Citations

The role of prostaglandin production in the control of regenerative function of endothelial progenitor cells (EPCs) has not been studied. We hypothesized that activation of cyclooxygenase (COX) enzymatic activity and the subsequent production of prostacyclin (PGI 2 ) is an important mechanism responsible for the regenerative function of EPCs. In the present study, we detected high levels of COX-1 protein expression and PGI 2 biosynthesis in human EPCs outgrown from blood mononuclear cells. Expression of COX-2 protein was almost undetectable under basal conditions but significantly elevated after treatment with tumor necrosis factor-α. Condition medium derived from EPCs hyperpolarized human coronary artery smooth muscle cells, similar to the effect of the PGI 2 analog iloprost. The proliferation and in vitro tube formation by EPCs were inhibited by the COX inhibitor indomethacin or by genetic inactivation of COX-1 or PGI 2 synthase with small interfering (si)RNA. Impaired tube formation and cell proliferation induced by inactivation of COX-1 were rescued by the treatment with iloprost or the selective peroxisome proliferator–activated receptor (PPAR)δ agonist GW501516 but not by the selective PGI 2 receptor agonist cicaprost. Downregulation of PPARδ by siRNA also reduced angiogenic capacity of EPCs. Iloprost failed to reverse PPARδ siRNA-induced impairment of angiogenesis. Furthermore, transfection of PGI 2 synthase siRNA, COX-1 siRNA, or PPARδ siRNA into EPCs decreased the capillary formation in vivo after transplantation of human EPCs into the nude mice. These results suggest that activation of COX-1/PGI 2 /PPARδ pathway is an important mechanism underlying proangiogenic function of EPCs.

We studied the arachidonic acid (AA)-mediated modulation of large-conductance Ca2+-activated K+ (BK) channels in coronary arterial smooth myocytes from lean control and Zucker Diabetic Fatty (ZDF) rats. A total of 1 μmol/l AA enhanced BK current by 274% in lean and by 98% in ZDF rats. After incubation with 10 μmol/l indomethacin, 1 μmol/l AA increased BK currents by 80% in lean and by 70% in ZDF rats. Vasoreactivity studies showed that the dilation of small coronary arteries produced by 1 μmol/l AA was reduced by 44% in ZDF rats. [3H]6-keto-prostagladin F1α ([3H]6-keto-PGF1α,), the stable metabolite of prostacyclin (PGI2), was the major [3H]AA metabolite produced by coronary arteries of lean vessels, but ZDF vessels produced only 15% as much [3H]6-keto-PGF1α. BK channel activation and vasorelaxation by iloprost were similar in lean and ZDF rats. Immunoblots showed a 73% reduction in PGI2 synthase (PGIS) expression in ZDF vessels compared with lean vessels, and there was no change in cyclooxygenase (COX) and BK channel expressions. Real-time PCR studies showed that mRNA levels of PGIS, COX-1, and COX-2 were similar between lean and ZDF vessels. We conclude that PGI2 is the major AA metabolite in lean coronaries, and AA-mediated BK channel activation is impaired in ZDF coronaries due to reduced PGIS activity.

Diabetic vascular dysfunction is associated with an increase in reactive oxygen species (ROS). In this study, we hypothesized that hyperglycemia-induced ROS generation would impair the function of large conductance Ca 2+ -activated K + (BK) channels, which are major determinants in vasorelaxation. We found that when cultured in high glucose (HG) (22 mmol/L), HEK293 cells showed a reduction in expressed hSlo current densities, as well as slowed activation and deactivation kinetics. When human coronary smooth muscle cells were cultured in HG, similar findings were observed for the BK currents. HG enhanced superoxide dismutase and suppressed catalase (CAT) expression in HEK293 cells, leading to a significant increase in intracellular ROS. The effects of HG were mimicked by hydrogen peroxide (H 2 O 2 ), and hSlo functions were restored by CAT gene transfer. Peroxynitrite inhibited hSlo current density but did not change channel kinetics. The hSloC911A mutant was insensitive to the effects of HG and H 2 O 2 . Hence, imbalance of antioxidant enzymes plays a critical role in ROS generation in HG, impairing hSlo functions through H 2 O 2 -dependent oxidation at cysteine 911. This may represent an important fundamental mechanism that contributes to the impairment of vasodilation in diabetes.

Background: Antiemetic guidelines recommend a combination of serotonin (5-HT 3 ) with a second agent such as droperidol or dexamethasone. Physicians have been reluctant to employ these guidelines due to concerns over the black-box warning of droperidol and safety concerns with a steroid. Objective: To assess the safety profiles of 5-HT 3 receptor antagonist (5-HT 3 RA) monotherapy and combination therapy with a steroid or droperidol for prophylaxis of postoperative nausea and vomiting (PONV). Methods: A MEDLINE search of English-language reports of randomized controlled trials (RCTs) was conducted (1966–September 2005) using the key terms 5-HT 3 , granisetron, ondansetron, dolasetron, tropisetron, PONV, postoperative, vomiting, emesis, and nausea. RCTs with treatment arms comparing 5-HT 3 RA monotherapy (granisetron, ondansetron, dolasetron, or tropisetron) with dexamethasone or droperidol or 5-HT 3 RA combinations and providing incidence data on adverse events were identified and reviewed. Within-study odds ratios with 95% confidence intervals were calculated to determine the incidence rates of all adverse events in RCTs using 5-HT 3 RA monotherapy and combination therapies. Overall effect sizes for frequently reported adverse events were estimated by pooling ORs using fixed- and random-effect models. Results: Pooled ORs (OR pooled ) for adverse events with 5-HT3RA/dexamethasone versus 5-HT 3 RA for PONV prophylaxis were not significant for any reported adverse events or the overall incidence of adverse events; 5-HT 3 RA/droperidol versus 5-HT 3 RA was significant only for decreased headache incidence (fixed model: OR pooled 0.35; 95% CI 0.18 to 0.69). The OR pooled for 5-HT 3 RA/dexamethasone versus dexamethasone was not significant for any reported adverse events except headaches (fixed model OR pooled 1.75; 95% CI 1.01 to 3.03), none of which was serious. OR pooled for 5-HT 3 RA/droperidol versus droperidol was not significant for any reported adverse events. Avascular necrosis, occult infection, and delayed wound healing were not observed with either combination therapy. Cardiac abnormalities were observed with 5-HT 3 RA/droperidol therapy. Conclusions: This meta-analysis indicates that either therapy has a safety profile similar to that of dexamethasone, droperidol, or 5-HT 3 RA.