1 2 Short communication 3 Rupatadine effectively prevents the histamine-induced up regulation 4 of histamine H 1 R and bradykinin B 2 R receptor gene expression in the 5 rat paw 6 Dimitra Molyva Q1 a , Konstantinos Kalokasidis a , Christos Poulios b , Hara Dedi a , 7 George Karkavelas b , Vassiliki Mirtsou a , Antonis Goulas a, * 8 a 1st Department of Pharmacology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece 9 b Department of Anatomic Pathology, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece 10 11 Introduction 12 Histamine H 1 receptor (H 1 R) plays a central role in early allergic 13 and inflammatory events as its activation is considered a main 14 cause of the increase in vascular permeability, a sine-qua-non for 15 oedema formation and cellular infiltration, characteristic of the 16 acute inflammatory response [1]. In addition, allergic pathology 17 has been associated with an increase in the gene expression of H 1 R, 18 as shown in a variety of experimental and clinical settings [2–4]. 19 In the rat paw, the intraplantar injection of histamine induces 20 the formation of considerable oedema which peaks at around 21 30 min to 1 h post-administration, an effect partially prevented by 22 loratadine, among other H 1 R antagonists [5,6]. Histamine-induced 23 paw oedema is generally considered not to be accompanied by 24 significant infiltration of inflammatory cells, but a few reports to 25 the opposite have been published in the past [7,8]. 26 Bradykinin is another potent vasodilator implicated in various 27 pathological situations involving increased vascular permeability, 28 most notably angioedema and allergic rhinitis [9]. Of the two 29 characterized bradykinin receptors, B 1 R is barely expressed in the 30 unstimulated rat paw while, on the other hand, B 2 R appears to be 31 constitutively expressed [10]. Cetirizine – an H 1 R antagonist – 32 has been shown in the past to attenuate the human cutaneous 33 vascular response to bradykinin [11] suggesting that histamine 34 may be involved in the regulation of bradykinin receptor gene Pharmacological Reports xxx (2014) xxx–xxx * Corresponding author. E-mail addresses: dmolyva@yahoo.com (D. Molyva), kkalokas@gmail.com (K. Kalokasidis), dr.poulios@hotmail.com (C. Poulios), chntenti@gmail.com (H. Dedi), gkarkav@med.auth.gr (G. Karkavelas), mirtsou@auth.gr (V. Mirtsou), goulas@med.auth.gr (A. Goulas). A R T I C L E I N F O Article history: Received 18 March 2014 Received in revised form 14 May 2014 Accepted 5 June 2014 Available online xxx Keywords: Histamine H1 receptor Bradykinin receptors Gene expression Rupatadine Rat paw A B S T R A C T Background: Activation of histamine H 1 receptor (H 1 R) is a well-known hallmark of allergic and inflammatory pathology. Both types of bradykinin receptors (B 1 R and B 2 R) are also known to contribute significantly to the latter and some sort of functional interaction between them and H 1 R has been alluded to in the past. Here we use an experimental model of rat paw oedema formation to examine the effect of exogenously added histamine on the gene expression of H 1 R and bradykinin receptors B 1 R and B 2 R, alone or in combination to rupatadine, a second generation antihistamine agent. Methods: Histamine-induced oedema formation was monitored with a plythesmometer. The gene Q2 expression of H 1 R, B 1 R and B 2 R was analyzed with both conventional and real-time PCR. Rupatadine fumarate was used in pure form and administered intraperitoneally, prior to histamine injection into the paw. Microscopy of haematoxylin and eosin-stained sections of paw tissue was used to examine effects on tissue architecture. Results: Histamine injection into the paw resulted in significant up regulation of H 1 R and B 2 R without inducing significant cellular infiltration, but appears to affect less the expression of B 1 R. Rupatadine was, under the conditions used in this study, very effective in preventing this effect and in suppressing oedema formation through its antihistamine action. Conclusion: Rupatadine has a suppressing effect on H 1 R and B 2 R gene expression which could add to its efficacy towards allergy and allergy-like conditions. ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences. G Model PHAREP 145 1–4 Please cite this article in press as: Molyva D, et al. Rupatadine effectively prevents the histamine-induced up regulation of histamine H 1 R and bradykinin B 2 R receptor gene expression in the rat paw. Pharmacol Rep (2014), http://dx.doi.org/10.1016/ j.pharep.2014.06.008 Contents lists available at ScienceDirect Pharmacological Reports jou r nal h o mep ag e: w ww .elsevier .co m /loc ate/p h arep http://dx.doi.org/10.1016/j.pharep.2014.06.008 1734-1140/ß 2014 Published by Elsevier Urban & Partner Sp. z o.o. on behalf of Institute of Pharmacology, Polish Academy of Sciences.