bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti‐amnesic effect of dimemorfan in mice
Authors: Wang Hui‐Hung , Chien Jyh‐Wei , Chou Yueh‐Ching , Liao Jyh‐Fei , Chen Chieh‐Fu 
Published: March 2003

Dimemorfan, an antitussive for more than 25 years, has previously been reported to be a relative high‐affinity ligand at sigma‐1 (σ1) receptor with the Ki value of 151 nM.
To test whether dimemorfan has anti‐amnesic effects similar to a σ1 receptor agonist, this study examined its effects on scopolamine‐ and β‐amyloid peptide‐(25‐35)‐induced amnesia in mice.
Dimemorfan (10–40 mg kg−1, i.p.) administered 30 min before the training trial, immediately after the training trial, or 30 min before the retention test significantly improved scopolamine (1 mg kg−1, i.p.)‐ or β‐amyloid peptide‐(25‐35) (3 nmol mouse−1, i.c.v.)‐induced amnesia in a step‐through passive avoidance test. Dimemorfan (5–40 mg kg−1, i.p.) pretreatment also attenuated scopolamine (8 mg kg−1, i.p.)‐induced amnesia in a water‐maze test. And, these anti‐amnesic effects of dimemorfan, like the putative σ1 receptor agonist (+)‐N‐allylnormetazocine ((+)‐SKF‐10047), were antagonized by a σ receptor antagonist haloperidol (0.25 mg kg−1, i.p.).
These results indicated that dimemorfan has anti‐amnesic effects and acts like a σ1 receptor agonist.

British Journal of Pharmacology (2003) 138, 941–949. doi:10.1038/sj.bjp.0705117
Ocular hypotensive effects of melatonin receptor agonists in the rabbit: further evidence for an MT3 receptor
Authors: Pintor Jesus , Peláez Teresa , Hoyle Charles H V , Peral Assumpta 
Published: March 2003

Melatonin is involved in the control of intraocular pressure during the night and day photoperiod. We have investigated the receptor that regulates intraocular pressure in New Zealand white rabbits by means of agonists and antagonists of melatonin receptors.
Melatonin and its analogues: 2‐Phe‐melatonin, 6‐Cl‐melatonin, 2‐I‐melatonin, 5‐ methoxycarbonylamino‐N‐acetyltryptamine (5‐MCA‐NAT) and N‐acetyltryptamine all produced a reduction in intraocular pressure. Dose‐response analysis for these compounds gave pD2 values of 9.3±0.24 for melatonin; 9.0±0.09 for 6‐Cl‐melatonin; 9.0±0.84 for 2‐I‐melatonin; 8.9±0.07 for 5‐MCA‐NAT; 8.7±0.18 for 2‐Phe‐melatonin and 9.4±0.30 for N‐acetyltryptamine (all n=8).
At a dose of 0.5 nmol (in 10 μl) melatonin and the selective melatonin MT3 agonist 5‐MCA‐NAT, induced greater reductions of intraocular pressure (22.8±2.3% and 32.5±1.4%, respectively) than the other compounds.
The melatonin‐receptor antagonists, prazosin, DH‐97 and 4‐P‐PDOT, reversed the effect of 5‐MCA‐NAT in a dose‐dependent manner, with pA2 values of 13.5±0.17 for prazosin, 10.6±0.16 for DH‐97 and 9.4±0.20 for 4‐P‐PDOT (n=8).
Cholinoceptor antagonists (hexamethonium and atropine) and α2‐ and β2‐adrenoceptor antagonists (yohimbine and ICI 118,551) partially reversed the effects produced by melatonin and 5‐MCA‐NAT, suggesting the possible involvement of cholinergic and noradrenergic systems in the hypotensive actions mediated by melatonin agonists. The α1‐adrenoceptor antagonist, corynanthine, had no significant effect.
The strong hypotensive effect of the MT3 agonist, 5‐MCA‐NAT, suggests that this compound may be a useful agent for treating those pathologies where intraocular pressure is abnormally elevated.

British Journal of Pharmacology (2003) 138, 831–836. doi:10.1038/sj.bjp.0705118
Pharmacological characterization of the homomeric and heteromeric UNC‐49 GABA receptors in C. elegans
Authors: Bamber Bruce A , Twyman Roy E , Jorgensen Erik M 
Published: March 2003

UNC‐49B and UNC‐49C are γ‐aminobutyric acid (GABA) receptor subunits encoded by the Caenorhabditis elegans unc‐49 gene. UNC‐49B forms a homomeric GABA receptor, or can co‐assemble with UNC‐49C to form a heteromeric receptor. The pharmacological properties of UNC‐49B homomers and UNC‐49B/C heteromers were investigated in Xenopus oocytes.
The UNC‐49 subunits are most closely related to the bicuculline‐ and benzodiazepine‐insensitive RDL GABA receptors of insects. Consistent with this classification, bicuculline (10 μM) did not inhibit, nor did diazepam (10 μM) enhance UNC‐49B homomeric or UNC‐49B/C heteromeric receptors.
The UNC‐49C subunit strongly affects the pharmacology of UNC‐49B/C heteromeric receptors. UNC‐49B homomers were much more picrotoxin sensitive than UNC‐49B/C heteromers (IC50=0.9±0.2 μM and 166±42 μM, respectively). Pentobarbitone enhancement was greater for UNC‐49B homomers compared to UNC‐49B/C heteromers. Propofol (50 μM) slightly enhanced UNC‐49B homomers but slightly inhibited UNC‐49B/C heteromers. Penicillin G (10 mM) inhibited UNC‐49B homomers less strongly than UNC‐49B/C heteromers (30% compared to 53% inhibition, respectively).
Several aspects of UNC‐49 pharmacology were unusual. Picrotoxin sensitivity strongly correlates with dieldrin sensitivity, yet UNC‐49B homomers were highly dieldrin resistant. The enhancing neurosteroid pregnanolone (5β‐pregnan‐3α‐ol‐20‐one; 10 μM) strongly inhibited both UNC‐49 receptors. Alphaxalone (10 μM), another enhancing neurosteroid, did not affect UNC‐49B homomers, but slightly inhibited UNC‐49B/C heteromers.
UNC‐49 subunits and mammalian GABAA receptor α, β, and γ subunit classes all share roughly the same degree of sequence similarity. Thus, although they are most similar to other invertebrate GABA receptors, the UNC‐49 receptors share significant structural and pharmacological overlap with mammalian GABAA receptors.

British Journal of Pharmacology (2003) 138, 883–893. doi:10.1038/sj.bjp.0705119
Different domains of the glucagon and glucagon‐like peptide‐1 receptors provide the critical determinants of ligand selectivity
Authors: Runge S , Wulff B S , Madsen K , Bräuner‐Osborne H , Knudsen L B 
Published: March 2003

Glucagon and glucagon‐like peptide‐1 (GLP‐1) are homologous peptide hormones with important functions in glucose metabolism. The receptors for glucagon and GLP‐1 are homologous family B G‐protein coupled receptors. The GLP‐1 receptor amino‐terminal extracellular domain is a major determinant of glucagon/GLP‐1 selectivity of the GLP‐1 receptor. However, the divergent residues in glucagon and GLP‐1 that determine specificity for the GLP‐1 receptor amino‐terminal extracellular domain are not known. Less is known about how the glucagon receptor distinguishes between glucagon and GLP‐1.
We analysed chimeric glucagon/GLP‐1 peptides for their ability to bind and activate the glucagon receptor, the GLP‐1 receptor and chimeric glucagon/GLP‐1 receptors. The chimeric peptide GLP‐1(7–20)/glucagon(15–29) was unable to bind and activate the glucagon receptor. Substituting the glucagon receptor core domain with the GLP‐1 receptor core domain (chimera A) completely rescued the affinity and potency of GLP‐1(7–20)/glucagon(15–29) without compromising the affinity and potency of glucagon. Substituting transmembrane segment 1 (TM1), TM6, TM7, the third extracellular loop and the intracellular carboxy‐terminus of chimera A with the corresponding glucagon receptor segments re‐established the ability to distinguish GLP‐1(7–20)/glucagon(15–29) from glucagon. Corroborant results were obtained with the opposite chimeric peptide glucagon(1–14)/GLP‐1(21–37).
The results suggest that the glucagon and GLP‐1 receptor amino‐terminal extracellular domains determine specificity for the divergent residues in the glucagon and GLP‐1 carboxy‐terminals respectively. The GLP‐1 receptor core domain is not a critical determinant of glucagon/GLP‐1 selectivity. Conversely, the glucagon receptor core domain contains two or more sub‐segments which strongly determine specificity for divergent residues in the glucagon amino‐terminus.

British Journal of Pharmacology (2003) 138, 787–794. doi:10.1038/sj.bjp.0705120
A potent tryptase inhibitor nafamostat mesilate dramatically suppressed pulmonary dysfunction induced in rats by a radiographic contrast medium
Authors: Sendo Toshiaki , Itoh Yoshinori , Goromaru Takeshi , Sumimura Tomoko , Saito Mami , Aki Keisei , Yano Takahisa , Oishi Ryozo 
Published: March 2003

Intravenous injection of ioxaglate (4 g iodine kg−1), an iodinated radiographic contrast medium, caused a marked protein extravasation, pulmonary oedema and a decrease in the arterial partial oxygen pressure in rats.
All of these reactions to ioxaglate were reversed by the pretreatment with gabexate mesilate (10 and 50 mg kg−1, 5 min prior to injection) or nafamostat mesilate (3 and 10 mg kg−1), in which the inhibition was complete after injection of nafamostat mesilate (10 mg kg−1).
Both gabexate mesilate and nafamostat mesilate inhibited the activity of purified human lung tryptase, although the latter compound was far more potent than the former.
Ioxaglate enhanced the nafamostat‐sensitive protease activity in the extracellular fluid of rat peritoneal mast cell suspensions.
Tryptase enhanced the permeability of protein through the monolayer of cultured human pulmonary arterial endothelial cells. Ioxaglate, when applied in combination with rat peritoneal mast cells, also produced the endothelial barrier dysfunction. These effects of tryptase and ioxaglate were reversed by nafamostat mesilate.
Consistent with these findings, immunofluorescence morphological analysis revealed that tryptase or ioxaglate in combination with mast cells increased actin stress fibre formation while decreasing VE‐cadherin immunoreactivity. Both of these actions of tryptase and ioxaglate were reversed by nafamostat mesilate.
These findings suggest that tryptase liberated from mast cells plays a crucial role in the ioxaglate‐induced pulmonary dysfunction. In this respect, nafamostat mesilate may become a useful agent for the cure or prevention of severe adverse reactions to radiographic contrast media.

British Journal of Pharmacology (2003) 138, 959–967. doi:10.1038/sj.bjp.0705121
5‐HT moduline: an endogenous inhibitor of 5‐HT1B/1D‐mediated contraction in pulmonary arteries
Authors: Murdoch R , Morecroft I , MacLean M R 
Published: March 2003

5‐HT moduline (5‐HTm) is tetrapeptide (Leu‐Ser‐Ala‐Leu) previously shown to act as a specific endogenous antagonist to central 5‐HT1B/1D receptors. Its effects were investigated in rat and rabbit pulmonary arteries (PAs).
In rabbit PAs, contractile responses to the 5‐HT1B/1D receptor agonist 5‐carboxamidotryptamine (5‐CT) were inhibited by 1 and 10 μM 5‐HTm in a non‐competitive fashion with the maximum contractile response (Emax, per cent of response to 50 mM KCl) being reduced from 65.6±7% (n=6) to 39.7±6.5% (n=6) and 25.2±7.9 (n=4), respectively. The ability of 5‐HTm to inhibit responses to 5‐CT was increased by the aminopeptidase inhibitor bestatin (10 μM).
In the rabbit PAs, the nitric oxide synthase inhibitor, Nω‐nitro‐L‐arginine methylester (L‐NAME) potentiated responses to 5‐CT (Emax: 106±22.5 (n=4)) and this response was also inhibited by 10 μM 5‐HTm (Emax: 38±13% (n=8)).
5‐HTm (10 μM) inhibited responses to 5‐CT in rat PAs, the Emax being reduced from 24.8±4.1% (n=7) to 15.5±3.7% (n=9). 5‐HTm induced relaxation of 5‐CT‐pre‐constricted rat PAs with a pIC50 of 9.0±0.6 (n=9).
In PAs from chronic hypoxic, pulmonary hypertensive rats, the maximum response to 5‐CT was increased to 80±8.5% (n=11). 5‐HTm reduced this response to 34.4±6.3% (n=12). L‐NAME markedly inhibited the ability of 5‐HTm to inhibit responses to 5‐CT (Emax before 5‐HTm: 100.5±16% (n=5), Emax after 5‐HTm: 107±11.3% (n=4)).
In conclusion we show here for the first time that 5‐HTm is a non‐competitive inhibitor of 5‐HT1B/1D receptor‐mediated constriction in PAs. In rat PAs, L‐NAME can inhibit this effect of 5‐HTm.

British Journal of Pharmacology (2003) 138, 795–800. doi:10.1038/sj.bjp.0705123
Interactions of atropine with heterologously expressed and native α3 subunit‐containing nicotinic acetylcholine receptors
Authors: Parker Julie C , Sarkar Deboshree , Quick Michael W , Lester Robin A J 
Published: March 2003

Atropine, a classical muscarinic antagonist, has been reported previously to inhibit neuronal nicotinic acetylcholine receptors (nAChRs). In the present study, the action of atropine has been examined on α3β4 receptors expressed heterologously in Xenopus oocytes and native nAChRs in medial habenula neurons.
At concentrations of atropine often used to inhibit muscarinic receptors (1 μM), responses induced by near‐maximal nicotine concentrations (100 μM) at negative holding potentials (−65 mV) are inhibited (14–30%) in a reversible manner in both α4 and α3 subunit‐containing heteromeric nAChRs. Half‐maximal effective concentrations (IC50 values) for atropine inhibition are similar for the four classes of heteromeric receptors studied (4–13 μM).
For α3β4 nAChRs in oocytes, inhibition by atropine (10 μM) is not overcome at higher concentrations of agonist, and is increased with membrane hyperpolarization. These results are consistent with non‐competitive antagonism – possibly ion channel block.
At low concentrations of both nicotine (10 μM) and atropine (<10 μM), potentiation (∼25%) of α3β4 nAChR responses in oocytes is observed. The relative balance between potentiation and inhibition is dependent upon membrane potential.
In rat medial habenula (MHb) neurons, atropine (0.3–3.0 μM) inhibited nicotine‐induced responses in both a concentration and membrane potential‐dependent manner (at −40 mV, IC50=4 μM), similar to the effects on α3β4–nAChRs in oocytes. However, unlike heterologously expressed receptors, potentiation was barely detectable at depolarized membrane potentials using low concentrations of nicotine (3–10 μM). Conversely, the weak agonist, choline (1–3 mM) was observed to augment responses of MHb nAChRs.

British Journal of Pharmacology (2003) 138, 801–810. doi:10.1038/sj.bjp.0705124
Dopamine D2‐like receptor‐mediated opening of K+ channels in opossum kidney cells
Authors: Gomes Pedro , Soares‐da‐Silva Patrício 
Published: March 2003

This study examined the effects of dopamine D1‐ and D2‐like receptor activation upon basolateral K+ (IK) currents and changes in membrane potential in opossum kidney (OK) cells.
The addition of amphotericin B (3 μg ml−1) to the apical side resulted in a rapid increase in IK, this effect being markedly inhibited by the addition of the K+ channel blockers barium chloride (1 mM) or glibenclamide (10 μM), but not apamin (1 μM). The K+ channel opener pinacidil increased the amphotericin B‐induced IK. The selective D2‐like receptor agonist quinerolane increased, in a concentration dependent manner (EC50=136 nM), IK across the basolateral membrane, this effect being abolished by pre‐treatment with pertussis toxin (PTX), S‐sulpiride (selective D2‐like receptor antagonist) and glibenclamide. The selective D1‐like receptor agonist SKF 38393 did not change IK. Both H‐89 (PKA inhibitor) and chelerythrine (PKC inhibitor) failed to prevent the stimulatory effect of quinerolane upon IK.
Quinerolane did not change basal levels of cyclic AMP and also failed to affect the forskolin‐induced increase in cyclic AMP levels.
The stimulation of D2‐like receptor was associated with a rapid hyperpolarizing effect, whereas D1‐like receptor activation was accompanied by increases in cell membrane potential. The hyperpolarizing effect of quinerolane (EC50=129 nM) was prevented by pre‐treatment with PTX, S‐sulpiride and glibenclamide.
It is concluded that stimulation of dopamine D2‐like, but not D1‐like, receptors coupled to PTX‐sensitive G proteins of the Gi/o class produce membrane hyperpolarization through opening of KATP channels.

British Journal of Pharmacology (2003) 138, 968–976. doi:10.1038/sj.bjp.0705125
Ajoene, a garlic compound, inhibits protein prenylation and arterial smooth muscle cell proliferation
Authors: Ferri Nicola , Yokoyama Kohei , Sadilek Martin , Paoletti Rodolfo , Apitz‐Castro Rafael , Gelb Michael H , Corsini Alberto 
Published: March 2003

Ajoene is a garlic compound with anti‐platelet properties and, in addition, was shown to inhibit cholesterol biosynthesis by affecting 3‐hydroxy‐3‐methyl‐glutaryl coenzyme A (HMG‐CoA) reductase and late enzymatic steps of the mevalonate (MVA) pathway.
MVA constitutes the precursor not only of cholesterol, but also of a number of non‐sterol isoprenoids, such as farnesyl and geranylgeranyl groups. Covalent attachment of these MVA‐derived isoprenoid groups (prenylation) is a required function of several proteins that regulate cell proliferation. We investigated the effect of ajoene on rat aortic smooth muscle cell proliferation as related to protein prenylation.
Cell counting, DNA synthesis, and cell cycle analysis showed that ajoene (1–50 μM) interfered with the progression of the G1 phase of the cell cycle, and inhibited rat SMC proliferation.
Similar to the HMG‐CoA reductase inhibitor simvastatin, ajoene inhibited cholesterol biosynthesis. However, in contrast to simvastatin, the antiproliferative effect of ajoene was not prevented by the addition of MVA, farnesol (FOH), and geranylgeraniol (GGOH). Labelling of smooth muscle cell cellular proteins with [3H]‐FOH and [3H]‐GGOH was significantly inhibited by ajoene.
In vitro assays for protein farnesyltransferase (PFTase) and protein geranylgeranyltransferase type I (PGGTase‐I) confirmed that ajoene inhibits protein prenylation. High performance liquid chromatography (HPLC) and mass spectrometry analyses also demonstrated that ajoene causes a covalent modification of the cysteine SH group of a peptide substrate for protein PGGTase‐I.
Altogether, our results provide evidence that ajoene interferes with the protein prenylation reaction, an effect that may contribute to its inhibition of SMC proliferation.

British Journal of Pharmacology (2003) 138, 811–818. doi:10.1038/sj.bjp.0705126
Desensitization of α2A‐adrenoceptor signalling by modest levels of adrenaline is facilitated by β2‐adrenoceptor‐dependent GRK3 up‐regulation
Authors: Bawa Tasneem , Altememi Ghazi F , Eikenburg Douglas C , Standifer Kelly M 
Published: March 2003

Adrenaline (ADR) and noradrenaline (NA) can simultaneously activate inhibitory α2‐ and stimulatory β‐adrenoceptors (AR). However, ADR and NA differ significantly in that ADR is a potent β2‐AR agonist while NA is not. Only recently has the interaction resulting from the simultaneous activation of α2‐ and β2‐AR been examined at the cellular level to determine the mechanisms of α2‐AR regulation following concomitant activation of both α2‐ and β2‐ARs by chronic ADR.
This study evaluates β2‐AR regulation of α2A‐AR signalling following chronic ADR (300 nM) and NA (1 and 30 μM) treatments of BE(2)‐C human neuroblastoma cells that natively express both β2‐ and α2A‐ARs.
Chronic (24 h) treatment with ADR (300 nM) desensitized the response to the α2A‐AR agonist, brimonidine, in BE(2)‐C cells. Addition of the β‐AR antagonist, propranolol, blocked the ADR‐induced α2A‐AR desensitization. Unlike ADR, chronic NA (1 μM) treatment had no effect on the α2A‐AR response. However if NA was increased to 30 μM for 24 h, α2A‐AR desensitization was observed; this desensitization was partially reversed by propranolol.
Chronic ADR (300 nM) treatment reduced α2A‐AR binding levels, contributing to the α2A‐AR desensitization. This decrease was prevented by addition of propranolol during ADR treatment. Chronic NA (30 μM), like ADR, treatment lowered specific binding, whereas 1 μM NA treatment was without effect.
Chronic ADR treatment produced a significant increase in GRK3 levels and this was blocked by propranolol or GRK2/3 antisense DNA treatment. This antisense DNA, common to both GRK2 and GRK3, also blocked chronic ADR‐induced α2A‐AR desensitization and down‐regulation.
Acute (1 h) ADR (300 nM) or NA treatment (1 μM) produced α2A‐AR desensitization. The desensitization produced by acute treatment was β‐AR independent, as it was not blocked by propranolol.
We conclude that chronic treatment with modest levels of ADR produces α2A‐AR desensitization by mechanisms that involve up‐regulation of GRK3 and down‐regulation of α2A‐AR levels through interactions with the β2‐AR.

British Journal of Pharmacology (2003) 138, 921–931. doi:10.1038/sj.bjp.0705127
S‐Nitrosocaptopril: in vitro characterization of pulmonary vascular effects in rats
Authors: Tsui Debbie Y Y , Gambino Agatha , Wanstall Janet C 
Published: March 2003

On rat isolated pulmonary arteries, vasorelaxation by S‐nitrosocaptopril (SNOcap) was compared with S‐nitrosoglutathione (GSNO) and nitroprusside, and inhibition by SNOcap of contractions to angiotensin I was compared with the angiotensin converting enzyme (ACE) inhibitor, captopril.
SNOcap was equipotent as a vasorelaxant on main (i.d. 2–3 mm) and intralobar (i.d. 600 μm) pulmonary arteries (pIC50 values: 5.00 and 4.85, respectively). Vasorelaxant responses reached equilibrium rapidly (2–3 min).
Pulmonary vasorelaxant responses to SNOcap, like GSNO, were (i) partially inhibited by the soluble guanylate cyclase inhibitor, ODQ (1H‐(1,2,4) oxadiazolo(4,3‐a)‐quinoxalin‐1‐one; 3 μM) whereas responses to nitroprusside were abolished and (ii) potentiated by hydroxocobalamin (HCOB; NO· free radical scavenger; 100 μM) whereas responses to nitroprusside were inhibited.
The relative potencies for pulmonary vasorelaxation compared with inhibition of platelet aggregation were: SNOcap 7 : 1; GSNO 25 : 1; nitroprusside >2000 : 1.
SNOcap, like captopril, concentration‐dependently and time‐dependently increased the EC50 for angiotensin I but not angiotensin II. The dependence on incubation time was independent of the presence of tissue but differed for SNOcap and captopril. This difference reflected the slow dissociation of SNOcap and instability of captopril, and precluded a valid comparison of the potency of the two drugs. After prolonged incubation (5.6 h) SNOcap was more effective than captopril.
Thus, in pulmonary arteries SNOcap (i) possesses NO donor properties characteristic of S‐nitrosothiols but different from nitroprusside and (ii) inhibits ACE at least as effectively as captopril. These properties suggest that SNOcap could be valuable in the treatment of pulmonary hypertension.

British Journal of Pharmacology (2003) 138, 855–864. doi:10.1038/sj.bjp.0705128
Regulation of intracellular cyclic AMP in skeletal muscle cells involves the efflux of cyclic nucleotide to the extracellular compartment
Authors: Godinho Rosely Oliveira , Costa‐Jr Valter Luiz 
Published: March 2003

This report analyses the intracellular and extracellular accumulation of cyclic AMP in primary rat skeletal muscle cultures, after direct and receptor‐dependent stimulation of adenylyl cyclase (AC).
Isoprenaline, calcitonin gene‐related peptide (CGRP) and forskolin induced a transient increase in the intracellular cyclic AMP that peaked 5 min after onset stimulation.
Under stimulation with isoprenaline or CGRP, the intracellular cyclic AMP initial rise was followed by an exponential decline, reaching 46 and 52% of peak levels in 10 min, respectively.
Conversely, the forskolin‐dependent accumulation of intracellular cyclic AMP decreased slowly and linearly, reaching 49% of the peak level in 30 min.
The loss of intracellular cyclic AMP from peak levels, induced by direct or receptor‐induced activation of AC, was followed by an increase in the extracellular cyclic AMP.
This effect was independent on PDEs, since it was obtained in the presence of 3‐isobutyl‐1‐methylxanthine (IBMX).
Besides, in isoprenaline treated cells, the beta‐adrenoceptor antagonist propranolol reduced both intra‐ and extracellular accumulation of cyclic AMP, whereas the organic anion transporter inhibitor probenecid reduced exclusively the extracellular accumulation.
Together our data show that direct or receptor‐dependent activation of skeletal muscle AC results in a transient increase in the intracellular cyclic AMP, despite the continuous presence of the stimulus. The temporal declining of intracellular cyclic AMP was not dependent on the cyclic AMP breakdown but associated to the efflux of cyclic nucleotide to the extracellular compartment, by an active transport since it was prevented by probenecid.

British Journal of Pharmacology (2003) 138, 995–1003. doi:10.1038/sj.bjp.0705130