Prevention of cyclosporine A-induced vascular toxicity by pentoxifylline.
To determine whether an in vivo treatment with pentoxifylline (PTX) can prevent the vascular toxicity of cyclosporine A (Cx), three groups of rats were studied in parallel. The first group received daily injections of Cx (20 mg/kg intramuscularly) and pentoxifylline (80 mg/kg intraperitoneally) for 7 days, the second group was treated with Cx only, and the third group served as control (vehicle treatment). Cx serum levels were similar in groups 1 and 2. In thoracic aortic rings isolated from Cx group (group 2), the concentration-response curves to phenylephrine were potentiated: there was a significant leftward shift (p less than 0.001 vs. control) in the EC50 values and an increase in the maximal responses (p less than 0.05). After mechanical removal of the endothelium or inhibition of endothelium-derived relaxing factor formation (incubation with NG-monomethyl-L-arginine, L-NMMA), this enhanced responsiveness to phenylephrine persisted. In preparations from the same group (group 2), the endothelium-dependent relaxations to acetylcholine (ACh) were decreased whereas the endothelium-independent relaxations to nitroprusside (NTP 0.01-10 nM) and forskolin (1 nM) were slightly attenuated but without changes in the maximal response. In the group cotreated with Cx and PTX (group 1), the responses to ACh, NTP, and forskolin were not different from controls whereas the greater responsiveness to phenylephrine was only partially attenuated. In vivo cotreatment with PTX may prevent the endothelial dysfunction and the functional changes in smooth muscle cells induced by Cx.
Berkenboom
G
G
Department of Cardiology, Erasme Hospital, Brussels, Belgium.
Unger
P
P
Goldman
M
M
Fang
Z Y
ZY
Fontaine
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D005576:Colforsin / Q000494:pharmacology; D016572:Cyclosporine / Q000633:toxicity*; D004730:Endothelium, Vascular / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009467:Neuromuscular Depolarizing Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010431:Pentoxifylline / Q000627:therapeutic use*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D014652:Vascular Diseases / Q000139:chemically induced / Q000517:prevention & control*; D019323:omega-N-Methylarginine
D009467:Neuromuscular Depolarizing Agents; D009599:Nitroprusside; D005576:Colforsin; D010656:Phenylephrine; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D016572:Cyclosporine; D001120:Arginine; D000109:Acetylcholine; D010431:Pentoxifylline