Metformin Improves Cardiac Functional Recovery After Ischemia in Rats

Abstract

The biguanide, metformin, is widely used for the treatment of type 2 diabetes mellitus. In the recently published United Kingdom Prospective Diabetes Study (UKPDS), it was shown that the use of metformin was associated with a reduction of macrovascular complications compared to other blood glucose-lowering strategies. The present study was aimed at determining whether metformin has direct beneficial effects on the heart. We tested the effects of metformin on cardiac functional recovery after a mild ischemic incident (stunning) in our isolated, erythrocyte perfused, rat working-heart model. Three groups were tested: vehicle, 50 and 500 µmol/l metformin (total n = 6). In diabetic rats, a concentration of 50 µM has been shown to reduce the blood glucose concentration. Slight metformin-induced increases in coronary blood flow during normoxia (pre-ischemically) and during reperfusion (post-ischemically) were observed and compared to vehicle (p < 0.05). Both metformin concentrations significantly reduced cardiac functional loss induced by the 12-min global ischemic incident compared with vehicle (3.4 ± 1.0 % and 3.5 ± 0.6 % loss during metformin versus 10.7 ± 0.8 % during vehicle, p < 0.001). This study clearly shows that metformin acutely improves cardiac function after a mild ischemic incident (stunning) in rats.

Key words

Myocardial - Biguanides - Type 2 Diabetes - Stunning - Coronary Blood Flow - Isolated Rat Heart

• 1 Schafer G. Biguanides. A review of history, pharmacodynamics and therapy.  Diabete Metab. 1983;  9 148-163
• 2 El-Mir M Y, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.  J Biol Chem. 2000;  275 223-228
• 3 Owen M R, Doran E, Halestrap A P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain.  Biochem. 2000;  J 348 Pt 3 607-614
• 4 UK Prospective Diabetes Study (UKPDS) Group .Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group (see comments) [published erratum appears in Lancet 1998 Nov 7; 352 (9139): 1557]. Lancet 1998 352: 854-865
• 5 Podesser B K, Hallstrom S, Schima H, Huber L, Weisser J, Kroner A, Furst W, Wolner E. The erythrocyte-perfused “working heart” model: hemodynamic and metabolic performance in comparison to crystalloid perfused hearts.  J Pharmacol Toxicol Methods. 1999;  41 9-15
• 6 Galinanes M, Hearse D J. Assessment of ischemic injury and protective interventions: the Langendorff versus the working rat heart preparation.  Can J Cardiol. 1990;  6 83-91
• 7 Verma S, McNeill J H. Metformin improves cardiac function in isolated streptozotocin-diabetic rat hearts.  Am J Physiol. 1994;  266 H714-719
• 8 Legtenberg R J, Houston R J, Oeseburg B, Smits P. Effects of sulfonylurea derivatives on ischemia-induced loss of function in the isolated rat heart.  Eur J Pharmacol. 2001;  419 85-92
• 9 Tian G H, Xiang B, Butler K W, Ghomeshi H R, Biro G P, Deslauriers R. Magnesium in St Thomas’ cardioplegic solution. A ³¹P-NMR and functional study in isolated rat and pig hearts.  Can J Appl Spectr. 1994;  39 69-75
• 10 Melchior W R, Jaber L A. Metformin: an antihyperglycemic agent for treatment of type II diabetes.  Ann Pharmacother. 1996;  30 158-164
• 11 Campbell I W, Howlett H C. Worldwide experience of metformin as an effective glucose-lowering agent: a meta-analysis.  Diabetes Metab Rev. 1995;  11 (Suppl. 1) S57-S62