneally for 14 days. After the rats were sacrificed, the thoracic aortas were suspended in organ chambers and evaluated for endothelium-dependent and endothelium-independent vascular responses.


RESULTS
Rapamycin administration resulted in increased relaxant responses to L-arginine and to greater concentrations of the calcium ionophore (A23187) in the aortas. However, potassium chloride, acetylcholine, sodium nitroprusside, and N(G)-nitro-L-arginine methyl ester responses remained unchanged. In addition, phenylephrine-induced contractions were significantly decreased in the aortas regardless of the presence of functional endothelium. In a series of in vitro experiments, isolated rat coronary endothelial cells were incubated with therapeutic concentrations of rapamycin (10 nmol/L). Nitrite accumulation in the supernatants revealed that rapamycin decreased nitrite release induced by interleukin-1beta but did not affect basal or A23187-stimulated nitrite levels. Western blot analysis demonstrated that rapamycin decreased inducible NO synthase protein expression in coronary endothelial cells.


CONCLUSIONS
Posttransplantation therapeutic concentrations of rapamycin not only preserve vascular endothelial function mediated by NO synthesis but possibly interact in vivo with adrenergic receptors in favor of vasodilatory mechanisms.
Parlar
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A
Department of Pharmacology and Clinical Pharmacology, Ege University School of Medicine, Izmir, Turkey.
Can
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C
Erol
A
A
Ulker
S
S
D000109:Acetylcholine / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D001120:Arginine / Q000378:metabolism; D015153:Blotting, Western; D000001:Calcimycin / Q000494:pharmacology; D018929:Cell Culture Techniques; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology; D008297:Male; D009573:Nitrites / Q000378:metabolism; D010656:Phenylephrine / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D020123:Sirolimus / Q000378:metabolism / Q000494:pharmacology*; D014664:Vasodilation
D007166:Immunosuppressive Agents; D053583:Interleukin-1beta; D009573:Nitrites; D010656:Phenylephrine; D000001:Calcimycin; D001120:Arginine; D000109:Acetylcholine; D020123:Sirolimus