Figure 2
Sickle mice and mice receiving transplants with marrow from sickle mice (BM-S) exhibit blunted pulmonary vasodilatory responses to NO and endothelium-dependent vasodilators, showing mean ± SEM for 5 or 6 mice per group. Responses to each vasodilator challenge are shown by the magnitude of drop in mean pulmonary artery pressure (PAP). (A) Sickle mice demonstrated less decrease in pulmonary arterial pressure in response to inhaled NO (data shown for 4 ppm). A similarly blunted response was observed at a lower NO dose (0.4 ppm, P < .05, data not shown). There was no systemic response to inhaled NO (not shown), consistent with the very brief half-life of NO in blood. (B) The NO donor sodium nitroprusside (10 μg/kg intravenous bolus) was similar to inhaled NO in the blunted pulmonary vasodilator response in sickle mice and BM-S mice compared with controls. Similar blunted responsiveness was observed at lower doses (3 μg/kg intravenous bolus, P < .05, data not shown). (C) The phosphodiesterase-5 inhibitor sildenafil (30 μg/kg/min), which acts through the cGMP pathway like NO, had blunted pulmonary vasodilatory responses in sickle mice. BM-S mice preserved more vasodilatory responsiveness to sildenafil than did sickle mice but were still significantly less responsive than controls (P < .05). (D) Bradykinin (3 μg/kg intravenous bolus) response was also blunted in the sickle mice. Similar results were observed at lower doses (0.3 and 1μg/kg, P < .05, data not shown). (E) Pulmonary vascular response to another endothelium-dependent vasodilator, adrenomedullin (0.3 μg/kg intravenous bolus), was likewise blunted in sickle mice and in BM-S mice. Similar results were observed at lower doses (0.1 μg/kg intravenous bolus, P < .05, data not shown). (F) Lung homogenate assays demonstrated significantly lower activity of cGMP-dependent protein kinase in mice with circulating sickle erythrocytes compared with wild-type and hemizygous controls (4 to 7 mice per group) using a colorimetric assay (CycLex, Nagano, Japan)52,60 according to followed manufacturer's specifications. Statistically significant differences, P < .05 by t test, are indicated as follows: *, versus hemizygous controls, #, versus recipients of marrow from wild-type mice (BM-C); **, sickle versus BM-S mice.

Sickle mice and mice receiving transplants with marrow from sickle mice (BM-S) exhibit blunted pulmonary vasodilatory responses to NO and endothelium-dependent vasodilators, showing mean ± SEM for 5 or 6 mice per group. Responses to each vasodilator challenge are shown by the magnitude of drop in mean pulmonary artery pressure (PAP). (A) Sickle mice demonstrated less decrease in pulmonary arterial pressure in response to inhaled NO (data shown for 4 ppm). A similarly blunted response was observed at a lower NO dose (0.4 ppm, P < .05, data not shown). There was no systemic response to inhaled NO (not shown), consistent with the very brief half-life of NO in blood. (B) The NO donor sodium nitroprusside (10 μg/kg intravenous bolus) was similar to inhaled NO in the blunted pulmonary vasodilator response in sickle mice and BM-S mice compared with controls. Similar blunted responsiveness was observed at lower doses (3 μg/kg intravenous bolus, P < .05, data not shown). (C) The phosphodiesterase-5 inhibitor sildenafil (30 μg/kg/min), which acts through the cGMP pathway like NO, had blunted pulmonary vasodilatory responses in sickle mice. BM-S mice preserved more vasodilatory responsiveness to sildenafil than did sickle mice but were still significantly less responsive than controls (P < .05). (D) Bradykinin (3 μg/kg intravenous bolus) response was also blunted in the sickle mice. Similar results were observed at lower doses (0.3 and 1μg/kg, P < .05, data not shown). (E) Pulmonary vascular response to another endothelium-dependent vasodilator, adrenomedullin (0.3 μg/kg intravenous bolus), was likewise blunted in sickle mice and in BM-S mice. Similar results were observed at lower doses (0.1 μg/kg intravenous bolus, P < .05, data not shown). (F) Lung homogenate assays demonstrated significantly lower activity of cGMP-dependent protein kinase in mice with circulating sickle erythrocytes compared with wild-type and hemizygous controls (4 to 7 mice per group) using a colorimetric assay (CycLex, Nagano, Japan)52,60  according to followed manufacturer's specifications. Statistically significant differences, P < .05 by t test, are indicated as follows: *, versus hemizygous controls, #, versus recipients of marrow from wild-type mice (BM-C); **, sickle versus BM-S mice.

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