Prejunctional Purinoceptors Research Articles

Pharmacology and Physiology of Perivascular Nerves Regulating Vascular Function: Purinergic Modulation of Vascular Sympathetic Neurotransmission

It is generally agreed that the release of norepinephrine (NE) is inhibited by activation of prejunctional purinoceptor. We examined the pharmacological properties of purinoceptors on vascular sympathetic nerve terminals and the source of endogenous adenyl purines. Electrically (1 Hz) evoked NE-release was inhibited by not only P1-agonists but also P2-agonists. Although the inhibition induced by P2-agonists was blocked by P1-antagonists, P2-agonists-induced inhibition was not due to the breakdown to adenosine. Therefore, there may be a new class of purinoceptor that is activated by both P1- and P2-agonists and antagonized by P1-antagonists. Electrical stimulation at 8 Hz but not at 1 Hz evoked the release of adenyl purines such as ATP, ADP, AMP and adenosine, in addition to NE; and the purines-release was blocked by an alpha1-antagonist. Methoxamine, an alpha1-agonist, also evoked the release of purines. Electrically (1 Hz)-evoked NE-release was inhibited by methoxamine, and this inhibition was blocked by not only an alpha1-antagonist but also a P1-antagonist. Therefore, the activation of alpha1-adrenoceptor appeared to release purines, which in turn inhibited NE-release via prejunctional purinoceptors. From these results, it is suggested that the unique purinoceptor and the endogenous purines released from alpha1-adrenoceptor-sensitive sources participate in the antidromic transsynaptic modulation of vascular sympathetic neurotransmission.

Effect of 9-(6,7-dideoxy-beta-D-allo-hept-5-ynofuranosyl)adenine on noradrenaline release from vascular sympathetic nerves.

1. The effects of 9-(6,7-dideoxy-beta-D-allo-hept-5-ynofuranosyl)adenine (HAK2701), a selective and potent ligand for P3 receptor-like protein, on the release of endogenous noradrenaline (NA) from electrically stimulated rat mesenteric artery and rabbit ear artery were compared with those of a number of purinoceptor agonists. 2. In the rat mesenteric artery, the P1 receptor agonists 2-chloroadenosine (2CA) and 5'-N-ethylcarboxamidoadenosine (NECA) and the P2 purinoceptor agonists beta,gamma-methylene ATP (betagammamATP) and 2-methylthio ATP (2mSATP) significantly inhibited the release of NA in a xanthine-sensitive manner. HAK2701 did not significantly inhibit the release of NA, the relative order of potency being betagammamATP > NECA > 2CA > 2mSATP >> HAK2701. 3. In the rabbit ear artery, both P1 and P2 receptor agonists significantly facilitated the release of NA in a xanthine-sensitive manner. HAK2701 also significantly facilitated the release of NA, the relative order of potency being HAK2701 > betagammamATP > 2CA > 2mSATP > NECA. 4. These findings suggest that HAK2701 may be a potent and selective agonist for facilitatory prejunctional purinoceptors, but not for inhibitory purinoceptors, on adrenergic nerve terminals.

Characterization of Prejunctional Purinoceptors Inhibiting Noradrenaline Release in Rat Mesenteric Arteries

The effects of purinoceptor agonists on noradrenaline NA release by electrical stimulation in rat mesenteric arteries were examined to clarify the pharmacological properties of prejunctional purinoceptors on adrenergic nerves. Adenosine and the other P1-receptor agonists, 5′-(N-ethylcarboxamido) adenosine and 2-chloroadenosine, significantly inhibited the release of NA. Also β, γ-methylene ATP and 2-methylthio ATP, P2-receptor agonists, significantly inhibited NA releases. The inhibitory effect of adenosine was significantly reduced by adenosine deaminase, but those of β, γ-methylene ATP and 2-methylthio ATP were not affected. This suggests that the inhibitory effects of P2-receptor agonists are not due to conversion into adenosine. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a Pi (Ai)-receptor antagonist, significantly reduced the inhibitory effects of not only the P1- but also P2-receptor agonists. Therefore, DPCPX appears to act on both prejunctional P1- and P2-receptor as an antagonist. Pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS), a P2-receptor antagonist, significantly reduced the inhibitory effects of the P2-receptor agonists, but not those of the P1-receptor agonists. From these findings in the rat mesenteric artery, the Pi -receptor agonist-induced inhibition of NA-release appears to be mediated via a well-known prejunc-tional P1-receptor of the Ai-subtype, but the P2-receptor agonist-induced inhibition appears to be mediated via an unidentified purinoceptor that is blocked not only by P2-receptor antagonists but also by P1-receptor antagonists.

Involvement of vanilloid receptors and purinoceptors in the Phoneutria nigriventer spider venom-induced plasma extravasation in rat skin

Phoneutria nigriventer venom causes stimulation of capsaicin-sensitive primary afferent neurons in the rat dorsal skin, leading to neurogenic plasma protein extravasation due to the release of tachykinin NK 1 receptor agonist. In this study we further investigated the mechanisms involved in the venom-induced activation of capsaicin-sensitive primary afferent neurons. The plasma extravasation in response to venom intradermally injected was measured in Wistar rats as the local accumulation of i.v. injected 125I-labelled human serum albumin into skin sites. The tachykinin NK 1 receptor agonist, d-Ala-[ l-Pro 9,Me-Leu 8]substance P-(7–11) (GR73632; 10–100 pmol/site), induced a significant plasma leakage that was abolished by the selective tachykinin NK 1 receptor antagonist, ( S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane chloride (SR140333; 1 nmol/site), whereas the leakage after venom (1–10 μg/site) was significantly inhibited (but not abolished) by SR140333. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8–37), failed to further reduce the residual plasma extravasation induced by venom plus SR140333. The μ-opioid receptor agonist, [ d-Ala 2,Me-Phe 4,Gly-ol 5]enkephalin (DAMGO), and the local anaesthetic, lignocaine, had no effect on the venom-induced plasma extravasation. Similarly, the L-, N- and P/Q-type voltage-sensitive Ca 2+ channel blockers (verapamil, ω-conotoxin MVIIA and MVIIC, respectively) as well as the Na + channel blockers, tetrodotoxin and carbamazepine, had no effect on the venom-induced effect. Neither the systemic treatment nor the local injection of ruthenium red prevented the venom-induced plasma extravasation. However, the vanilloid receptor antagonist, N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2 H-2-benzazepine-2-carbothioamide (capsazepine; 120 μmol/kg, i.v.), reduced by 48% ( P<0.05) the venom (10 μg/site)-induced plasma extravasation. A significant inhibitory effect was also observed with the P 2 purinoceptor agonists, adenosine 5′-triphosphate (ATP; 10 and 30 nmol/site) and adenosine 5′-diphosphate (ADP; 10 nmol/site). The involvement of histamine and/or 5-hydroxytryptamine (5-HT) in the venom-induced plasma extravasation was ruled out since neither histamine and 5-HT receptor antagonists nor depletion of mast cells by compound 48/80 affected the venom response. This was further supported by the failure of venom to degranulate in vitro peritoneal mast cells. In conclusion, only vanilloid receptors and P 2 prejunctional purinoceptors had an inhibitory effect on the neurogenic plasma extravasation evoked by P. nigriventer venom in rat dorsal skin.

Discrimination of prejunctional purinoceptors on adrenergic nerves in rabbit ear artery

Discrimination of prejunctional purinoceptors on adrenergic nerves in rabbit ear artery

Participation of cAMP in the facilitatory action of β,γ-Methylene ATP on the noradrenaline release from rabbit ear artery

β,γ-Methylene ATP (βγ-mATP) significantly facilitated the electrically (4 Hz) evoked release of noradrenaline (NA) from the rabbit ear artery by activation of prejunctional purinoceptors on the sympathetic nerve terminals. In the present study, we investigated whether intracellular cAMP is involved in the purinoceptor mediated facilitatory mechanisms. Forskolin, an adenylate cyclase activator, and 8-bromo cAMP, a cAMP analogue, significantly enhanced the NA-release. The enhancement of NA-release by βγ-mATP was significantly potentiated by Ro20-1724, a phosphodiesterase inhibitor, but abolished by SQ22536, an adenylate cyclase inhibitor. Both drugs alone had no effect on the NA-release. N-ethylmaleimide and pertussis toxin, inhibitors of G i-proteins, did not affect the NA-release, or the enhancement of NA-release by βγ-mATP. Alone Cholera toxin (CTX), an activator of G s-proteins, significantly increased the NA-release, but in the presence of CTX, βγ-mATP could not produce further enhancement of the NA-release. These results suggest that cAMP is closely associated with the facilitatory action of βγ-mATP on NA-release in the rabbit ear artery.

ChemInform Abstract: Characterization of the Facilitatory Modulation of Adrenergic Neurotransmission via Prejunctional Purinoceptors in Rabbit Ear Artery

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P–79 - Characterization of prejunctional purinoceptors on adrenergic nerves in the rat mesenteric artery

P–79 - Characterization of prejunctional purinoceptors on adrenergic nerves in the rat mesenteric artery

Reduction of voltage-dependent Mg 2+ block of NMDA receptor response by neuronal injury

Phoneutria nigriventer venom causes stimulation of capsaicin-sensitive primary afferent neurons in the rat dorsal skin, leading to neurogenic plasma protein extravasation due to the release of tachykinin NK1 receptor agonist. In this study we further investigated the mechanisms involved in the venom-induced activation of capsaicin-sensitive primary afferent neurons. The plasma extravasation in response to venom intradermally injected was measured in Wistar rats as the local accumulation of i.v. injected 125I-labelled human serum albumin into skin sites. The tachykinin NK1 receptor agonist, d-Ala-[l-Pro9,Me-Leu8]substance P-(7–11) (GR73632; 10–100 pmol/site), induced a significant plasma leakage that was abolished by the selective tachykinin NK1 receptor antagonist, (S)-1-[2-[3-(3,4-dichlorphenyl)-1 (3-isopropoxyphenylacetyl) piperidin-3-yl] ethyl]-4-phenyl-1 azaniabicyclo [2.2.2]octane chloride (SR140333; 1 nmol/site), whereas the leakage after venom (1–10 μg/site) was significantly inhibited (but not abolished) by SR140333. The calcitonin gene-related peptide (CGRP) receptor antagonist, CGRP-(8–37), failed to further reduce the residual plasma extravasation induced by venom plus SR140333. The μ-opioid receptor agonist, [d-Ala2,Me-Phe4,Gly-ol5]enkephalin (DAMGO), and the local anaesthetic, lignocaine, had no effect on the venom-induced plasma extravasation. Similarly, the L-, N- and P/Q-type voltage-sensitive Ca2+ channel blockers (verapamil, ω-conotoxin MVIIA and MVIIC, respectively) as well as the Na+ channel blockers, tetrodotoxin and carbamazepine, had no effect on the venom-induced effect. Neither the systemic treatment nor the local injection of ruthenium red prevented the venom-induced plasma extravasation. However, the vanilloid receptor antagonist, N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2H-2-benzazepine-2-carbothioamide (capsazepine; 120 μmol/kg, i.v.), reduced by 48% (P<0.05) the venom (10 μg/site)-induced plasma extravasation. A significant inhibitory effect was also observed with the P2 purinoceptor agonists, adenosine 5′-triphosphate (ATP; 10 and 30 nmol/site) and adenosine 5′-diphosphate (ADP; 10 nmol/site). The involvement of histamine and/or 5-hydroxytryptamine (5-HT) in the venom-induced plasma extravasation was ruled out since neither histamine and 5-HT receptor antagonists nor depletion of mast cells by compound 48/80 affected the venom response. This was further supported by the failure of venom to degranulate in vitro peritoneal mast cells. In conclusion, only vanilloid receptors and P2 prejunctional purinoceptors had an inhibitory effect on the neurogenic plasma extravasation evoked by P. nigriventer venom in rat dorsal skin.

Effect of 8-sulfophenyl theophylline on endogenous noradrenaline release from sympathetic nerves of the rabbit ear artery.

1. The release of endogenous noradrenaline (NA) and adenyl purine (ATP, ADP, AMP and adenosine) from the rabbit ear artery, evoked by electrical stimulation (ES; 16 Hz), was examined. 2. ES evoked a significant release of NA and purine; the ratio of the amount of total purine released to NA released was approximately 180 on a molar base. 3. ES-evoked purine release was significantly reduced by the denudation of the endothelium and abolished by the alpha 1-adrenoceptor antagonist, prazosin (1 mumol/L). 4. ES-evoked NA release was significantly reduced by a P1-purinoceptor antagonist, 8-sulfophenyl theophylline (8SPT). Purine release was slightly reduced by 8SPT. 5. These results suggest that endogenous NA released by ES results in the release of a large amount of purine, which may, in turn, increase the release of NA by acting on prejunctional purinoceptors on sympathetic nerve terminals.

S24-1 - Facilitatory modulation of adrenergic neurotransmission via prejunctional purinoceptors in rabbit ear artery.

S24-1 - Facilitatory modulation of adrenergic neurotransmission via prejunctional purinoceptors in rabbit ear artery.

Effect of methoxamine on noradrenaline release in the caudal artery of hypertensive rats.

1. The effect of methoxamine, an alpha1-adrenoceptor agonist, on the overflow of endogenous noradrenaline (NA) was examined in the electrically field stimulated (EFS) caudal artery obtained from Wistar rats, Wistar-Kyoto rats (WKY) and age-matched spontaneously hypertensive rats (SHR). 2. Methoxamine inhibited the EFS-evoked release of endogenous NA in the arteries from Wistar rats and WKY, but not in the arteries of SHR. 2-chloroadenosine, a purinoceptor agonist, also inhibited the NA release in the arteries from normotensive rats but not in the arteries of SHR. 3. The inhibitory effect of methoxamine was blocked by adenosine deaminase and potentiated by adenosine uptake inhibitor, dipyridamole. 4. Methoxamine caused the release of adenine nucleotides and adenosine from the caudal arteries of WKY and SHR. 5. These suggest that the inhibitory effect of methoxamine on NA release is mediated by endogenous adenyl purines and that the failure of methoxamine to inhibit NA release in the caudal artery of SHR is due to a dysfunction of the prejunctional purinoceptors on sympathetic nerve terminals.

Prejunctional autoinhibition of purinergic transmission in circular muscle of guinea-pig ileum; a mechanism distinct from P 1-purinoceptor activation

The role of prejunctional purinoceptors (P 1-subtype) in the control of ATP-release from inhibitory motoneurons was investigated electrophysiologically, by studying fast purinergic inhibitory junction potentials (IJPs) in guinea-pig ileal circular muscle. Pressure ejections of adenosine and ATP (but not of α, β-methylene ATP) onto circular muscle depressed the amplitude of fast IJPs, indicating the presence of prejunctional P 1-purinoceptors. An adenosine (A 1/2)-receptor antagonist, theophylline (10 −8–10 −4 M), increased the amplitude of fast IJPs in a dose-related manner (EC 50 − 17.5 μM), suggesting the existence of a basal ‘adenosine tone’ that regulated ATP-release from ileal motoneurons. However, three methylxanthine derivatives, caffeine (10 −8–10 −4 M), 3-isobutyl-1-methylxanthine (IBMX; 10 −8–10 −4 M) and the potent A 1-receptor antagonist 1,3-dipropyl-8-(2-amino-4-chlorophenyl)-xanthine (DPCPX; 10 −8–10 −4 M), failed to potentiate fast IJPs and placed in doubt the existence of this inhibitory adenosine tone. Caffeine and IBMX, but not DCPCX, hyperpolarised ileal circular muscle in a dose-related manner and reduced IJP-amplitude; DPCPX did not alter the amplitude of IJPs. The non-specific inhibitor of phosphodiesterases, Ro-20-1724 (5 × 10 −7–5 × 10 −5 M), increased the amplitude of fast. IJPs, mimicking the actions of theophylline. To this extent, facilitation of inhibitory transmission appeared to involve phosphodiesterase inhibition and modification of intra-axonal cAMP levels and phosphorylation of intra-axonal protein kinases. The phenomenon of IJP rundown, presumed to be a manifestation of prejunctional autoinhibition, was studied using theophylline and DPCPX as A 1-receptor antagonists. Theophylline enhanced the extent of IJP rundown, while the more potent A 1-antagonist DPCPX was inactive, suggesting that IJP-rundown did not involve P 1/A 1-receptors. It was concluded that P 1-purinoceptors do not play a significant role in the regulation of evoked ATP-release, at least at low stimulus rates of less than 2 Hz, although P 1 purinoceptors were present on motoneurons. Instead, there appears to be another mechanism, regulated by intra-axonal phosphodiesterases and involving cAMP, that controls ATP-release from ileal motoneurons.

Prejunctional modulation of noradrenaline release in mouse and rat vas deferens: contribution of P1- and P2-purinoceptors.

1. Prejunctional purinoceptors modulating the release of noradrenaline were compared in mouse and rat vas deferens. Tissue slices were preincubated with [3H]-noradrenaline and then superfused and stimulated electrically, in most experiments by trains of 60 pulses, 1 Hz. 2. In mouse vas deferens, 2-chloroadenosine (IC50 0.24 microM), beta,gamma-methylene-ATP (IC50 3.8 microM), alpha,beta-methylene-ATP (IC50 2.9 microM) and 2-methylthio-ATP (only 30 microM tested) reduced the evoked overflow of tritium. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX), 10 nM, antagonized the effect of 2-chloro-adenosine (apparent pKB 10.2) as well as of beta,gamma-methylene-ATP (apparent pKB 9.6) and alpha,beta-methylene-ATP. Suramin, 300 microM, attenuated the effect of 2-chloroadenosine at best very slightly, antagonized the effect of beta,gamma-methylene-ATP (apparent pKB 4.5) and, when combined with DPCPX 10 nM, caused a further marked shift to the right of the concentration-response curve of beta,gamma-methylene-ATP beyond the shift produced by DPCPX alone. 3. In rat vas deferens, 2-chloroadenosine (IC50 0.20 microM), beta,gamma-methylene-ATP (IC50 4.8 microM), alpha,beta-methylene-ATP (IC50 3.0 microM) and 2-methylthio-ATP (only 30 microM tested) also reduced the evoked overflow of tritium. DPCPX, 10 nM, antagonized the effect of 2-chloroadenosine (apparent pKB 9.7) as well as of beta,gamma-methylene-ATP (apparent pKB 9.6) and alpha,beta-methylene-ATP. Suramin, 300 microM, did not change the effect of 2-chloroadenosine, attenuated the effect of beta,gamma-methylene-ATP at best very slightly and, when combined with DPCPX, caused at best a very small shift to the right of the concentration-response curve of beta,gamma-methylene-ATP beyond the shift produced by DPCPX alone.4. It is concluded that prejunctional purinoceptor mechanisms in mouse and rat vas deferens are similar. In either species, both nucleosides such as adenosine and nucleotides such as beta,gamma-methylene-ATP activate a common release-inhibiting receptor which is a Pl- or, more specifically, A1-purinoceptor.There seems to be no need to postulate the existence of a novel prejunctional P3-purinoceptor.Moreover, the sympathetic terminal axons possess an additional P2-purinoceptor in both species which is activated by some nucleotides such as beta,gamma-methylene-ATP and 2-methylthio-ATP, although the activation of the P2-purinoceptor by beta,gamma-methylene-ATP is difficult to demonstrate in the rat.

Methoxamine enhances the release of endogenous noradrenaline from rabbit ear artery: possible involvement of ATP.

The effect of methoxamine, an alpha 1-adrenoceptor agonist, on the electrically-evoked release of endogenous noradrenaline was examined in the isolated rabbit ear artery. Noradrenaline was quantified by high performance liquid chromatography-electrochemical detection. The release of adenine nucleotides and nucleosides by methoxamine was examined using high performance liquid chromatography-fluorescence detection. The release of noradrenaline evoked by electrical field stimulation (EFS) at 4 Hz was reduced by tetrodotoxin 0.3 mumol/l and clonidine 1 mumol/l by approximately 80% and 50%, respectively. On the other hand, methoxamine at 10 but not 1 mumol/l enhanced the release of noradrenaline to approximately twice the control, and the enhancement was prevented by prazosin 1 mumol/l. The facilitatory action of methoxamine was also abolished after desensitization of P2-purinoceptors by alpha,beta-methylene ATP 30 mumol/l as well as by the presumed P2-purinoceptor antagonist suramin given at 10 mumol/l. Exogenous ATP 10 mumol/l significantly enhanced the EFS-evoked release of noradrenaline, and the enhancement was abolished by alpha,beta-methylene ATP and suramin. None of the drugs changed the spontaneous outflow of noradrenaline. These results indicate that endogenous ATP, acting at prejunctional purinoceptors, may participate in the facilitatory effect of methoxamine. Indeed, methoxamine 10 mumol/l significantly enhanced the spontaneous outflow of ATP and, less so, ADP. The methoxamine evoked release of ATP and ADP was antagonized by prazosin 1 mumol/l. It is concluded that methoxamine releases endogenous ATP from postjunctional sites which then, via prejunctional purinoceptors, facilitates action potential-evoked release of noradrenaline in rabbit ear artery.

Inhibition of field stimulation-induced contractions of rat cauda epididymis by purinoceptor agonists but not by adrenoceptor agonists.

1. Adenosine, AMP, ADP, and ATP were approximately equipotent in inhibiting contractions evoked by field stimulation (10 Hz, 60 V, 1 ms, 10 s) of isolated preparations of rat cauda epididymis. Adenosine had no significant effect on contractions induced by the exogenous application of either noradrenaline or ATP. 2. The effects of adenosine and AMP were markedly potentiated by the adenosine uptake inhibitor, dipyridamole. In contrast there was only a two-fold potentiation of the effects of ATP and no potentiation of the effects of ADP by dipyridamole. 3. Inhibitory responses to both adenosine and ATP were blocked by 8-phenyltheophylline. Neither the P2Y-purinoceptor antagonist, reactive blue 2, nor P2X purinoceptor antagonist alpha,beta-methylene ATP, blocked the inhibitory effects of ATP. 4. Several stable analogues of adenosine, namely 5'-(N-ethyl) carboxamidoadenosine (NECA), N6-cyclohexyl-adenosine (CHA), L-N6-(2-phenyl-isopropyl)adenosine (L-PIA), D-N6-(2-phenyl-isopropyl)adenosine (D-PIA) and 2-chloroadenosine (CADO) also inhibited nerve stimulation-induced contractions. NECA was the most potent. L-PIA and D-PIA were approximately equipotent, except in the presence of dipyridamole, when the potency of L-PIA exceeded that of D-PIA. 5. Field stimulation-induced contractions of the rat cauda epididymis were unaffected by the alpha 2-adrenoceptor agonists clonidine and xylazine; isoprenaline in high concentrations produced phentolamine-sensitive inhibition of contractions evoked by field stimulation and exogenous application of noradrenaline. 6. These findings taken together are consistent with the possibility that prejunctional purinoceptors, which are atypical in that they are directly activated by both ATP and adenosine, mediate inhibition of neurotransmission in this tissue. No evidence for the presence of functional alpha 2-adrenoceptors modulating neurotransmission was obtained.

Participation by purines in the modulation of norepinephrine release by methoxamine

The α 1-receptor agonist methoxamine reduced, by a prazosin sensitive mechanism, the nerve stimulation evoked release of norepinephrine in the rat caudal artery. The effect of methoxamine was also antagonized by the purinoceptor antagonist 8-(p-sulfophenyl)theophylline suggesting an involvement of endogenous purines in this process. Indeed, methoxamine caused the release of adenine nucleotides and adenosine, an action which was blocked by prazosin. These results suggest that methoxamine releases ATP or a related purine which in turn decreases transmitter release by acting on prejunctional purinoceptors.

O-176 - Pharmacological characterization of prejunctional purinoceptors on vascular adrenergic nerves

O-176 - Pharmacological characterization of prejunctional purinoceptors on vascular adrenergic nerves

Characterization of prejunctional purinoceptors on adrenergic nerves of the rat caudal artery.

The effects of a number of purinoceptor agents on the release of endogenous noradrenaline from the electrically stimulated rat caudal artery were determined. Noradrenaline was quantified by high performance liquid chromatography-electrochemical detection techniques. Both P1-receptor and P2-receptor agonists reduced the release of noradrenaline; the relative order of potency being 2-chloroadenosine greater than beta, gamma methylene ATP greater than ATP greater than or equal to adenosine. The adenosine uptake inhibitor S-p-nitro-benzyl-6-thioguanosine potentiated the effects of adenosine but not those of the adenine nucleotides. This suggests that the nucleotides do not need to be converted to adenosine to produce a prejunctional inhibition of the release of noradrenaline. The P1-receptor antagonist 8-(p-sulfophenyl) theophylline reduced the inhibitory effects of both P1- and P2-receptor agonists as did the photolysis of tissues with an intense light source. The findings indicate that prejunctional purinoceptors that mediate an inhibition of the release of noradrenaline from the adrenergic nerves of the caudal artery may not be adequately defined as either P1- or P2-receptors and thus appear to represent a unique receptor. We suggest referring to these receptors as P3-purinoceptors.