Prolongation of murine cardiac allograft survival with vesnarinone.
Vesnarinone is a non-glycoside positive inotropic drug that has immunomodulating actions. In the present study, the effects of vesnarinone on both cardiac allografts and lymphocytes were investigated. First, in a mouse model of primary vascularized heterotopic cardiac transplantation, the oral vesnarinone treatment at a dose of 50 mg/kg/day prolonged median graft survival time significantly as compared with the vehicle-treated control. Histopathological examination revealed that cellular infiltration and interstitial edema were less prominent in the vesnarinone-treated than in the vehicle-treated allografts. The plasma concentrations of vesnarinone in mice treated with a single dose of 50 mg/kg were within the range of clinical relevance. To clarify the mechanism of action, in vitro studies were performed. The generation of specific cytotoxic T lymphocytes in mixed lymphocyte culture was significantly suppressed by the treatment with vesnarinone, especially at 3 and 10 microg/ml. The production of interferon-gamma in the co-culture was also suppressed by 10 microg/ml vesnarinone. However, the level of cyclic adenosine monophosphate was not significantly affected by vesnarinone at 10 microg/ml. The results suggest that vesnarinone acts beneficially on rejecting cardiac allografts through its lymphocyte-suppressive property, although this property may not be closely associated with the inhibiting action of the drug on the cyclic adenosine monophosphate-phosphodiesterase enzyme.
Hirozane
T
T
Department of Internal Medicine, Faculty of Medicine, Kyoto University, Japan.
Matsumori
A
A
Furukawa
Y
Y
Matsui
S
S
Matoba
Y
Y
Sasayama
S
S
D000276:Adjuvants, Immunologic / Q000097:blood / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D002478:Cells, Cultured; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D011719:Pyrazines; D011804:Quinolines / Q000097:blood / Q000494:pharmacology*; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects; D013997:Time Factors; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
D000276:Adjuvants, Immunologic; D007376:Interleukin-2; D011719:Pyrazines; D011804:Quinolines; C041667:vesnarinone; D007371:Interferon-gamma