TY - JOUR
T1 - CNI-1493 prolongs survival and reduces myocyte loss, apoptosis, and inflammation during rat cardiac allograft rejection
AU - Yang, Xiaochun
AU - Szabolcs, Mathias
AU - Minanov, Oktavijan
AU - Ma, Ningsheng
AU - Sciacca, Robert R.
AU - Bianchi, Marina
AU - Tracey, Kevin J.
AU - Michler, Robert E.
AU - Cannon, Paul J.
PY - 1998/7
Y1 - 1998/7
N2 - Cytokines and cytotoxic agents, including nitric oxide (NO) released by macrophages, play important roles during cardiac allograft rejection. In contrast to agents that suppress T-lymphocyte function, CNI-1493 is a multivalent guanylhydrazone compound that inhibits the synthesis and release of proinflammatory cytokines and NO from macrophages. This study investigated the effects of CNI-1493 on rejecting rat cardiac allografts by using Lewis to Wistar-Furth heterotopic cardiac transplants. CNI-1493 (2 mg/kg i.p., b.i.d.) or vehicle (water) was administered beginning the day before surgery. Rat cardiac allograft survival to cessation of heart beat, apoptosis of cardiac myocytes, degree of myocardial inflammation, and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), protein, and enzyme activity were studied at days 1, 3, 5, and 7 after transplantation. Allograft survival was increased significantly by 26% from 7.5 ± 0.8 days in vehicle-treated rats (n = 6) to 9.5 ± 1.2 days in CNI-1493-treated rats (n = 8, p < 0.05). Apoptotic cells per mm2 myocardium decreased from 2.25 ± 1.25 to 0.84 ± 0.49 at day 3 and 31.2 ± 2.9 to 17.6 ± 5.43 at day 5 after transplantation with CNI-1493 treatment (p < 0.05). The number of apoptotic myocytes and loss of cardiac muscle cells also decreased significantly at day 5 in the treated animals (p < 0.05). The reduction of myocyte loss at day 5 coincided with a significant decrease of the inflammatory response and reduced macrophage influx (p < 0.05). Myocardial iNOS mRNA, protein, and enzyme levels increased during the course of allograft rejection, and CNI-1493 did not significantly reduce iNOS expression in the rejecting rat allograft. CNI-1493 prolongs allograft survival and reduces myocyte loss, apoptosis, and inflammation during rat cardiac allograft rejection. These effects of CNI-1493 appear to be unrelated to altered NO synthesis but may be related to effects of the drug to inhibit macrophage synthesis of cytokines.
AB - Cytokines and cytotoxic agents, including nitric oxide (NO) released by macrophages, play important roles during cardiac allograft rejection. In contrast to agents that suppress T-lymphocyte function, CNI-1493 is a multivalent guanylhydrazone compound that inhibits the synthesis and release of proinflammatory cytokines and NO from macrophages. This study investigated the effects of CNI-1493 on rejecting rat cardiac allografts by using Lewis to Wistar-Furth heterotopic cardiac transplants. CNI-1493 (2 mg/kg i.p., b.i.d.) or vehicle (water) was administered beginning the day before surgery. Rat cardiac allograft survival to cessation of heart beat, apoptosis of cardiac myocytes, degree of myocardial inflammation, and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA), protein, and enzyme activity were studied at days 1, 3, 5, and 7 after transplantation. Allograft survival was increased significantly by 26% from 7.5 ± 0.8 days in vehicle-treated rats (n = 6) to 9.5 ± 1.2 days in CNI-1493-treated rats (n = 8, p < 0.05). Apoptotic cells per mm2 myocardium decreased from 2.25 ± 1.25 to 0.84 ± 0.49 at day 3 and 31.2 ± 2.9 to 17.6 ± 5.43 at day 5 after transplantation with CNI-1493 treatment (p < 0.05). The number of apoptotic myocytes and loss of cardiac muscle cells also decreased significantly at day 5 in the treated animals (p < 0.05). The reduction of myocyte loss at day 5 coincided with a significant decrease of the inflammatory response and reduced macrophage influx (p < 0.05). Myocardial iNOS mRNA, protein, and enzyme levels increased during the course of allograft rejection, and CNI-1493 did not significantly reduce iNOS expression in the rejecting rat allograft. CNI-1493 prolongs allograft survival and reduces myocyte loss, apoptosis, and inflammation during rat cardiac allograft rejection. These effects of CNI-1493 appear to be unrelated to altered NO synthesis but may be related to effects of the drug to inhibit macrophage synthesis of cytokines.
KW - Allograft
KW - CNI-1493
KW - Macrophage
KW - Rejection
UR - http://www.scopus.com/inward/record.url?scp=0031800038&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0031800038&partnerID=8YFLogxK
U2 - 10.1097/00005344-199807000-00023
DO - 10.1097/00005344-199807000-00023
M3 - Article
C2 - 9676735
AN - SCOPUS:0031800038
SN - 0160-2446
VL - 32
SP - 146
EP - 155
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 1
ER -