Direct vascular effects in the rat of the vehicles used for the intravenous and oral administration of cyclosporin A.
1. The contraction and relaxation responses to the polyoxyethylated vehicles currently used for the intravenous and oral administration of cyclosporin A in allograft recipients were studied in isolated rat aorta. The results were compared with those obtained with commercially available cyclosporin A for intravenous administration. 2. None of these compounds affected resting tension, noradrenaline-induced contraction or endothelium-independent relaxation produced by sodium nitroprusside or bumetanide. However, they all reversed the relaxation induced by acetylcholine, carbamylcholine or adenosine 5'-triphosphate, by a factor of approximately 66%. 3. This reversal of relaxation was unaffected by indomethacin and did not require the presence of cyclosporin A in the vehicles, and was completely abolished by L-arginine (3 x 10(-5) mol/l). 4. It is concluded that vehicles used for commercial preparations of cyclosporin A interfere with the synthesis of endothelium-derived relaxing factor at an early stage during which L-arginine is made available for enzymatic degradation.
Amorena
C
C
Instituto de Investigaciones Cardiológicas, Facultad de Medicina, Buenos Aires, Argentina.
Castro
A
A
Müller
A
A
Villamil
M F
MF
D000284:Administration, Oral; D000818:Animals; D046508:Culture Techniques; D003524:Cyclosporins / Q000008:administration & dosage* / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D003524:Cyclosporins; C022131:cremophor; D011092:Polyethylene Glycols