Effects of thrombolytic drugs and a selective endothelin-1 receptor antagonist on acute pulmonary thromboembolism in dogs.
BACKGROUND
It has been shown that neurohumoral factors other than mechanical obstruction are involved in the pathophysiology of acute pulmonary thromboembolism (APTE). The aim of this study was to investigate the effects of thrombolytic drugs, a selective endothelin-1 receptor (ET-1R) antagonist alone or their combination on APTE in a canine model.


METHODS
Twenty dogs were randomly assigned to five groups: sham, model, urokinase (UK), BQ123, and combination (UK plus BQ123). The dogs in the sham group underwent sham surgery. APTE was induced in the other four groups by intravenous injection of autologous blood clots. Dogs in the UK, BQ123 and combination groups received UK, BQ123 (a selective ET-1R antagonist), or UK plus BQ123, respectively. The dogs in the model group were given saline. Mean pulmonary artery pressure (mPAP), serum concentrations of ET-1, thromboxane (TXB2), and tumor necrosis factor (TNF)-alpha were determined at different time points following the induction of APTE.


RESULTS
UK and BQ123 alone markedly decreased mPAP in APTE. By comparison, the reduction was more significant in the combination group. Compared with the sham group ((-0.90 +/- 0.61) mmHg), mPAP increased by (7.44 +/- 1.04), (3.42 +/- 1.12) and (1.14 +/- 0.55) mmHg in the model group, UK alone and BQ123 alone groups, respectively, and decreased by (2.24 +/- 0.67) mmHg in the combination group (P < 0.01). Serum ET-1 concentrations in the BQ123 and combination groups were (52.95 +/- 8.53) and (74.42 +/- 10.27) pg/ml, respectively, and were significantly lower than those in the model and UK groups ((84.56 +/- 7.44) and (97.66 +/- 8.31) pg/ml respectively; P < 0.01). Serum TNF-alpha concentrations were significantly lower in the BQ123 group than in the model, UK and combination groups (P < 0.05).


CONCLUSIONS
Our results indicate that the selective ET-1R antagonist BQ123 not only reduces the increase of mPAP and serum ET-1 level, but also inhibits the production of TNF-alpha, and attenuates the local inflammatory response induced by APTE. Selective ET-1R antagonists may be beneficial to the treatment of APTE, particularly when used in combination with a thrombolytic agent.
Han
Li
L
Department of Respiratory Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Li
Qing-yun
QY
Zhou
Ling
L
Wang
Xi
X
Bao
Zhi-yao
ZY
Li
Min
M
Wan
Huan-ying
HY
Shi
Guo-chao
GC
D000818:Animals; D004285:Dogs; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D010456:Peptides, Cyclic / Q000627:therapeutic use*; D011655:Pulmonary Embolism / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D011897:Random Allocation; D013931:Thromboxanes / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D005343:Fibrinolytic Agents; D010456:Peptides, Cyclic; D013931:Thromboxanes; D014409:Tumor Necrosis Factor-alpha; C072247:cyclo(Trp-Asp-Pro-Val-Leu)