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

Abstract 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 B receptor binding was significantly increased in CLI (median 4, range 1-8 vs 2, range 1-3, dpm × 10 3 /mm 2 , p = 0.01, Mann-Whitney test) whilst ET A 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 ET B receptors in particular may play an important role in the pathophysiology of CLI underscoring the therapeutic potential of ET B receptor antagonists in the management of CLI. Eur J Vasc Endovasc Surg 25 , 443-450 (2003)