Endothelial dysfunction in renal transplant recipients maintained on cyclosporine.
BACKGROUND
Hypertension is almost universal following renal transplantation and may contribute to the already poor cardiovascular prognosis of this group. Cyclosporine-induced hypertension is a particular problem and has variously been attributed to increased sympathetic nerve activity, salt and water retention, and increased circulating endothelin levels. However, the effects of cyclosporine on the L-arginine/nitric oxide (NO) system in vivo in humans are unknown. In this present study, we examined basal and stimulated NO production from the vascular endothelium in cyclosporine-treated renal transplant recipients using the technique of forearm venous plethysmography.


METHODS
In study 1, stimulated NO production was assessed in 9 cyclosporine-treated renal transplant recipients (CsA), 7 azathioprine-treated renal transplant recipients (AZA), and 12 controls, using carbachol (an endothelium-dependent vasodilator) and sodium nitroprusside (an endothelium-independent vasodilator). In study 2, basal NO production was assessed in 9 cyclosporine-treated patients and 11 controls using L-NMMA (inhibits NO synthase), with norepinephrine as a control vasoconstrictor. Drugs were infused into the nondominant forearm through a sterile 27-gauge needle, and changes in forearm blood flow (FBF) were measured using venous occlusion plethysmography.


RESULTS
In study 1, sodium nitroprusside caused a similar dose-dependent increase in FBF in all groups. However, the median (range) percentage increase FBF to carbachol (3 micrograms/min) was markedly reduced in the CsA patients (188.8; 72.5 to 385.1) compared with AZA patients (378.1; 124.0 to 548.9; P = 0.042) and to controls (303.8; 124.8 to 813.3; P = 0.028). In study 2, the maximum percentage reduction in FBF to L-NMMA (4 mumol/min) was less pronounced in CsA patients (-19.5; -4.7 to -63.1) compared with controls (-39.5; -15.7 to -52.8; P = 0.056), and while controls vasoconstricted to the maximum dose of norepinephrine (240 pmol/min) as expected (-26.9; -1.4 to -38.6), CsA patients as a group tended to vasodilate (7.9; -36.8 to 92.6; P = 0.02).


CONCLUSIONS
These data demonstrate impaired stimulated and basal NO production in CsA patients, indicating endothelial dysfunction. This may predispose patients to atherosclerosis and may be involved in the etiology of post-transplant hypertension.
Morris
S T
ST
Department of Medicine & Therapeutics, Western Infirmary, Glasgow, Scotland, United Kingdom.
McMurray
J J
JJ
Rodger
R S
RS
Farmer
R
R
Jardine
A G
AG
D000328:Adult; D001379:Azathioprine / Q000627:therapeutic use; D002217:Carbachol / Q000627:therapeutic use; D016572:Cyclosporine / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005542:Forearm / Q000098:blood supply; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D011184:Postoperative Period; D012039:Regional Blood Flow / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D016572:Cyclosporine; D002217:Carbachol; D001379:Azathioprine