doi: 10.1111/j.1472-8206.2009.00763.x ORIGINAL ARTICLE Effect of chronic pre-treatment with angiotensin converting enzyme inhibition on skeletal muscle mitochondrial recovery after ischemia/reperfusion Fabien Thaveau a,1 , Joffrey Zoll b,c,1 , Jamal Bouitbir b,c , Benoı ˆt N’Guessan b , Philippe Plobner b , Nabil Chakfe a , Jean-Georges Kretz a , Ruddy Richard b,c , Franc ¸ois Piquard b,c , Bernard Geny b,c * a Department of Vascular Surgery, Nouvel Hopital Civil, Strasbourg, France b Department of Physiology and EA 3072, Faculty of Medicine, Louis Pasteur University, France c Service de Physiologie et d’Explorations Fonctionnelles, Nouvel Ho ˆpital Civil, Strasbourg, France INTRODUCTION Critical lower limb ischemia is a serious condition which prevalence will readily increase in the future with the general aging of the population. Presence of peripheral arterial disease (PAD), often associated with a decreased left ventricular ejection fraction, confers an increased risk of death from cardiovascular cause, supporting the recommendation for strong atherosclerotic risk reduc- tion strategies [1]. The degree of muscle alteration participates also in the prognosis of patients having major vascular surgeries Keywords ACE inhibition, ischemia–reperfusion, mitochondria, muscle, peripheral arterial disease, renin–angiotensin Received 8 January 2009; revised 25 May 2009; accepted 16 June 2009 *Correspondence and reprints: bernard.geny@chru-strasbourg.fr 1 These authors contributed equally to this work. ABSTRACT Impaired skeletal muscle energetic participates in peripheral arterial disease (PAD) patient’s morbidity and mortality. Angiotensin converting enzyme inhibition (ACEi), cornerstone for pharmacologic risk factor management in PAD patients, might also be interesting by protecting skeletal muscle energetic. We therefore determined whether chronic ACEi might reduce ischemia-induced mitochondrial respiratory chain dysfunction in the frequent setting of hindlimb ischemia–reperfusion. Ischemic legs of rats submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hindlimb followed by reperfusion without (IR, n = 11) or after ACEi (n = 14; captopril 40 mg/kg per day during 28 days before surgery) were studied and compared to that of sham-operated animals (n = 11). The effect of ACEi on the non-ischemic contralateral leg was also determined in the ACEi group. Maximal oxidative capacities (V max ) and complexes I, II and IV activities of the mitochondrial respiratory chain of the gastrocnemius muscle were determined using glutamate– malate, succinate and TMPD–ascorbate substrates. Arterial blood pressure was significantly decreased after ACEi (124 ± 2.8 vs. 108 ± 4.19 mmHg; P = 0.01). Ischemia–reperfusion reduced V max (4.4 ± 0.4 vs. 8.7 ± 0.5 lmol O 2 /min/g dry weight, )49%, P < 0.001), affecting mitochondrial complexes I, II and IV activities. ACEi failed to modulate ischemia-induced dysfunction (V max 5.1 ± 0.7 lmol O 2 /min/ g dry weight) or the non-ischemic contralateral muscle respiratory rate. Ischemia– reperfusion significantly impaired the mitochondrial respiratory chain I, II and IV complexes of skeletal muscle. Pharmacologic pre-treatment with ACEi did not prevent or increase such alterations. Further studies might be useful to improve the pharmacologic conditioning of PAD patients needing arterial revascularization. ª 2009 The Authors Journal compilation ª 2009 Socie ´ te ´ Franc ¸aise de Pharmacologie et de The ´ rapeutique Fundamental & Clinical Pharmacology 24 (2010) 333–340 333 Fundamental & Clinical Pharmacology