Contents lists available at ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Full length article Further analysis of the inhibition by agmatine on the cardiac sympathetic outflow: Role of the α 2 -adrenoceptor subtypes Luis Cobos-Puc a, ⁎ , Hilda Aguayo-Morales a , Janeth Ventura-Sobrevilla a , Diana Luque-Contreras a , Miguel Chin-Chan b a Facultad de Ciencias Químicas, Universidad Autónoma de Coahuila, Boulevard Venustiano Carranza esquina con Ing. José Cárdenas Valdés, Colonia República, C.P. 25280 Saltillo, Coahuila, Mexico b Facultad de Ciencias Químico-Biológicas, Universidad Autónoma de Campeche, Av. Universidad s/n, Col. Buenavista, C.P. 24039 Campeche, Campeche, Mexico ARTICLE INFO Chemical compounds studied in this article: Agmatine sulfate salt (PubChem CID: 2794990) BRL 44408 maleate salt (PubChem CID: 71311805) imiloxan hydrochloride (PudChem CID: 172975) JP-1302 dihydrochloride (PubChem CID: 540335) AGN 192403 hydrochloride (PubChem CID: 11957452) desipramine hydrochloride (PubChem CID: 65327) gallamine triethiodide (PubChem CID: 6172) Keywords: Agmatine α 2A -adrenoceptor Sympatho-inhibition I 1 -imidazoline receptor α 2C -adrenoceptor ABSTRACT This study has investigated the role of the α 2 -adrenoceptor subtypes involved in the inhibition of the cardiac sympathetic outflow induced by intravenous (i.v) infusions of agmatine. Therefore, we analysed the effect of an i.v. bolus injections of the selective antagonists BRL 44408 (300 μg/kg; α 2A ), imiloxan (3000 μg/kg; α 2B ), and JP-1302 (300 μg/kg; α 2C ) given separately, and their combinations: BRL 44408 plus Imiloxan, JP 1302 plus imiloxan, BRL 44408 plus JP-1302, BRL 44408 plus imiloxan plus JP-1302 on the cardiac sympatho-inhibition of agmatine. Also, the effect of the combination BRL 44408 plus JP-1302 plus AGN 192403 (3000 μg/kg; I 1 antagonist) was evaluated. In this way, i.v. infusions of 1000 μg/kg min of agmatine, but not 300, inhibited the tachycardic response induced by electrical stimulation. Furthermore, the antagonists used or their combinations had no effect on the electrically-induced tachycardic response. On the other hand, the inhibitory response of agmatine was: (1) partially antagonized by BRL 44408 or JP-1302 given separately, a similar response was observed when we administered their combination with imiloxan, but not by imiloxan alone, (2) antagonized in greater magnitude by the combination BRL 44408 plus JP-1302 or the combination BRL 44408 plus imiloxan plus JP-1302, and (3) abolished by the combination BRL 44408 plus JP-1302 plus AGN 192403. Taken together, these results demonstrate that the α 2A - and α 2C -adrenoceptor subtypes and I 1 -imidazoline receptors are involved in the inhibition of the cardiac sympathetic outflow induced by agmatine. 1. Introduction Agmatine is synthesized by decarboxylation of L-arginine by the enzyme arginine decarboxylase in mammal tissues. It is broadly expressed in the central nervous system, as well as in the digestive and cardiovascular system. This amine can be a potential neurotrans- mitter or neuromodulator since: (1) is present in central neurons, (2) is released in response to presynaptic depolarization by calcium-depen- dent mechanisms, (3) acts through several receptors (e.g. imidazoline receptors and α 2 -adrenoceptors among others) located in postsynaptic neurons, and (4) exerts systemic actions on the cardiovascular system (Molderings and Haenisch, 2012; Raasch et al., 2001). Agmatine interacts with the α 2 -adrenoceptors in a complex way. For instance, agmatine can act as an agonist by binding to an allosteric site and as an antagonist at the ligand recognition site of the α 2 - adrenoceptors (Molderings et al., 2000). This dual action of agmatine explains why does not behave as an α 2 -agonist or α 2 -antagonist in some tissues (Pineda et al., 1996; Pinthong et al., 1995). Even so, the α 2 -adrenoceptors mediate some of the biological responses of agmatine such as its antinociceptive (Santos et al., 2005), antidepressant (Jiang et al., 2008), and anticonvulsant (Demehri et al., 2003)effects, besides the potentiation of the analgesic action of morphine (Yesilyurt and Uzbay, 2001). Agmatine depresses the cardiovascular function in the rat by inhibiting sympathetic nerves activity when administered as intrave- nous (i.v.) bolus injection (Raasch et al., 2002; Schafer et al., 1999). In concordance with the above, we have shown in previous studies that agmatine, given as i.v. infusion, inhibits the tachycardic response http://dx.doi.org/10.1016/j.ejphar.2017.03.009 Received 6 December 2016; Received in revised form 16 February 2017; Accepted 10 March 2017 ⁎ Corresponding author. E-mail address: luis.cobos@uadec.edu.mx (L. Cobos-Puc). European Journal of Pharmacology xxx (xxxx) xxx–xxx 0014-2999/ © 2017 Elsevier B.V. All rights reserved. Please cite this article as: Cobos-Puc, L.E., European Journal of Pharmacology (2017), http://dx.doi.org/10.1016/j.ejphar.2017.03.009