Delayed
gastric ulcer healing is a well recognized problem associated with the use of
cyclooxygenase (COX) inhibitors. In contrast, NO-releasing COX inhibitors do not interfere with
ulcer healing. These divergent effects may in part be due to differences in their effects on platelets, which are known to influence
ulcer healing. Therefore, we compared the effects of a nonselective COX inhibitor (
flurbiprofen), a
nitric oxide-releasing COX inhibitor (HCT-1026), and a selective
COX-2 inhibitor (
celecoxib) on
gastric ulcer healing, angiogenesis, and platelet/serum levels of
vascular endothelial growth factor (
VEGF) and
endostatin.
Gastric ulcers were induced in rats by serosal application of
acetic acid. Daily treatment with the test drugs was started 3 days later and continued for 1 week.
Celecoxib and
flurbiprofen impaired angiogenesis and delayed
ulcer healing, as well as increasing serum
endostatin levels relative to those of
VEGF.
HCT-1026 did not delay
ulcer healing nor impair angiogenesis, and also did not change the ratio of serum
endostatin to
VEGF. Incubation of human umbilical vein endothelial cells with serum from
celecoxib- or
flurbiprofen-treated rats resulted in suppressed proliferation and increased apoptosis, effects that were reversed by an antiendostatin antibody. These results demonstrate a previously unrecognized mechanism through which nonsteroidal antiinflammatory drugs can delay
ulcer healing, namely, through altering the balance of anti- and proangiogenic factors in the serum. The absence of a delaying effect of
HCT-1026 on
ulcer healing may be related to the maintenance of a more favorable balance in serum levels of pro- and antiangiogenic
growth factors.