ELSEVIER Life Sciences, Vol. 60, No. 17, zyxwvutsrqponmlkj 1419-1430, 1997 pp. Copyright 0 1997 Ekvier Science Inc. Printed in the USA. All rights resaid 0024-3205/97 517.00 + IM zyxwvut PI1 SOO24-3205(97)00093-3 P2X-PURJNOCEPTORS IN THE HEART: ACTIONS OF ATP AND UTP Guglielmina Froldi, Katia Varania, Alessandro Chinellato, Eugenio Ragazzi, Laura Caparrotta and Pier Andrea Boreaa Department of Pharmacology, University of Padova, Largo E. Meneghetti 2,35 131 Padova, Italy. a Institute of Pharmacology, University of Ferrara, Via Fossato di Mortara 19,44 100 Ferrara, Italy (Received in final form January 23, 1997) Summary Positive inotropic effects of ATP and UTP (1pM - In&Q were studied in isolated rat and guinea pig cardiac tissues. The potency order obtained was ATPWTE’ in both species, suggesting possible interaction with P2X- purinoceptors. Binding studies using [3H]a$-methylene A’I’P as marker of P2X-purinoceptors revealed two receptor sites: one high-, the other low-affinity, in atria and ventricles from rat and guinea pig. Both ATP and UTP were found to bind high&inity sites of [3H]a,p- methylene ATP. The effects of various calcium inhibitors such as nifdipine, dantrolene, ryanodine and TMB-8 on positive inotropic effects induced by ATP and UTP were also studied. The results suggest that ATP and UTP may increase inotropism by interaction with PZX-purinoceptors by means of a calcium-dependent mechanism. Key Words: positive inotropism, ATP, UTP, P2X-purinoceptors, [3H]c@methylene ATP, Ca++-inhibitors Extracellular ATP induces various physiologic effects in several systems, including the cardiovascular apparatus. These effects are mediated by specific ATP receptors (P2-purinoceptors). Based on the rank order of agonist potencies of ATP analogues, four main subtypes of P2- purinoceptors have been reported: P2x, P2y, P2z and P2.r (l-2). In cardiovascular tissues, P2x and P5 are the purinoceptor subtypes generally accepted as responsible for the effects induced by ATP(3). P2x- and P2y-purinoceptors have been differentiated according to the selectivity of a$- methylene ATP (a&meATP) to P2x- and 2-methylthio ATP (2-MeSATP) to P2y-purinoceptors (1). a$-meATP is also used to desensitize P2x-purinoceptors selectively (1). The PZX-purinoceptor is a typical ligand-gated cation channel, whereas P2Y is coupled via G protein to ion channels or other intracellular second messengers (3). * Correspondence to: Dr. G. Froldi, Department of Pharmacology, University of Padova, Largo E. Meneghetti 2, I-35131 Padova, Italy. Tel.: +39-49-8275092; fax: +39-49-8275093; e-mail: mina@dfem.unipd.it