Inhibition of inducible nitric oxide synthase attenuates established acute cardiac allograft rejection.
BACKGROUND
We previously demonstrated that continuous treatment with aminoguanidine, a selective inhibitor of nitric oxide production by inducible nitric oxide synthase, attenuated acute cardiac allograft rejection.


METHODS
A rat transplant model was used to determine (1) when inducible nitric oxide synthase was expressed in the allograft heart during unmodified acute rejection and (2) whether pulse therapy with aminoguanidine attenuated the histologic changes of established acute rejection, in comparison with the effects of pulse therapy with corticosteroids.


RESULTS
Inducible nitric oxide synthase messenger RNA and protein were expressed during early and late acute rejection. Pulse therapy with aminoguanidine inhibited nitric oxide production and attenuated the histologic changes of acute rejection, but not as effectively as corticosteroid therapy (rejection scores of 4.1 +/- 0.4, 2.5 +/- 0.9, and 1.4 +/- 0.6 on postoperative day 8, for untreated, aminoguanidine-, and dexamethasone-treated allografts, respectively (scale, 0 to 5; p < 0.05).


CONCLUSIONS
(1) Inducible nitric oxide synthase expression first occurs during early acute allograft rejection and persists throughout rejection and (2) nitric oxide is an important effector molecule in acute rejection. Inducible nitric oxide synthase inhibition may offer a therapeutic adjunct in the management of acute rejection.
Worrall
N K
NK
Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110, USA.
Misko
T P
TP
Sullivan
P M
PM
Hui
J J
JJ
Ferguson
T B
TB
D000818:Animals; D003907:Dexamethasone / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use; D006084:Graft Rejection / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D006146:Guanidines / Q000008:administration & dosage / Q000627:therapeutic use*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000502:physiology; D008297:Male; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D014183:Transplantation, Heterologous / Q000009:adverse effects / Q000502:physiology; D014184:Transplantation, Homologous
D004791:Enzyme Inhibitors; D005938:Glucocorticoids; D006146:Guanidines; D012333:RNA, Messenger; D003907:Dexamethasone; D019001:Nitric Oxide Synthase; C004479:pimagedine