Abstract
Endothelin- (ET-1) is involved in the pathogenesis of several ischemic diseases. We investigated the hypotheses that ET-1 is involved in the pathogenesis of experimental critical hind limb ischemia and that ET-1 receptor antagonists have a protective effect. Critical hind limb ischemia was achieved by exclusion of the femoral artery and embolization of collateral vessels in rats. The induction of endothelin system components by ischemia was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) (mRNAs) and immunoassay (peptides) in the plasma and ischemic muscles 5 hr (H5), 5 days (D5) and 14 days (D14) after ischemia. Two groups of rats received 100 mg/kg/day of either Bosentan, a mixed ET(A/B) receptor antagonist (n = 12), or LU 135252, a selective ET(A) receptor antagonist (n = 9), and a control group without treatment (n = 12) served as control. Muscle blood flow and ischemia were monitored in the ischemic limb by laser Doppler and phosphorylase activity, respectively. The procedure induced an 80% decrease in muscle blood flow and complete suppression of phosphorylase activity without necrosis. At day 14, the tissue blood flow remained reduced by 70% and phosphorylase activity was suppressed completely. There was up-regulation of preproendothelin-1, preproET-3, endothelin converting enzyme-1, and ET(A). ET(B) receptor mRNAs in ischemic muscle at day 5 and day 14 was accompanied by an increase in muscle concentration of ET-1 at day 5, without significant changes in plasma endothelin. Treatment with Bosentan and LU 135252 increased tissue blood flow and reduced muscle ischemia at day 14. Tissue production of ET- 1 is up-regulated in experimental critical hind limb ischemia. Inhibition of the endothelin system by a mixed ET(A/B) receptor antagonist may protect, at least in part, against muscle injury.
Highlights
Despite percutaneous or surgical revascularisation, morbidity and mortality of critical leg ischemia remain high [1]
368 402 856 662 426 299 bp, base pairs; ET, endothelin; ECE-1, endothelin converting enzyme-1; glyceraldehyde-3phosphate deshydrogenase (GAPDH), glyceraldehyde-3-phosphate dehydrogenase; Preproendothelin-1, of ischemia showed that muscular blood flow was similar in the two hind limbs for each muscle tested
The present study used an original model of chronic critical hind limb ischemia in the rat
Summary
Despite percutaneous or surgical revascularisation, morbidity and mortality of critical leg ischemia remain high [1]. We investigated the hypotheses that ET-1 is involved in the pathogenesis of experimental critical hind limb ischemia and that ET-1 receptor antagonists have a protective effect. The induction of endothelin system components by ischemia was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) (mRNAs) and immunoassay (peptides) in the plasma and ischemic muscles 5 hr (H5), 5 days (D5) and 14 days (D14) after ischemia. Muscle blood flow and ischemia were monitored in the ischemic limb by laser Doppler and phosphorylase activity, respectively. Results: The procedure induced an 80% decrease in muscle blood flow and complete suppression of phosphorylase activity without necrosis. At day 14, the tissue blood flow remained reduced by 70% and phosphorylase activity was suppressed completely. Treatment with Bosentan and LU 135252 increased tissue blood flow and reduced muscle ischemia at day 14. Inhibition of the endothelin system by a mixed ETA/B receptor antagonist may protect, at least in part, against muscle injury
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