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Cyclooxygenase inhibitors attenuate bradykinin-induced vasoconstriction in septic isolated rat lungs
L G Fischer1, M W Hollmann, D J Horstman
1Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Westfälische-Wilhelms-Universität Münster, Germany.
Unlabelled:
Cyclooxygenase (COX) products play an important role in modulating sepsis and subsequent endothelial injury. We hypothesized that COX inhibitors may attenuate endothelial dysfunction during sepsis, as measured by receptor-mediated bradykinin (BK)-induced vasoconstriction and/or receptor-independent hypoxic pulmonary vasoconstriction (HPV). Rats were administered intraperitoneally a nonselective COX inhibitor (indomethacin, 5 or 10 mg/kg) or a selective COX-2 inhibitor (NS-398, 4 or 8 mg/kg) 1 h before lipopolysaccharide (LPS, 15 mg/kg), or saline (control). Three hours later, the rats were anesthetized, the lungs were isolated, and pulmonary vasoreactivity was assessed with BK (0.3, 1.0, and 3.0 microg) and HPV (3% O(2)). Perfusion pressure was monitored as an index of vasoconstriction. To investigate what receptor-subtype is mediating BK responses, the BK(1)-receptor antagonist des-Arg(9)-[Leu(8)]-BK, the BK(2)-receptor antagonist HOE-140, or the thromboxane A(2)-receptor antagonist SQ 29548 (all at 1 microM) were added to the perfusate. BK-induced vasoconstriction was significantly increased in LPS lungs (1.4-5.2 mm Hg) compared with control (0.1-1.1 mm Hg). In LPS lungs, indomethacin 10 mg/kg significantly decreased BK vasoconstriction by 78% +/- 9%, whereas 5 mg/kg did not. NS-398, 4 mg/kg, significantly attenuated BK vasoconstriction at 0.3 microg (71% +/- 7%) and 1.0 microg (56% +/- 12%), whereas 8 mg/kg attenuated 0.3 microg BK (57% +/- 14%), compared with LPS lungs. HPV was increased in LPS lungs (21.5 +/- 2 mm Hg) compared with control lungs (9.8 +/- 0.6 mm Hg). Indomethacin 5 mg/kg increased HPV in LPS lungs; otherwise, HPV was not altered by COX inhibition. BK-induced vasoconstriction was prevented by BK(2), but not BK(1) or thromboxane A(2)-receptor antagonism. This study suggests that nonselective COX inhibition, and possibly inhibition of the inducible isoform COX-2, may attenuate sepsis-induced, receptor-mediated vasoconstriction in rats.
Implications:
This study demonstrated that, in an isolated rat lung model, nonselective inhibition of the cyclooxygenase pathway, and possibly selective inhibition of the inducible cyclooxygenase-2 isoform, may attenuate sepsis-induced endothelial dysfunction.
Insights
Cyclooxygenase (COX) inhibitors may reduce sepsis-induced endothelial dysfunction by attenuating bradykinin-induced vasoconstriction. This suggests potential therapeutic benefits of COX inhibition in sepsis, particularly targeting the COX-2 pathway.
Area of Science:
- Pharmacology
- Physiology
- Sepsis Research
Background:
- Cyclooxygenase (COX) products influence sepsis and endothelial injury.
- Endothelial dysfunction in sepsis involves altered vasoreactivity.
Purpose of the Study:
- To investigate if COX inhibitors can attenuate endothelial dysfunction during sepsis.
- To assess the effects of COX inhibitors on bradykinin (BK)-induced vasoconstriction and hypoxic pulmonary vasoconstriction (HPV).
Main Methods:
- Rats were treated with indomethacin (nonselective COX inhibitor) or NS-398 (selective COX-2 inhibitor) before lipopolysaccharide (LPS) administration.
- Isolated rat lungs were used to measure pulmonary vasoreactivity to BK and HPV.
- Receptor antagonists (BK1, BK2, Thromboxane A2) were employed to identify mediating pathways.
Main Results:
- LPS significantly increased BK-induced vasoconstriction and HPV.
- Indomethacin (10 mg/kg) and NS-398 (4 mg/kg) significantly attenuated BK-induced vasoconstriction in LPS lungs.
- HPV was not significantly altered by COX inhibition, except for an increase with indomethacin (5 mg/kg).
- BK-induced vasoconstriction was mediated by BK2 receptors.
Conclusions:
- Nonselective COX inhibition, and potentially selective COX-2 inhibition, may attenuate sepsis-induced receptor-mediated vasoconstriction.
- These findings suggest a role for COX pathways in sepsis-related endothelial dysfunction.