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Adrenomedullin is a hypotensive peptide newly found in human pheochromocytoma tissue.1 The peptide comprises 52 amino acids with an intramolecular disulphide bond. The mRNA of adrenomedullin has been detected in normal adrenal medulla, heart, kidney, and lung. Adrenomedullin is produced in endothelial cells, vascular smooth muscle cells, and fibroblasts.2Adrenomedullin receptors are expressed in both vascular smooth muscle cells and vascular endothelial cells. Adrenomedullin has a vasorelaxant effect, antagonising the vasospastic effect of endothelin-1 and seems to be implicated in the physiological and pathological control of circulation. Through multiple biological effects in the circulatory system, adrenomedullin appears to reduce plasma volume and blood pressure, thereby protecting the cardiovascular system.3Furthermore, adrenomedullin regulates not only vascular tonus but also vascular function through the autocrine/paracrine system, stimulating cAMP formation in a dose dependent manner,3 and exerting an anti-inflammatory effect by inhibiting the production of a chemoattractant from alveolar macrophages.4
Systemic sclerosis (SSc) is a chronic disease of unknown cause characterised by vascular changes and fibrosis of the skin and the visceral organs. Major complications of SSc are renal, myocardial, and pulmonary. Pulmonary hypertension (PH) is a common cause of death in patients with SSc. In the plasma of patients with PH the endothelin-1 level is raised.5 In addition, it was recently reported that the adrenomedullin level is raised also in the plasma of patients with Raynaud's disease6 or rheumatoid arthritis.7 Therefore, we measured the concentrations of adrenomedullin and endothelin-1 in the plasma from patients with SSc, with or without PH, to elucidate the role of adrenomedullin in the pathogenesis of PH in SSc.
We obtained plasma from three women with SSc with PH (aged 43–72), 10 patients with SSc without PH (nine women, one man, aged 22–60), and one female patient with primary PH. The diagnosis of SSc was based on accepted criteria.8 We diagnosed PH in patients with SSc whose right ventricular systolic pressure was higher than 25 mm Hg measured by echocardiogram. In the three patients with SSc with PH we confirmed PH by catheterisation. The pressures of the pulmonary artery of these three patients were 45, 51, and 54 mm Hg, respectively. All patients with SSc had diffuse-type SSc without interstitial pneumonia, which was diagnosed as interstitial fibrosis by computed tomography. The three patients with PH were taking the following drugs: triclopidine hydrochloride (patient 1), nifedipine and triclopidine hydrochloride (patient 2), and nicardipine hydrochloride and methylprednisolone (patient 3).
For the comparison group we selected patients with diffuse-type SSc without PH, as all of three patients with SSc with PH had diffuse-type SSc. Six normal volunteers (three women and three men, age 29–40) were also studied. Concentrations of adrenomedullin were measured by radioimmunoassay. Statistical significance was analysed with the Mann-Whitney U test.
Concentrations of adrenomedullin in the plasma were significantly higher in patients with SSc with PH than in those with SSc without PH (p = 0.011) or than in normal volunteers (p = 0.020) (fig 1A). The concentrations of adrenomedullin or endothelin-1 in the plasma from a patient with primary PH were similar to those from patients with SSc without PH (data not shown). The levels of endothelin-1 in patients with SSc with PH were raised compared with those in patients with SSc without PH (p = 0.41) (fig 1B). We did not measure levels of endothelin-1 in normal volunteers (fig 1B).
We recently obtained similar results when measuring the levels of the mature form of adrenomedullin and total adrenomedullin in a different group of patients with SSc with (patients 4, 5, and 6) or without PH, by immunoradiometric assay. The three patients with SSc with PH were women aged 43–54, and two patients with SSc without PH were women aged 47 and 55. The duration of disease was two to seven years. The pulmonary artery pressures of patients 4, 5, and 6 were 46, 59, and 60 mmHg, respectively. The levels of adrenomedullin in the plasma of patients 4, 5, and 6 were 24.9, 58.1, and 27.5, respectively, whereas those of the two patients with SSc without PH were 16.4 and 14.7 pg/ml. These results, however, did not reach statistical significance as the number of patients was small.
Patients 4, 5, and 6 were taking the following drugs: nifedipine, tocopherol acetate, and beraprost sodium (patient 4); nifedipine and triclopidine hydrochloride (patient 5); and nifedipine (patient 6). Levels of adrenomedullin in the plasma were significantly higher in patients with SSc with PH than in healthy volunteers (p=0.011).
Our results suggest that the amount of adrenomedullin is insufficient to inhibit either the spasm of pulmonary vessels or the proliferation of endothelial cells of the vessels, though the levels of adrenomedullin in plasma increased enough to antagonise the effects of endothelin-1 in patients with SSc. It has been recently reported that chronic infusion of adrenomedullin reduces PH and right ventricular hypertrophy in rats.9 Thus our results also suggest the possibility that interventions aimed at controlling the balance of adrenomedullin and endothelin-1 might prove fruitful in preventing PH in patients with SSc.
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