Ali Mahdi1, Tong Jiao1, Yahor Tratsiakovich1, Bernhard Wernly1,2,3,4, Jiangning Yang1, Claes-Göran Östenson5, A H Jan Danser6, John Pernow1,7, Zhichao Zhou1. 1. Unit of Cardiology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. 2. Department of Anaesthesiology, Perioperative Medicine and Intensive Care Medicine, Paracelsus Medical University of Salzburg, Salzburg, Austria. 3. Department of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria. 4. Center for Public Health and Healthcare Research, Paracelsus Medical University of Salzburg, Salzburg, Austria. 5. Department of Molecular Medicine and Surgery, Endocrinology and Diabetology, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden. 6. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 7. Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden.
Abstract
INTRODUCTION: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. METHODS: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. RESULTS: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. CONCLUSIONS: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.
INTRODUCTION: Sunitinib, a multi-targeted tyrosine kinase receptor inhibitor used to treat renal-cell carcinoma and gastrointestinal stromal tumor, was recently shown to have a beneficial effect on metabolism in type 2 diabetes (T2D). Endothelial dysfunction is a key factor behind macro- and microvascular complications in T2D. The effect of sunitinib on endothelial function in T2D remains, however, unclear. We therefore tested the hypothesis that sunitinib ameliorates endothelial dysfunction in T2D. METHODS: Sunitinib (2 mg/kg/day, by gavage) was administered to T2D Goto-Kakizaki (GK) rats for 6 weeks, while water was given to GK and Wistar rats as controls. Hemodynamic, inflammatory, and metabolic parameters as well as endothelial function were measured. RESULTS: Systolic, mean arterial blood pressures, plasma tumor necrosis factor α levels, kidney weight to body weight (BW) ratio, and glucose levels were higher, while BW was lower in GK rats than in Wistar rats. Six-week treatment with sunitinib in GK rats did not affect these parameters but suppressed the increase in glucose levels. Endothelium-dependent relaxations were reduced in both aortas and mesenteric arteries isolated from GK as compared to Wistar rats, which was markedly reversed in both types of arteries from GK rats treated with sunitinib. CONCLUSIONS: This study demonstrates that sunitinib has a glucose-lowering effect and ameliorates endothelial dysfunction in both conduit and resistance arteries of GK rats.
Authors: A Alameddine; Z Fajloun; J Bourreau; G Gauquelin-Koch; M Yuan; D Gauguier; S Derbre; A Ayer; M A Custaud; N Navasiolava Journal: J Physiol Pharmacol Date: 2015-04 Impact factor: 3.011