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RESEARCH PRODUCT

LSC Abstract – Lung-derived prostacyclin (PGI) in endothelial dysfunction in db/db mice

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Aim: Increased risk of pulmonary hypertension and not clear response of pulmonary endothelium to diabetes were reasons to compare nitric oxide (NO) and PGI-dependent function in pulmonary and systemic circulation in diabetes type II. Methods: In fasted db mice (male, 20 weeks) we compared the function of pulmonary (isolated perfused lung-IPL) and aortic endothelium (wire myograph). It was supported by determination of nitrite(NO 2 - )/nitrate(NO 3 - ), PGI production, immunostaining (IMS) and western blot. Results: In diabetic IPL NO-dependent modulation of hypoxic pulmonary vasoconstriction was impaired but filtration coefficient increased; response to U46619 was enhanced; cumulative generation of NO 2 - was decreased (NO 3 - , basals not changed) but 6-keto-PGF 1α increased. In diabetic lungs CD141 but not eNOS IMS was increased, fibrosis of parenchyma was weak and ultrastructural endothelial changes pronounced. In diabetic aortic rings impairment of acetylcholine-induced vasodilation, ionophore-stimulated NO 2 - (not basal) and 6-keto-PGF 1α production were observed. CD141 but not eNOS IMS was lower. In diabetes general protein nitration and nitration of PGI synthase (PGIS) were substantially increased in aorta but not in the lungs. Conclusions: Advanced diabetes affects pulmonary circulation resulting in (1) increased permeability of microcirculation and vasoreactivity; (2) impairment of NO-dependent vascular function paralleled with aorta; (3) increased PGI production contrasted with aorta; (4) weak nitration of pulmonary PGIS as oppose to systemic. In the diabetic lungs impairment of NO-dependent function was not alongside production of PGI; it may be due to the relative resistance to non-enzymatic nitration of PGIS.