Inhibition of the IP‐receptor does not improve the cardiovascular changes in murine model of endotoxemia

Abstract

Selective inhibition of cyclooxygenase 2 (COX‐2) results in reduced systemic prostacyclin (PGI2) production. The levels of COX‐2 and PGI2 are increased in endotoxemia, and we therefore hypothesized that PGI2 plays an important role in the cardiovascular failure observed during sepsis.Chronic indwelling catheters were placed in femoral artery and vein in mice and the effect of the PGI2‐receptor (IP) antagonist BR5064 (Bayer, 0.1 mg/kg) and the PGI2 analogue, Beraprost (1 μg/kg) on blood pressure was tested. Injection of Beraprost induced a significant fall in blood pressure from 103 to 77 mmHg with no effect on heart rate. BR5064 did not change resting blood pressure and heart rate, but blocked the effect of Beraprost. Next, an LPS bolus (2 mg/kg) was given which led to a significantly reduced blood pressure and heart rate (106±7 to 75±2 mmHg and 627±53 to 306±33 bpm, respectively) 8 hours after injection (n=11).Pre‐treatment with BR5064 before LPS, did not improve the cardiovascular changes: 104±3 to 78±2 mmHg and 654±9 to 429±57 bpm respectively (n=10).We therefore conclude that while the IP‐antagonist specifically inhibits the IP‐receptor, it does not prevent the acute deterioration of cardiovascular function in a model of endotoxemia which suggest that prostacyclin signaling is less important for the observed cardiovascular impairment.Support: the Danish medical research council and Novo Nordisk foundation.