Cardiovascular Pharmacology Lack of beneficial metabolic effects of quercetin in adult spontaneously hypertensive rats Miguel Romero a,1 , Rosario Jiménez a,1 , Belén Hurtado a , Juan Manuel Moreno b , Isabel Rodríguez-Gómez b , Rocío López-Sepúlveda a , Antonio Zarzuelo a,2 , Francisco Pérez-Vizcaino c,3 , Juan Tamargo c , Félix Vargas b , Juan Duarte a, ⁎ a Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain b Department of Physiology, School of Medicine, University of Granada, Spain c Department of Pharmacology, School of Medicine, University Complutense of Madrid, Spain abstract article info Article history: Received 2 April 2009 Received in revised form 21 October 2009 Accepted 3 November 2009 Available online 10 November 2009 Keywords: Quercetin Spontaneously hypertensive rat Endothelial dysfunction Insulin resistance Insulin sensitivity is partly dependent on insulin-mediated nitric oxide (NO) release and antioxidants may decrease insulin resistance by amelioring NO bioavailability. The effects of chronic therapy with the antioxidant quercetin on blood pressure, vascular function and glucose tolerance in male spontaneously hypertensive rats (SHR), a model of genetically hypertension and insulin resistance, were analyzed. Rats were divided into four groups, WKY vehicle, WKY quercetin, SHR vehicle and SHR quercetin. Animals were daily administered by gavage for four weeks: vehicle, quercetin in vehicle (10 mg/kg body weight). Blood pressure was followed by tail-cuff plethysmography. Chronic quercetin treatment reduced systolic blood pressure, and significantly reduced left ventricular (-10%) and renal (-6%) hypertrophy. However, oral glucose tolerance test, homeostatic model assessment of insulin resistance, total cholesterol and triglycerides were unaffected by quercetin in both strains of rats. It also improved the blunted aortic endothelium- dependent relaxation to acetylcholine, without affecting both endothelium-dependent relaxation to insulin and endothelium-independent relaxation to sodium nitroprusside in SHR. In WKY rats, quercetin in vitro and in vivo, impaired the relaxation to insulin. Quercetin reduced both plasma malondialdehyde levels and aortic superoxide production in SHR. Furthermore, quercetin inhibited insulin-stimulated protein kinase B (Akt)- and endothelial NO synthase (eNOS) phosphorylation. In conclusion, quercetin reduced blood pressure, left ventricular and renal hypertrophy and improved NO-dependent acetylcholine relaxation. However, and despite its antioxidant effects, quercetin was unable to improve insulin sensitivity possibly through its specific interference with the insulin signalling pathway. © 2009 Elsevier B.V. All rights reserved. 1. Introduction The vascular endothelium contributes importantly to the regulation of cardiovascular and metabolic homeostasis (Kim et al., 2006). Reciprocal relationships between endothelial dysfunction, insulin resistance and hypertension may help coupling hemodynamic and metabolic abnormal- ities observed in important interrelated public health problems, including diabetes, obesity, hypertension, coronary heart disease, atherosclerosis, and the metabolic syndrome (Kim et al., 2006; Sowers, 2004). The link between hypertension and insulin resistance is also present in some animal models of hypertension. The spontaneously hypertensive rat (SHR) is not only genetically hypertensive but also shows endothelial dysfunction and increased fasting levels of insulin consistent with metabolic insulin resistance (Reaven and Chang, 1991). Thus the SHR may be a useful model to explore the relationship between metabolic and hemodynamic dysregulations. Endothelial dysfunction in the insulin- resistant state is characterized by decreased endothelial production of nitric oxide (NO) as well as excess production of superoxide anion (O 2 - ), resulting in the degradation of NO before it can reach the vascular smooth muscle cells (Shinozaki et al., 1999). Moreover, oxidative stress generation impaired pancreatic β-cell insulin secretion (Bast et al., 2002) and interfered with insulin signalling pathway, thereby accelerating the progression to overt type 2 diabetes from insulin resistance (Evans et al., 2003). In fact, studies in animal models of diabetes and several clinical trials with insulin-resistant individuals indicate that antioxidants improve insulin sensitivity (Ceriello and Motz, 2004). Flavonoids have high antioxidant activities as free radical scavengers and as inhibitors of enzymes generating reactive oxygen species (Hollman and Katan, 1999). Flavonoids may preserve β-cell European Journal of Pharmacology 627 (2010) 242–250 ⁎ Corresponding author. Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain. Tel.: +34 958244088; fax: +34 958248264. E-mail address: jmduarte@ugr.es (J. Duarte). 1 Equal contributors to this work. 2 From CIBEREHD. 3 From CIBERES. 0014-2999/$ – see front matter © 2009 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2009.11.006 Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar