Cardiovascular pharmacology Nitric oxide and K ir 6.1 potassium channel mediate isoquercitrin- induced endothelium-dependent and independent vasodilation in the mesenteric arterial bed of rats Arquimedes Gasparotto Junior a,n , Renê dos Reis Piornedo b , Jamil Assreuy b , José Eduardo Da Silva-Santos b,nn a Laboratory of Electrophysiology and Cardiovascular Pharmacology, Faculty of Health Sciences, Universidade Federal da Grande Dourados, Rodovia Dour- ados-Itahum, km 12, P.O. Box 533, 79 804-970 Dourados, MS, Brazil b Laboratory of Cardiovascular Biology, Department of Pharmacology, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil article info Article history: Received 3 April 2016 Received in revised form 30 June 2016 Accepted 3 August 2016 Available online 3 August 2016 Keywords: Isoquercitrin Mesenteric arterial bed Potassium channel Vasodilation Chemical compounds studied in this article: Acetylcholine chloride (Pubchem CID 6060) Glibenclamide (PubChem CID: 3488) Iberiotoxin (PubChem CID 16132435) Indomethacin (PubChem CID 3715) Isoquercitrin (PubChem CID 5280804) N-Nitroarginine methyl ester (PubChem CID 39836) Phenylephrine hydrochloride (PubChem CID: 5284443) Tetraethylammonium chloride (PubChem CID 5946) abstract The vascular effect of flavonoid isoquercitrin was investigated in the perfused mesenteric vascular bed of rats. In preparations with functional endothelium isoquercitrin (100, 300 and 1000 nmol) dose-depen- dently reduced the perfusion pressure by 13 72.2, 33 73.9, and 58 73.7 mm Hg, respectively. En- dothelium removal or inhibition of the nitric oxide synthase enzymes by L-NAME did not change the effects of 100 and 300 nmol isoquercitrin, but reduced by 30–40% the vasodilation induced by 1000 nmol isoquercitrin. Perfusion with nutritive solution containing 40 mM KCl abolished the vasodilatory effect of all isoquercitrin doses. Treatment with glibenclamide, a K ir 6.1 (ATP-sensitive) potassium channel blocker, inhibited vasodilation induced by 100 and 300 nmol isoquercitrin, but only partially reduced the effect of 1000 nmol isoquercitrin. The non-selective K Ca (calcium-activated) potassium channel blocker tetra- ethylammonium, but not the selective K Ca 1.1 channel blocker iberiotoxin, reduced by around 60% va- sodilation induced by all isoquercitrin doses. In addition, association of tetraethylammonium and glib- enclamide, or L-NAME and glibenclamide, fully inhibited isoquercitrin-induced vasodilation. Our study shows that isoquercitrin induces vasodilation in resistance arteries, an effect mediated by K þ channel opening and endothelial nitric oxide production. & 2016 Elsevier B.V. All rights reserved. 1. Introduction Isoquercitrin (quercetin-3-O-β-D-glucopyranoside; Fig. 1A), one of the major glycosidic forms of natural flavonol quercetin (3,5,7,30,40-pentahydroxyflavone), is ubiquitously distributed in the plant kingdom. In recent years, several flavonols, including isoquercitrin, have been described as potential therapeutic agents for a number of disorders. Isoquercitrin has attracted great commercial interest, mainly because it is easily obtained by the enzymatic hydrolysis of the flavonoid rutin (Hasumura et al., 2004). Moreover, isoquercitrin is significantly more soluble in water and displays better absorption rates than other quercetin forms after its oral administration (Morand et al., 2000), following a linear absorption kinetics in rodents (He et al., 2013; Li et al., 2008; Zhou et al., 2011). Interestingly, a highly soluble form of isoquercitrin named “enzymatically modified (α-glucosylated) isoquercitrin”– EMIQ – was previously registered by the U.S. Food and Drug Administration to protect flavors and colors in non-al- coholic beverages and flavored milk products, mainly due to its antioxidant properties. A wide range of biological effects have been attributed to iso- quercitrin (for a detailed review see Valentová et al. (2014)). Iso- quercitrin has shown to be a scavenger of reactive oxygen species Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/ejphar European Journal of Pharmacology http://dx.doi.org/10.1016/j.ejphar.2016.08.006 0014-2999/& 2016 Elsevier B.V. All rights reserved. n Corresponding author. nn Correspondence to: Department of Pharmacology, Universidade Federal de Santa Catarina, Campus Universitário, Room 116, Trindade – Florianópolis, SC 88 040-900, Brazil. E-mail addresses: arquimedesgasparotto@gmail.com (A. Gasparotto Junior), j.e.silva.santos@ufsc.br (J.E. Da Silva-Santos). European Journal of Pharmacology 788 (2016) 328–334