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NEUROPHARMACOLOGY
Laboratório de Farmacologia, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal
Received May 21, 2003; accepted July 10, 2003.
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Abstract |
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ATP. The P2Y antagonists reactive blue 2 (RB2) and 2-methylthioadenosine 5'-monophosphate (2-MeSAMP) increased, whereas the P2X antagonist pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulfonate) (PPNDS) decreased evoked tritium overflow. The inhibitory effect of 2-MeSATP was antagonized by RB2 (10 µM) and by 2-MeSAMP (10 µM) but not by the selective P2Y1 receptor antagonist 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate (MRS 2179; 10 µM). When, besides P1 receptors, inhibitory P2Y receptors were blocked with RB2, 
,
-methyleneadenosine 5'-triphosphate (,-meATP), ,
-imidoadenosine 5'-triphosphate (,-imidoATP), ,-methyleneadenosine 5'-triphosphate (,-meATP), 2-MeSATP, and ATP enhanced tritium overflow up to 140%, with the following order of potency: ,-meATP > 2-MeSATP = ATP = ,-meATP ,-imidoATP. The facilitatory effects of ,-MeATP and ,-imidoATP were prevented by PPNDS. Under the same conditions, apyrase attenuated, whereas the ectonucleotidase inhibitor 6-N,N-diethyl-D-,-dibromomethylene 5'-triphosphate enhanced tritium overflow, an effect that was prevented by PPNDS. In the prostatic portion of the rat vas deferens, endogenous ATP exerts a dual and opposite modulation of noradrenaline release: an inhibition through activation of P2Y receptors with a pharmacological profile similar to that of the P2Y12 and P2Y13 receptors and a facilitation through activation of P2X receptors with a pharmacological profile similar to that of P2X1 and P2X3, or PX2/P2X3 receptors.
; Westfall et al., 2002) but also as a presynaptic modulator (von Kügelgen et al., 1999). The released ATP exerts effects on nerve terminals and on postsynaptic cells, by activation of membrane receptors named P2 receptors. P2 receptors are a family of receptors that comprises two groups: ionotropic P2X receptors and metabotropic P2Y receptors (Ralevic and Burnstock, 1998). Seven subtypes of P2X subunits, named P2X1 to P2X7, have been identified at the molecular level, which by homo- or hetero-oligomeric assembly may form functional receptor channels (Torres et al., 1999). The P2Y receptor group currently includes the cloned mammalian receptors P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and the UDP-glucose receptor, now renamed P2Y14 (Ralevic and Burnstock, 1998; Abbracchio et al., 2003). The P2Y receptors can be grouped according to their sensitivity to purines and/or to pyrimidines into three functional groups: 1) P2Y1, P2Y12, and P2Y13, 2) selective pyrimidinoceptors (P2Y6), and 3) receptors with mixed selectivity (P2Y2, P2Y4, and P2Y11; von Kügelgen and Wetter, 2000; White et al., 2003).
In many sympathetic innervated tissues, adenine nucleotides such as ATP and its analogs have been shown to inhibit action potential-evoked release of noradrenaline by direct activation of presynaptic inhibitory P2Y receptors (von Kügelgen et al., 1999). In addition to presynaptic inhibitory P2Y receptors, sympathetic nerve terminals may also be endowed with excitatory P2 receptors. Cultured rat sympathetic neurons (Boehm, 1999; Nörenberg et al., 1999) and postganglionic sympathetic nerves that innervate the heart (Sperlágh et al., 2000; Sesti et al., 2002, 2003) express P2X receptors that are present on axon terminals and mediate an enhancement of noradrenaline release.
In rat vas deferens, a sympathetic innervated tissue, a P2 receptor-mediated inhibition of noradrenaline release has been demonstrated previously (Kurz et al., 1993). However, the receptor subtype involved has not been identified. Furthermore, immunohistochemical studies have shown that, in this tissue, P2X receptors are also present on nerve terminals (Vulchanova et al., 1996; Lee at al. 2000), but their putative involvement on modulation of noradrenaline release was never investigated.
Therefore, the aims of the present study were 1) to study the role of ATP on modulation of noradrenaline release, 2) to characterize pharmacologically the P2 receptor subtypes that mediate the inhibitory effects of ATP on noradrenaline release, and 3) to investigate whether P2X receptors also participate on the modulation of noradrenaline release in the rat vas deferens. In this study, only the prostatic portion of rat vas deferens was used because in this preparation the importance of ATP as transmitter is particularly relevant (Sneddon and Machaly, 1992).
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Materials and Methods |
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2-autoreceptors). Up to five identical periods of electrical stimulation were applied (Stimulator II; Hugo Sachs Elektronik, March-Hugstetten, Germany; constant current mode, rectangular pulses, 1-ms width, 50-mA current strength, and 18 V cm-1 voltage drop between electrodes). The first, starting at t = 30 min (S0) was not used for determination of tritium outflow. The subsequent periods (S1 to S4), also consisting of 100 pulses at 8 Hz, started at t = 60 min with 30-min intervals. Concentration-response curves for P2 receptor agonists were obtained by adding the agonists at increasing concentration 8 min before S2, S3, and S4 up to the end of each stimulation period. Concentration-response curves for P2 receptor antagonists were obtained by adding antagonists 20 min before S2,S3, and S4 at increasing concentrations. When indicated, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) (100 nM; to block adenosine A1 receptors), 4-(2[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)phenol (ZM 241385) (100 nM; to block adenosine A2 receptors), and RB2 (10 µM; to block P2Y receptors) were added throughout superfusion.
Data Evaluation. The outflow of tritium was expressed as fraction of the tissue tritium content at the onset of the respective collection period (fractional rate of outflow, minute-1). Effects of drugs on basal tritium outflow were estimated by the bn/b1 ratios and were expressed as percentage of the mean ratio obtained in the appropriate control; bn was the fractional rate of outflow in the 5-min period before S2, S3, and S4 (b2, b3, and b4, respectively), and b1 was the fractional rate of outflow in the 5-min period before S1. The overflow of tritium evoked by electrical stimulation was calculated as the difference between "total tritium outflow during the 10-min period after start of stimulation" and the estimated "basal outflow," being expressed as percentage of tritium content of the tissue at the onset of stimulation. Effects of drugs added after S1 on tritium overflow were evaluated as ratios of the overflow elicited by S2, S3, and S4 (Sn) and the overflow elicited by S1 (Sn/S1). Sn/S1 values obtained in individual experiments in which a test compound A was added after S1 were calculated as percentage of the respective mean ratio in the appropriate control group (solvent instead of A). When interaction of drug A, added after S1, and a drug B added either after S1 or at the beginning of superfusion, was studied, the "appropriate control" was a group in which B alone was used.
Drugs. Levo-[ring-2,5,6-3H]noradrenaline, specific activity 46.8 Ci mmol-1 was from DuPont-NEN (Garal, Lisboa, Portugal); ADP, ATP, apyrase grade VI (EC 3.6.1.5
[EC]
), DPCPX, desipramine hydrochloride, 2-MeSADP, 2-MeSAMP, 2-MeSATP, ,-imidoATP, ,-meATP, ,-meATP, suramin hexasodium, RB2 (basilen blue E-3G), and yohimbine hydrochloride were from Sigma (Sintra, Portugal); ZM 241385, 8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalene-trisulfonic acid hexasodium (NF 279), 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate tetrammonium (MRS 2179), 6-N,N-diethyl-D-,-dibromomethylene 5'-triphosphate triammonium (ARL 67156), pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid tetrasodium (PPADS), and PPNDS were from Tocris (Bristol, UK). Stock solutions up to 10 mM were made in dimethyl sulfoxide or water and kept at -20°C. Solutions of drugs were prepared immediately before use and solvent was added to the superfusion medium in parallel control experiments.
Statistical Analysis. Results are presented as means ± S.E.M.; n is the number of tissue preparations. Effect of drugs on basal tritium outflow and evoked tritium overflow was tested for significance by an analysis of variance followed by the Dunnett's multiple comparison test. P values lower than 0.05 were taken to indicate significant differences.
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Results |
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) and with the adenosine A2A receptor antagonist ZM 241385 (Poucher et al., 1995) did not change either basal tritium outflow or evoked tritium overflow. When, in addition to P1 antagonists, the P2Y antagonist RB2 (10 µM) was added throughout superfusion, basal tritium outflow and evoked tritium overflow were increased (Table 1). Basal tritium outflow and evoked tritium overflow remained constant throughout the experiment, regardless of the drugs added throughout superfusion, with bn/b1 and Sn/S1 values close to unity (not shown). Basal tritium outflow was not changed by drugs added after S1, except by the P2 antagonists PPADS, PPNDS, and RB2 (see below).
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Influence of P2 Receptor Agonists on Tritium Overflow. Electrical stimulation of prostatic portion of rat vas deferens by 100 pulses/8 Hz caused an overflow of tritium that was modified by several purine nucleotides. The nucleotides were tested in the presence of the P1 antagonists DPCPX (100 nM; to block adenosine A1 receptors) and ZM 241385 (100 nM; to block adenosine A2 receptors), to avoid contribution of these receptors to the effects of nucleotides. Under these conditions, ,-meATP and ,-meATP slightly increased, ,-imidoATP did not change, whereas 2-Me-SATP, 2-MeSADP, ADP, and ATP decreased evoked tritium overflow in a concentration-dependent manner (Fig. 1). Adenosine (1 mM) only caused a small decrease of evoked tritium overflow (S2/S1 = 87 ± 3%; n = 4; P < 0.05). The apparent order of potency of nucleotides that decreased evoked tritium overflow was: 2-MeSATP > 2-MeSADP > ADP ATP. As shown in Fig. 2, the effect of 2-MeSATP was prevented by the nonselective P2Y antagonist RB2 (10 µM) and by the P2Y12 and P2Y13 antagonist 2-MeSAMP (10 µM; Hollopeter et al., 2001; Zhang et al., 2002) but not by the selective P2Y1 antagonist MRS 2179 (10 µM; Boyer et al., 1998).
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Influence of P2 Receptor Agonists on Tritium Overflow, in the Presence of RB2. The results obtained with nucleotides suggest that, in addition to inhibitory P2Y receptors, facilitatory P2 receptors may also be involved on the modulation of tritium overflow. Because there are no selective agonists for each of the P2 receptors, the effects of nucleotides were reevaluated in the presence of 10 µM RB2 (added at beginning of superfusion and kept throughout) to block inhibitory P2Y receptors.
When inhibitory P2Y receptors were blocked, ,-meATP, ,-meATP, 2-MeSATP, ,-imidoATP, and ATP, but not 2-MeSADP, caused a concentration-dependent increase on evoked tritium overflow (Fig. 3). The apparent order of potency of nucleotides that caused a facilitation of evoked tritium overflow was ,-meATP > 2-MeSATP = ATP = ,-meATP ,-imidoATP.
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The facilitatory effects of ,-meATP and ,-imidoATP were prevented by the P2X antagonist PPNDS (3 µM; Lambrecht, 2000; Fig. 4), suggesting an involvement of facilitatory P2X receptors on the modulation of evoked tritium overflow.
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Influence of P2 Receptor Antagonists on Tritium Overflow. The effect of several P2 antagonists on evoked tritium overflow was also tested to investigate whether the ATP released was tonically activating the P2 receptors under the stimulation conditions used.
The P2 antagonists suramin and RB2 (3-30 µM) caused a concentration-dependent increase on evoked tritium overflow, whereas PPADS, PPNDS, and RB2 (100 and 300 µM) caused a concentration-dependent decrease on the evoked tritium overflow (Table 2). They also decreased basal tritium outflow: PPADS (3-30 µM) up to 22 ± 2% (n = 9; P < 0.01), PPNDS (1-10 µM) up to 37 ± 5% (n = 6; P < 0.01), and RB2 (30-100 µM) up to 51 ± 3% (n = 6; P < 0.01). The effects of RB2 and PPNDS on evoked tritium overflow were not changed when P1 receptors were blocked (100 nM DPCPX plus 100 nM ZM 241385), excluding a major contribution of endogenous adenosine to the effects of P2 antagonists (Fig. 5). Furthermore, the selective P2X1 antagonist NF 279 (Damer et al., 1998) decreased evoked tritium overflow, although much less than PPNDS, and the P2Y12 and PY13 antagonist 2-MeSAMP increased, whereas the selective P2Y1 antagonist MRS 2179 had no effect on tritium overflow (Fig. 5).
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Influence of Apyrase and ARL 67156 on Tritium Overflow. To confirm that the decrease on evoked tritium overflow caused by the more selective P2X antagonists PPNDS and PPADS (Lambrecht 2000) was due to blockade of a facilitation of noradrenaline release mediated by endogenous ATP, the effect of apyrase (an enzyme that metabolizes ATP; Zimmermann, 1999) and of the ectonucleotidase inhibitor ARL 67156 (Crack et al., 1995) was investigated. Apyrase and ARL 67156 were tested in the presence of DPCPX (100 nM), ZM 241385 (100 nM), and RB2 (10 µM; the concentration that prevented the inhibitory effect of 2-Me-SATP and caused a concentration-dependent increase on tritium overflow; Figs. 2 and 5), to remove the influence of P1 receptors and inhibitory P2Y receptors, respectively. Apyrase (5 U/ml) decreased, whereas ARL 67156 (50 µM) increased evoked tritium overflow (Fig. 6). The facilitatory effect of ARL 67156 was prevented by PPNDS (3 µM; Fig. 6), supporting the observation that endogenous ATP may increase evoked tritium overflow by activation of facilitatory P2X receptors.
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Discussion |
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), noradrenaline release was inhibited by ATP and by other nucleotides such as 2-MeSATP and enhanced by the P2 antagonists suramin and RB2. It is unlikely that effects of ATP and other nucleotides tested on noradrenaline release are due to adenosine because they were still observed in the presence of the P1 antagonists DPCPX and ZM 241385 (Fig. 1). Therefore, changes in tritium overflow caused by nucleotides and P2 antagonists are, most likely, mediated by prejunctional P2 receptors, with the inhibitory effects being mediated by prejunctional P2Y receptors.
Inhibitory P2Y Receptors. From the P2Y receptors already cloned, only the P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14 subtypes have been shown to occur in mammalian tissues (Ralevic and Burnstock, 1998; Abbracchio et al., 2003). Involvement of P2Y2, P2Y4, P2Y6, and P2Y11 subtypes on the inhibition of noradrenaline release may be excluded by the following reasons: 1) P2Y2 is only weakly activated by 2-MeSATP, 2-MeSADP, and ADP (Nicholas et al., 1996), nucleotides that caused a marked inhibition of noradrenaline release; 2) P2Y4 is insensitive to suramin (Charlton et al., 1996), an antagonist that caused a facilitation of noradrenaline release in the present study, possibly by preventing a tonic activation of inhibitory P2Y receptors; 3) P2Y6 is selective for uridine nucleotides, is very weakly activated by 2-MeSATP, and is not activated by ATP and ADP (Nicholas et al., 1996), whereas, in the present study, 2-MeSATP was the most potent compound at the inhibitory P2 receptors; and 4) the P2Y11 is sensitive to suramin and RB2 but is not activated by ADP (Communi et al., 1997, 1999) that, in the present study, caused a concentration-dependent inhibition of noradrenaline release.
The P2Y1, P2Y12, and P2Y13 subtypes are receptors with a very similar agonist profile. The order of potency of nucleotides that activate these receptors is 2-MeSADP 2-MeSATP > ADP ATP (Boyer et al., 1996; Hollopeter et al., 2001; Zhang et al., 2002). This agonist profile is very similar to that observed for inhibitory P2Y receptors in the present study: 2-MeSATP > 2-MeSADP > ADP ATP. Therefore, P2Y1, P2Y12, and P2Y13 subtypes are the most serious candidates to mediate that inhibition of noradrenaline release.
P2Y1 receptors are blocked by MRS 2179, which is selective for this receptor subtype (Boyer et al., 1998) and also by RB2, suramin, and PPADS, with similar potencies (Boyer et al., 1994). Furthermore, it has been shown that P2Y1 receptors can close N-type Ca2+ channels in neurons (Filippov et al., 2000), a mechanism that may explain the inhibitory effect of nucleotides on transmitter release. The lack of antagonism by MRS 2179 of inhibitory effects caused by 2-MeSATP, combined with the observation that, per se, MRS 2179 did not change noradrenaline release, whereas PPADS decreased noradrenaline release, exclude the involvement of P2Y1 receptors on inhibition of noradrenaline release in the prostatic portion of the rat vas deferens. Furthermore, the observation that nucleotides, such as 2-MeSATP and 2-Me-SADP, decreased noradrenaline release even in the presence of the adenosine A1-receptor antagonist DPCPX (at a concentration that is about 200 times higher than its affinity constant at the adenosine A1 receptor; Lohse et al., 1987) excludes the involvement of the recently described heteromers of P2Y1 and adenosine A1 receptors (Yoshioka et al., 2001) or the P3 receptor (Forsyth et al., 1991) on the inhibition of noradrenaline release caused by these nucleotides.
P2Y12 and P2Y13 subtypes are both blocked by 2-Me-SAMP, with similar potency (Hollopeter at 2001; Zhang et al., 2002). Because 2-MeSAMP prevented the inhibitory effects of 2-MeSATP, the PY12 and/or the P2Y13 receptor subtypes are the strongest candidates to mediate an inhibition of noradrenaline release in the prostatic portion of rat vas deferens. Contribution of P2Y12 receptors can be questioned because ATP is an antagonist at P2Y12 receptors (Hollopeter et al., 2001). However, the involvement of the P2Y12 receptors cannot be completely excluded because there is the possibility that ATP may be partly metabolized to ADP that is an agonist at these receptors.
Participation of P2Y13 receptors, and eventually P2Y12 receptors, on modulation of noradrenaline release is compatible with their known distribution and coupling system. P2Y13 receptors are widely expressed (Zhang et al., 2002) and like P2Y12 receptors, are negatively coupled to adenylate cyclase through activation of a Gi/o protein (Hollopeter et al., 2001; Kublick and von Kügelgen, 2002; Zhang et al., 2002). Recently, several studies have shown that P2Y12- and PY13-like receptors may mediate an inhibition of neuronal Ca2+ channels (Powell et al., 2000; Kulick and von Kügelgen, 2002; Unterberger et al., 2002; Kubista et al., 2003). This signaling pathway is also activated by other presynaptic receptors that inhibit transmitter release (Boehm and Kubista, 2002).
Facilitatory P2X Receptors. Our results also show that some purine nucleotides including ATP may also enhance noradrenaline release in the prostatic portion of rat vas deferens. This conclusion is supported by the observation that nucleotides, such as ,-meATP, increased noradrenaline release, even when inhibitory P2Y receptors were blocked, and by the observation that the PX antagonists PPADS, PPNDS, and NF 279 decreased noradrenaline release, an effect that is most likely due to an attenuation of a release-enhancing effect of endogenous ATP. Evidence that endogenous ATP was activating facilitatory P2 receptors was obtained by changing the levels of endogenous ATP under conditions of low influence of inhibitory P2Y receptors. The ATP-metabolizing enzyme apyrase decreased noradrenaline release, most likely by preventing the release enhancing effects of endogenous ATP, whereas the ecto-ATPase inhibitor ARL 67156, which prevents ATP degradation, increased noradrenaline release, most likely by favoring the release-enhancing effects of endogenous ATP.
P2Y11 receptors can couple to intracellular pathways that may lead to a facilitation of transmitter release (Communi et al., 1997) and can be activated by ,-meATP (van der Weyden et al., 2000), but their involvement on the facilitation of noradrenaline release is unlikely because they are blocked by RB2 but not by PPADS (Communi et al., 1999; van der Weyden et al., 2000). Therefore, the P2 receptors that mediate facilitation of noradrenaline release seem to belong to the P2X receptor subtype, as observed in other sympathetic sympathetic innervated tissues (Sperlágh et al., 2000; Sesti et al., 2003, 2003) and in cultured sympathetic neurons (Boehm, 1999).
From all functional P2X receptors known, homomeric P2X1 or P2X3 receptors and heteromeric receptors composed of P2X2/P2X3, P2X1/P2X5, and P2X4/P2X6 subunits are activated by ,-meATP (Nörenberg and Illes, 2000). Immunohistochemical studies have shown that only the P2X1, P2X2, and P2X3 subunits are expressed in rat vas deferens (Lee et al., 2000) and that some of them, namely, the P2X2 and P2X3 subunits, are found on nerves fibers and nerve terminals (Vulchanova et al., 1996; Lee et al., 2000).
The antagonist profile of facilitatory P2 receptors that modulate noradrenaline release is similar to that described for homomeric P2X1 or P2X3 receptors and for heteromeric P2X2/P2X3 receptors (Lambrecht, 2000). The agonist profile observed, ,-meATP > 2-MeSATP = ATP = ,-meATP ,-imidoATP, is slightly different from that described for homomeric P2X1 or P2X3 receptors and heteromeric P2X2/P2X3 receptors (2-MeSATP ATP > ,-meATP; Nörenberg and Illes, 2000). This discrepancy may not indicate the presence of a different P2X receptor subtype but be just a consequence of the coexistence of P2Y and P2X receptors that are activated by the same nucleotides; 2-MeSATP may also activate inhibitory receptors disturbing a clear definition of the order of potency of agonists at facilitatory P2X receptors.
In conclusion, endogenous ATP exerts a dual and opposite modulation of noradrenaline release in the prostatic portion of the rat vas deferens: an inhibition through activation of P2Y receptors with a pharmacological profile similar to that of the recently cloned P2Y12 and/or P2Y13 subtypes and a facilitation through activation of P2X receptors that have a pharmacological profile similar to that of homomeric P2X1 and P2X3 or heteromeric P2X2/P2X3 receptors.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: 2-MeSATP, 2-methylthioadenosine-5'-triphosphate; 2-MeSADP, 2-methylthioadenosine-5'-diphosphate; RB2, reactive blue 2; 2-MeSAMP, 2-methylthioadenosine 5'-monophosphate; MRS 2179, 2'-deoxy-N6-methyladenosine 3',5'-bisphosphate; ,-meATP, ,-methyleneadenosine 5'-triphosphate; ,-imidoATP, ,-imidoadenosine 5'-triphosphate; ,-meATP, ,-methyleneadenosine 5'-triphosphate; PPNDS, pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4',8'-disulphonate); DPCPX, 8-cyclopentyl-1,3-dipropylxanthine; ZM 241385, 4-(2[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3-a][1,3,5]triazin-5-ylamino]ethyl)-phenol; NF 279, 8,8'-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid; ARL 67156, 6-N,N-diethyl-D-,-dibromomethylene 5'-triphosphate; PPADS, pyridoxalphosphate-6-azophenyl-2',4'-disulfonic acid.
Address correspondence to: Dr. Jorge Gonçalves, Laboratório de Farmacologia, Faculdade de Farmácia, Universidade do Porto, Rua Aníbal Cunha, 164, 4050-047 Porto, Portugal. E-mail: jorge.goncalves{at}ff.up.pt
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