Effect of iloprost on plasma asymmetric dimethylarginine and plasma and platelet serotonin in patients with peripheral arterial occlusive disease

https://doi.org/10.1016/j.prostaglandins.2006.06.005Get rights and content

Abstract

Background

Iloprost, a prostacyclin analogue, is used in the treatment of peripheral arterial occlusive disease at Leriche–Fontaine stages III–IV, through intravenous infusion for at least 21 days. Recently, iloprost has been shown to be safe and effective in critical limb ischemia patients when administered per 7 days. We investigated in patients at Leriche–Fontaine stages III–IV the effect of 1-week treatment with iloprost on plasma asymmetric dimethylarginine (ADMA), plasma and platelet serotonin, and on clinical response.

Methods and results

Twenty-four critical limb ischemia patients (16 men and 8 women, mean age 76 ± 9.7 years) were included in the study and treated with intravenous iloprost (titrated from 0.5 up to 1.5 ng/kg/min) for 16 h a day for seven consecutive days. Blood samples were drawn before infusion on days 1, 4 and 8 of treatment, under the same conditions. Clinical assessment was performed by clinical evaluation, ankle/brachial pressure index and treadmill exercise test. During treatment with iloprost patients clinically improved and plasma levels of ADMA significantly decreased (p < 0.001). We also observed a significant increase of serotonin (p < 0.01) in platelets and a significant decrease of serotonin (p < 0.001) in plasma. Similar variations of ADMA and serotonin were found in two subgroups of patients, diabetics and non-diabetics.

Conclusions

One-week treatment with iloprost in critical limb ischemia patients induced changes of peripheral markers of endothelial dysfunction and atherosclerosis, such as ADMA and serotonin, associated to a clinical improvement.

Introduction

Iloprost, a synthetic analogue of prostacyclin, is commonly used in the treatment of peripheral arterial occlusive disease (PAOD) at the stage of critical ischaemia (Leriche–Fontaine stages III–IV) when revascularisation is not feasible [1], [2], [3], [4]. Compared to prostacyclin, iloprost presents similar pharmacodynamic effects, and offers practical advantages due to a greater chemical stability and longer plasma half-life [5]. It has been currently administered through intravenous infusion for 6 h/day for 28 days at a maximal dose of 2 ng/kg/min. Recent studies [6], [7], [8] have shown that iloprost can be safe and effective in critical limb ischemia patients when administered with a shorter schedule of treatment (16 h/day for 7 days at a maximal dose of 1.5 ng/kg/min). The efficacy of iloprost has been attributed to its ability to induce arterial vasodilation, inhibition of platelet activation and citoprotection against the ischaemia-reperfusion injury; fibrinolytic, anti-inflammatory and proangiogenic activities have been also described [9], [10], [11], [12]. However, the exact mechanism of action of iloprost is still unknown. Critical limb ischemia mainly results from atherosclerotic processes occluding the arteries of the lower extremities. Recent studies have shown the role of markers of atherosclerosis and endothelial dysfunction, such as asymmetric dimethylarginine (ADMA) and serotonin, in vascular atherosclerotic processes. In particular, ADMA is a product of protein turnover derived by methylation of arginine residues and is normally present in human plasma. Competing with l-arginine as the substrate for NO synthase, ADMA decreases the production of NO by the endothelium. Elevation of ADMA has been associated to endothelial dysfunction, evidenced by impaired endothelium-dependent vasodilation, hyperaggregability of platelets, and enhanced monocyte adhesion [13], [14], [15], [16]. High levels of plasma ADMA were noticed in patients affected by end stage renal disease, coronary artery disease, peripheral arterial occlusive disease, stroke, hypertension, congestive heart failure, hyperlipidaemia, and diabetes [17], [18], [19], [20], [21], [22], [23], [24]. As for serotonin (5-HT), it is synthesized in the enterochromaffin cells by trypthophan, released into blood stream, incorporated in platelets and stored in dense granules. At the site of endothelial lesions, platelets aggregate and release 5-HT that is able to induce vasoconstriction and aggregation of platelets in presence of endothelial injury, mitogenesis of arterial smooth muscle cells and endothelial cells, and synthesis of IL6 in vascular smooth muscle cells [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. Variations of plasma and platelet serotonin levels were described in patients with coronary artery disease [36], [37].

Our study is aimed at investigating the effect of 1-week treatment with iloprost in critical limb ischemia patients on circulating levels of ADMA, as well as on clinical response.

Section snippets

Methods

Twenty-four patients (16 men and 8 women, mean age 76 ± 9.7 years) were included in the study. Inclusion criteria were the presence of PAOD Fontaine stage III or IV unsuitable for revascularisation; diagnosis was made by clinical criteria and duplex ultrasonography. Exclusion criteria were the presence of decompensated heart failure, severe coronary artery disease, kidney or liver failure. Clinical characteristics of patients are reported in Table 1. Twelve patients were affected by diabetes

Plasma serotonin

Plasma serotonin of all the patients significantly decreased (p < 0.01) from 0.31 ± 0.04 μmol/L on day 1 to 0.30 ± 0.03 μmol/L on day 4 and 0.29 ± 0.03 μmol/L on day 8. Serotonin concentrations of diabetic and non-diabetic patients are shown in Fig. 1. No significant differences were found comparing concentrations at each time between diabetic and non-diabetic patients.

Platelet serotonin

Platelet serotonin significantly increased (p < 0.001) from 1.32 ± 0.44 μmol/200 000 cell on day 1 to 1.43 ± 0.45 μmol/200 000 cell on day 4 and 1.55

Discussion

This study showed that in patients affected by critical limb ischemia the intravenous infusion of iloprost 16 h daily per week induced variations of the biological parameters ADMA and serotonin, used as a markers of endothelial dysfunction and atherosclerotic disease. This effect was associated to a positive clinical response, as shown by the reduction of rest pain and improvement of ulcer healing. According to recent observations, our study confirmed that iloprost was safe and effective if

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