alpha-naphthyl-thiourea and Hypoxia

Pulmonary arterial hypertension (PH), a progressive, incurable, and deadly disease, predominantly develops in women. Growing body of evidence suggest that dysregulated estradiol (E2) metabolism influences the development of PH and that some of the biological effects of E2 are mediated by its major non-estrogenic metabolite, 2-metyhoxyestradiol (2ME). The objective of this study was to examine effects of 2ME in chronic hypoxia (CH)-induced PH and alpha-naphthylthiourea (ANTU)-induced acute lung injury and PH. In addition, we investigated the effects of exposure to different levels of CH on development of PH. Chronic exposure to 15% or 10% oxygen produced similar increases in right ventricle peak systolic pressure (RVPSP) and pulmonary vascular remodeling, but oxygen concentration-dependent increase in hematocrit. Notably, right ventricle (RV) hypertrophy correlated with level of hypoxia and hematocrit, rather than with magnitude of RVPSP. The latter suggests that, in addition to increased afterload, hypoxia (via increased hematocrit) significantly contributes to RV hypertrophy in CH model of PH. In CH-PH rats, preventive and curative 2ME treatments reduced both elevated RVPSP and pulmonary vascular remodeling. Curative treatment with 2ME was more effective in reducing hematocrit and right ventricular hypertrophy, as compared to preventive treatment. Single ANTU injection produced lung injury, i.e., increased lungs weight and induced pleural effusion. Treatment with 2ME significantly reduced pleural effusion and, more importantly, eliminated acute mortality induced by ANTU (33% vs 0%, ANTU vs. ANTU+2ME group). Chronic treatment with ANTU induced PH and RV hypertrophy and increased lungs weight. 2-ME significantly attenuated severity of disease (i.e., reduced RVPSP, RV hypertrophy and pulmonary vascular injury). This study demonstrates that 2ME has beneficial effects in chronic hypoxia- and acute lung injury-induced PH and provides preclinical justification for clinical evaluation of 2ME in pulmonary hypertension.

Topics: 2-Methoxyestradiol; Animals; Hypertension, Pulmonary; Hypoxia; Rats; Rats, Sprague-Dawley; Thiourea

We investigated the effects of lung injury due to alpha-naphthylthiourea (ANTU) on pulmonary vascular reactivity. Rats were treated with ANTU (10 mg/kg ip) or the vehicle Tween 80. Four hours later, lungs from ANTU-treated rats had increased wet-to-dry weight ratios, bronchial lavage protein concentrations, and perivascular edema. To test vascular reactivity, lungs were isolated and perfused with blood at constant flow rate, while mean pulmonary arterial pressure was monitored. ANTU-treated lungs vasoconstricted earlier than Tween-treated lungs in response to severe airway hypoxia (fractional inspired O2 0%). ANTU-treated lungs vasoconstricted in response to 10% O2, while Tween-treated lungs failed to respond to 10% O2, indicating that the threshold for hypoxic vasoconstriction was decreased by ANTU. ANTU also decreased the threshold for and increased the magnitude of angiotensin II pressor responses, indicating that the increased vasoreactivity was not specific for hypoxia. Addition of meclofenamate to perfusates increased the rate and magnitude of responses to 0% O2 in Tween-treated lungs, but did not change the responses of ANTU-treated lungs. Light microscopy of ANTU-treated lungs showed no pulmonary arterial obstruction, and electron microscopy revealed mild capillary endothelial cell injury. We conclude that enhanced pulmonary vascular reactivity accompanies the increased-permeability pulmonary edema caused by ANTU. A similar increase in vasoreactivity might contribute to pulmonary hypertension observed in patients with the adult respiratory distress syndrome.

Topics: Angiotensin II; Animals; Blood Vessels; Hypoxia; Lung; Male; Meclofenamic Acid; Oxygen; Polysorbates; Pulmonary Circulation; Pulmonary Edema; Rats; Rats, Inbred Strains; Thiourea; Time Factors; Vasoconstriction