Enhanced vasoconstrictor effect of big endothelin-1 in patients with atherosclerosis: relation to conversion to endothelin-1
Introduction
The 21-amino acid peptide endothelin-1 (ET-1) is produced by vascular endothelial cells [1] from the 38-amino acid precursor peptide, big ET-1, by the endothelin-converting enzyme (ECE) [2], [3]. Two different ECE forms, termed ECE-1 and ECE-2, have been isolated but their chemical nature and tissue distribution suggest that ECE-1 is responsible for the conversion of big ET-1 to ET-1 in the vascular bed. The functional effects of ET-1 are mediated by activation of the two receptors ETA [4] and ETB [5]. The ETA receptor is located on vascular smooth muscle cells and mediates potent and long-lasting vasoconstriction. Stimulation of the ETB receptor results in either vasoconstriction or vasodilatation via release of nitric oxide depending on whether the receptor is localized on vascular smooth muscle cells or on the endothelium. Administration of ET-1 to healthy humans results in vasoconstriction in several vascular beds such as in the heart [6], in the kidney [7] and in skeletal muscle [8]. The selective ETA receptor antagonist BQ123 and the inhibitor of ECE, phosphoramidon, evoke increases in forearm blood flow [9], [10]. These findings strongly suggest that endogenous ET-1 contributes to basal vascular tone.
ET-1 may contribute to the progression of several cardiovascular disorders such as congestive heart failure, hypertension and ischemic heart disease [11]. It has also been speculated that ET-1 is of importance in atherosclerosis [12]. Besides its vasoconstrictor effects, ET-1 is a mitogen for vascular smooth muscle cells [13]. ET-1 may also indirectly recruit monocytes by stimulating macrophages to synthesize monocyte chemoattractant protein-1 [14], allowing monocyte invasion into the arterial wall which is an essential step in atherogenesis [15]. The expression of ET-1 is enhanced in smooth muscle cells and macrophages of human atherosclerotic plaques [16]. These findings indicate that ET-1 may be of pathophysiological importance in atherogenesis. This is further supported by the observations that ETA receptor antagonists inhibit the development of atherosclerotic lesions and improve endothelial function in experimental atherosclerosis [12], [17].
The increased production of ET-1 in atherosclerotic arteries may be due to enhanced expression and activity of ECE-1 in the vascular wall [18], [19]. Accordingly, ECE-1 activity was enhanced in isolated endothelium-denuded human atherosclerotic coronary arteries [20] as well as in rabbit atherosclerotic arteries [19] in vitro. The in vivo vasoconstrictor effect evoked by local conversion of big ET-1 to ET-1 in patients with atherosclerosis has not been investigated previously. In the present study we tested the hypothesis that the vasoconstrictor effect of big ET-1 is enhanced in patients with atherosclerosis due to increased conversion to ET-1 in the vascular bed.
Section snippets
Subjects
The study was performed on nine male patients with atherosclerosis and nine healthy male controls. Some basal characteristics of the study population are presented in Table 1. The patients had symptoms of intermittent claudication with significant atherosclerotic lesions and flow obstructions in the large arteries of the legs as determined by ultrasound scanning and/or angiography. Six of them also had coronary artery disease (angina pectoris that had required coronary revascularization or
Study subject characteristics
The basal characteristics of the patients and control subjects are summarized in Table 1. Ultrasound examination of the brachial artery revealed that the mean of anterior and posterior wall thickness in relation to the inner diameter was significantly larger in the patient group than in the control group (Table 2). There was no evidence of significant stenotic lesions or flow obstructions in any subject.
Hemodynamic effects of big ET-1
Infusion of big ET-1 caused a dose-dependent and progressive reduction in forearm blood flow
Discussion
The main finding of the present study is that big ET-1 evokes a significantly more pronounced vasoconstrictor response in the forearm of patients with atherosclerosis than in healthy controls. Enhanced reduction in forearm blood flow was apparent already after 10 min of infusion of the low dose of big ET-1, and it was maintained throughout the infusion period. Moreover, the forearm vascular resistance was increased two times more in patients than in controls, clearly demonstrating an enhanced
Acknowledgements
The present study was supported by grants from the Swedish Medical Research Council (10857, 10354 and 12233), the Swedish Heart and Lung Foundation, King Gustav and Queen Victoria Foundation and the Karolinska Institute. We are grateful to Dr Thomas Subkowski, BASF Ag, Germany for providing the ECE-1 antibody, to Professor Lars Rydén for valuable criticism on the manuscript and to Mrs Marita Wallin, Mrs Carina Nihlén, Ms Margareta Stensdotter and Ms Mariette Lengquist for expert technical
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