Cyclooxygenase-2 inhibition and thromboxane A (2) receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model.
Summary of "Cyclooxygenase-2 inhibition and thromboxane A (2) receptor antagonism attenuate hypoxic pulmonary vasoconstriction in a porcine model."
AIM:
Hypoxic pulmonary vasoconstriction (HPV) causes pulmonary hypertension that may lead to right heart failure. We hypothesized that the COX-2 inhibitor nimesulide and the thromboxane A (2) receptor antagonist daltroban would attenuate HPV.
METHODS:
Haemodynamic measurements and blood sampling were performed in 18 anaesthetized, mechanically ventilated pigs, with mean ± SEM weights of 31.3 ± 0.6 kg, in normoxia (F (i) O (2) ~0.21) and hypoxia (F (i) O (2) ~0.10), before and 5, 15 and 45 min after initiation of right atrial infusion of nimesulide (n = 6) or daltroban (n = 6), respectively, and in six control pigs.
RESULTS:
Compared with normoxia, hypoxia (n = 18) increased mean pulmonary artery pressure by 15.8 ± 0.8 mmHg (P < 0.001), pulmonary vascular resistance (PVR) by 2.7 ± 0.3 WU (P < 0.05) and mean right atrial pressure by 2.3 ± 0.3 mmHg (P < 0.001). In the control pigs, mean pulmonary artery pressure, PVR and mean right atrial pressure remained stable (P = ns) throughout 45 min hypoxia, compared with hypoxia baseline. Nimesulide decreased mean pulmonary artery pressure by 3.7 ± 1.3 mmHg after 45 min (P < 0.013), as well as PVR by 0.8 ± 0.2 WU (P < 0.05), levelling off after 15 min. Daltroban transiently increased (P < 0.001) mean pulmonary artery pressure and mean right atrial pressure by 7.2 ± 1.2 and 2.7 ± 0.4 mmHg, respectively, but they returned to hypoxia baseline (P = ns) within 5 min. Daltroban then decreased mean pulmonary artery pressure to after 45 min be 4.2 ± 1.6 mmHg lower (P < 0.005) than at hypoxia baseline.
CONCLUSION:
COX-2 inhibition and thromboxane A(2) receptor antagonism attenuate HPV by decreasing mean pulmonary artery pressure by approximately 10-11%, as measured 45 min after initiation of nimesulide or daltroban infusion respectively.
Affiliation
The Öresund Cardiovascular Research Collaboration, The Clinic for Heart Failure and Valvular Disease, Skåne University Hospital, Lund, Sweden; Department of Cardiology, Lund University, Lund, Sweden; The Copenhagen Muscle Research Centre, Rigshospitalet
Journal Details
This article was published in the following journal.
Name: Acta physiologica (Oxford, England)
ISSN: 1748-1716
Pages:
Links
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/22554045
- DOI: http://dx.doi.org/10.1111/j.1748-1716.2012.02437.x
Medical and Biotech [MESH] Definitions
4,5-dihydro-1-(3-(trifluoromethyl)phenyl)-1h-pyrazol-3-amine
A dual inhibitor of both cyclooxygenase and lipoxygenase pathways. It exerts an anti-inflammatory effect by inhibiting the formation of prostaglandins and leukotrienes. The drug also enhances pulmonary hypoxic vasoconstriction and has a protective effect after myocardial ischemia.
Thromboxane-a Synthase
An enzyme found predominantly in platelet microsomes. It catalyzes the conversion of PGG(2) and PGH(2) (prostaglandin endoperoxides) to thromboxane A2. EC 5.3.99.5.
Cyclooxygenase 2 Inhibitors
A subclass of cyclooxygenase inhibitors with specificity for CYCLOOXYGENASE-2.
Thromboxane A2
An unstable intermediate between the prostaglandin endoperoxides and thromboxane B2. The compound has a bicyclic oxaneoxetane structure. It is a potent inducer of platelet aggregation and causes vasoconstriction. It is the principal component of rabbit aorta contracting substance (RCS).
Misonidazole
A nitroimidazole that sensitizes normally radio-resistant hypoxic cells to radiation. It may also be directly cytotoxic to hypoxic cells and has been proposed as an antineoplastic.
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