Nitric Oxide (NO) and endothelin-1 (ET-1) are key modulators of endothelial vessels and actively participate in the pathophysiology of vaso-occlusive events. Sickle cell anemia (SCA) is an important model for the study of blood cells/endothelium interactions. In SCA vaso-occlusive events may be severe and cumulative. Adrenomedullin (ADM) is a strong hypotension-inducer and mediates diuresis, natriuresis and vasodilation. Adrenomedullin levels are raised in chronic cardiovascular conditions. The aim of this study was to investigate the role of adrenomedullin in SCA and its relationship to endothelin-1 and nitric oxide. A cohort of 111 children with HbSS SCA was studied with 18 age-matched controls of sub-Sahara African ethnicity. The patients were in four clinical groups:

  • steady state (n=55, mean age 5.3 years),

  • patients undergoing chest crisis (n=9, mean age 5.3 years),

  • on hydroxyurea (n=30, mean age 7.2 years),

  • on transfusion therapy (n=17, mean age 6.5 years).

A third cohort of patients with HbSC genotype (n=13, mean age 6 years) all in steady state was also included. Pro-adrenomedullin and c-terminal endothelin-1 precursor (CT-proET-1) were measured by coated tube assays according to the method by

Morgenthaler et al (Clin Chem.2005;51:1823–29)
and
Papassotiriou et al (Clin Chem.2006;52(6):1144–51)
, nitric oxide was quantified according to the Griess reaction. Results (median and interquartile range) are shown in table 1. Overall pro-adrenomedullin levels were raised in chest crisis: 0.38 nmol/l (0.31–0.49) vs steady state: 0.27 nmol/l (0.25–0.32; p<0.01) and control: 0.28 nmol/l (0.27–0.31; p <0.01). CT-proET-1 levels were reduced in patients on hydroxyurea therapy: 43.6 pmol/l (12.6–49.6) vs control: 55.1 pmol/l (45.2–63.9; p<0.05). Nitric oxide levels were significantly lower in chest crisis (19.3 mmol/l plasma; 10.7–19.9) compared to hydroxyurea (22.2 mmol/l plasma; 18.3–28.4; p<0.05), and HbSC (30.6 mmol/l plasma; 20.8–39.5; p<0.05) and approach significance when compared to steady state (22.5mmol/l plasma; 16.9–28.2; p=0.07). This study indicates that during chest crisis plasma adrenomedullin levels are elevated compared to normal controls and SCA patients in steady state (see figure 1). Plasma nitric oxide levels are diminished. These observations indicate that markers of ongoing vascular damage are evident in children with SCA with chest crises, and suggest that treatments that prevent onset or progression of pulmonary hypertension, such as bosentan, may also have a role in the prevention of pulmonary hypertension in children with SCA.

Table 1. ADM, ET-1, NO and hematological/biochemical values in SCA patients and controls. IR= interquartile range.

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Figure 1.
Figure 1. ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range.
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ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range.

Figure 1.
Figure 1. ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range.
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ADM and NO levels in sickle cell patients and controls. Bars indicate median and interquartile range.

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Topics:
adrenomedullin, plasma, sickle cell anemia, pediatrics, endothelin-1, nitric oxide, hydroxyurea, proadrenomedullin, pulmonary hypertension, bosentan

Disclosures: No relevant conflicts of interest to declare.

Author notes

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2008, The American Society of Hematology
2008
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