Evidence for the involvement of endothelin-1 but not urotensin-II in chronic lower limb ischaemia in man

• Published in: European journal of vascular and endovascular surgery Vol. 25; no. 5; pp. 443 - 450
• Main Authors: Tsui, J.C.S., Baker, D.M., Biecker, E., Shaw, S., Dashwood, M.R.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2003
• Subjects: Aged; Aged, 80 and over; Amputation; Autoradiography; Case-Control Studies; Chronic Disease; Chronic ischaemia; Endothelin receptors; Endothelin-1; Endothelin-1 - metabolism; Female; Humans; Immunoenzyme Techniques; Ischemia - metabolism; Ischemia - surgery; Leg - blood supply; Male; Middle Aged; Muscle, Skeletal - blood supply; Muscle, Skeletal - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - analysis; Skeletal muscle; Statistics, Nonparametric; Up-Regulation; Urotensin-II; Urotensins - metabolism; Urotensin-II; Endothelin receptors; Skeletal muscle; Chronic ischaemia; Endothelin-1
• ISSN: 1078-5884; 1532-2165
• DOI: 10.1053/ejvs.2002.1855

Background: endogenous vasoconstrictor peptides may play a role in the pathophysiology of critical limb ischaemia (CLI). This study investigated endothelin-1 (ET-1) and urotensin-II (U-II) mRNA expression, peptide distribution and ET receptor subtype binding in chronically ischaemic muscle. Methods: open muscle biopsies were taken from patients undergoing amputations for CLI and from patients undergoing coronary artery bypass surgery (controls). ET-1 and U-II mRNA expression in muscle biopsies was studied using real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). ET-1 and U-II immunohistochemistry was performed on muscle sections and ET receptor binding studied using in vitro autoradiography. Results: ET-1 mRNA expression was significantly increased in CLI compared to controls (p < 0.05) whilst no significant change in U-II expression occurred. ET-1 immunoreactivity was also increased in CLI with no difference in U-II immunostaining observed. ETB receptor binding was significantly increased in CLI (median 4, range 1-8 vs 2, range 1-3, dpm × 103/mm2, p = 0.01, Mann-Whitney test) whilst ETA receptor binding was not significantly raised. Binding was associated with microvessels and macrophages. Conclusions: in CLI, the ET-1 pathway is upregulated but U-II is unaffected. ET-1 may vasoconstrict microvessels and mediate inflammation in chronically ischaemic muscle. ET-1 binding to ETB receptors in particular may play an important role in the pathophysiology of CLI underscoring the therapeutic potential of ETB receptor antagonists in the management of CLI. Eur J Vasc Endovasc Surg 25, 443-450 (2003)