Pharmacological evidence for N-methyl-D-aspartate receptors on nigrostriatal dopaminergic nerve terminals

1991 ◽  
Vol 69 (10) ◽  
pp. 1416-1421 ◽  
Author(s):  
Kenneth M. Johnson ◽  
Yow-Juin Jeng
Keyword(s):  
Nmda Receptors ◽  
Phosphonic Acid ◽  
Channel Blocker ◽  
Nmda Antagonist ◽  
Nerve Terminals ◽  
Dependent Manner ◽  
Additional Mechanism ◽  
Concentration Dependent Manner ◽  
Nmda Channel ◽  
Da Release

The efflux of tritium from rat striatal synaptosomes labelled with [3H]dopamine was utilized as an index of dopamine (DA) release for the purpose of characterizing the receptors underlying the effects of L-glutamate. N-Methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA), and kainate each induced DA release in the absence of Mg2+, though NMDA was much more efficacious and only the NMDA response was inhibited by Mg2+. The response to L-glutamate was potentiated in a concentration-dependent manner by glycine. Further, it was completely inhibited by the competitive NMDA antagonist 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid and by the NMDA channel blocker phencyclidine. Finally, the response to L-glutamate was unaffected by either tetrodotoxin or the kainite–AMPA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione. These data demonstrate the presence of NMDA receptors on dopaminergic nerve terminals that mediate the ability of L-glutamate to release DA and suggest an additional mechanism by which information from the nigrostriatal and corticostriatal pathways may be integrated.Key words: N-methyl-D-aspartate, receptors, dopamine, nigrostriatal, synaptosomes.

Vasorelaxing Activity of Stilbenoid and Phenanthrene Derivatives from Brasiliorchis porphyrostele: Involvement of Smooth Muscle CaV1.2 Channels

Planta Medica ◽  
2020 ◽  
Vol 86 (09) ◽  
pp. 631-642
Author(s):  
Watcharee Waratchareeyakul ◽  
Fabio Fusi ◽  
Miriam Durante ◽  
Amer Ahmed ◽  
Walter Knirsch ◽  
...  
Keyword(s):  
Channel Blocker ◽  
Antihypertensive Agents ◽  
Dependent Manner ◽  
Vascular Effects ◽  
Concentration Dependent Manner ◽  
Spasmolytic Activity ◽  
Depth Analysis ◽  
Cav1.2 Channels ◽  
Vasorelaxant Activity

AbstractFive compounds, 3,4′-dihydroxy-3′,5,5′-trimethoxydihydrostilbene, 1; 3,4′-ihydroxy-3′,5′-dimethoxydihydrostilbene, 2; 3,4′-dihydroxy-5,5′-dimethoxydihydrostilbene, 3; 9,10-dihydro-2,7-dihydroxy-4,6-dimethoxyphenanthrene, 4; and the previously unreported 1,2,6,7-tetrahydroxy-4-methoxyphenanthrene, 5 were isolated from the South American orchid, Brasiliorchis porphyrostele. An in-depth analysis of their vascular effects was performed on in vitro rat aorta rings and tail main artery myocytes. Compounds 1 – 4 were shown to possess vasorelaxant activity on rings pre-contracted by the α 1 receptor agonist phenylephrine, the CaV1.2 stimulator (S)-(−)-Bay K 8644, or depolarized with high K+ concentrations. However, compound 5 was active solely on rings stimulated by 25 mM but not 60 mM K+. The spasmolytic activity of compounds 1 and 4 was significantly affected by the presence of an intact endothelium. The KATP channel blocker glibenclamide and the KV channel blocker 4-aminopyridine significantly antagonized the vasorelaxant activity of compounds 4 and 1, respectively. In patch-clamp experiments, compounds 1 – 4 inhibited Ba2+ current through CaV1.2 channels in a concentration-dependent manner, whereas neither compound 4 nor compound 1 affected K+ currents through KATP and KV channels, respectively. The present in vitro, comprehensive study demonstrates that Brasiliorchis porphyrostele may represent a source of vasoactive agents potentially useful for the development of novel antihypertensive agents that has now to be validated in vivo in animal models of hypertension.

scholarly journals Citrus bergamiaRisso Elevates Intracellular Ca2+in Human Vascular Endothelial Cells due to Release of Ca2+from Primary Intracellular Stores

2013 ◽  
Vol 2013 ◽  
pp. 1-7 ◽  
Author(s):  
Purum Kang ◽  
Seung Ho Han ◽  
Hea Kyung Moon ◽  
Jeong-Min Lee ◽  
Hyo-Keun Kim ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Channel Blocker ◽  
Vascular Endothelial Cells ◽  
Umbilical Vein ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Concentration Dependent Manner ◽  
Carbonyl Cyanide ◽  
Intracellular Ca ◽  
Umbilical Vein Endothelial Cells

The purpose of the present study is to examine the effects of essential oil ofCitrus bergamiaRisso (bergamot, BEO) on intracellular Ca2+in human umbilical vein endothelial cells. Fura-2 fluorescence was used to examine changes in intracellular Ca2+concentration[Ca2+]i. In the presence of extracellular Ca2+, BEO increased[Ca2+]i, which was partially inhibited by a nonselective Ca2+channel blocker La3+. In Ca2+-free extracellular solutions, BEO increased[Ca2+]iin a concentration-dependent manner, suggesting that BEO mobilizes intracellular Ca2+. BEO-induced[Ca2+]iincrease was partially inhibited by a Ca2+-induced Ca2+release inhibitor dantrolene, a phospholipase C inhibitor U73122, and an inositol 1,4,5-triphosphate (IP3)-gated Ca2+channel blocker, 2-aminoethoxydiphenyl borane (2-APB). BEO also increased[Ca2+]iin the presence of carbonyl cyanide m-chlorophenylhydrazone, an inhibitor of mitochondrial Ca2+uptake. In addition, store-operated Ca2+entry (SOC) was potentiated by BEO. These results suggest that BEO mobilizes Ca2+from primary intracellular stores via Ca2+-induced and IP3-mediated Ca2+release and affect promotion of Ca2+influx, likely via an SOC mechanism.

Inhibition of adenosine-induced coronary vasodilation by block of large-conductance Ca(2+)-activated K+ channels

1994 ◽  
Vol 267 (4) ◽  
pp. H1455-H1460 ◽  
Author(s):  
F. Cabell ◽  
D. S. Weiss ◽  
J. M. Price
Keyword(s):  
Coronary Arteries ◽  
Channel Blocker ◽  
Dependent Manner ◽  
Maximal Inhibition ◽  
Concentration Dependent Manner ◽  
Channel Modulation ◽  
Cyclic Monophosphate ◽  
Kca Channels ◽  
Thromboxane A2 Analogue

The aim of the present study was to investigate the contribution of large-conductance calcium-activated potassium (large-conductance KCa) channels to adenosine (Ado)- and nitroprusside-mediated relaxation in small coronary arteries. Canine subepicardial arteries (170 +/- 23 microns at 120 mmHg) were studied as in vitro pressurized vessels. Pressure-diameter experiments showed myogenic tone over a physiological range of pressures. Tone was increased with the thromboxane A2 analogue 9,11-dideoxy-11 alpha,9 alpha-epoxy-methanoprostaglandin F2 alpha (U-46619). Tetraethylammonium (TEA+; 1 mM) significantly inhibited Ado-induced [and by implication, adenosine 3',5'-cyclic monophosphate (cAMP)-induced] relaxations at Ado concentrations ranging from 0.1 to 10 microM with maximal inhibition (61 +/- 8%) at 1 microM Ado. The large-conductance KCa-channel blocker iberiotoxin (IbTX; 0.01-0.1 microM) inhibited Ado-mediated relaxation in a concentration-dependent manner. Inhibition by IbTX increased with increasing vessel pressure (i.e., 45 +/- 12% at 40 mmHg and 83 +/- 20% at 120 mmHg). TEA+ had a minimal effect (8 +/- 3%) on relaxation induced by nitroprusside. Similar results were found with acetylcholine and bradykinin. These results suggest that (in dog coronary arteries with diameter < 200 microns) large-conductance KCa-channel modulation may play a major role in cAMP-mediated relaxation but is not significant in guanosine 3',5'-cyclic monophosphate-mediated relaxation.

Effects of Mg2+ on Ca2+ waves and Ca2+ transients of rat ventricular myocytes

1996 ◽  
Vol 270 (3) ◽  
pp. H907-H914 ◽  
Author(s):  
H. Terada ◽  
H. Hayashi ◽  
N. Noda ◽  
H. Satoh ◽  
H. Katoh ◽  
...  
Keyword(s):  
Sarcoplasmic Reticulum ◽  
Channel Blocker ◽  
Ventricular Myocytes ◽  
Inhibitory Effect ◽  
Antiarrhythmic Action ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Triggered Activity ◽  
Rat Ventricular Myocytes ◽  
High Concentrations

It has been shown that the occurrence of the transient inward current, which is responsible for triggered activity, was often associated with propagating regions of increased intracellular Ca2+ concentration ([Ca2+]i), i.e., the “Ca2+ wave.” To investigate the mechanism of antiarrhythmic action of Mg2+, we have studied effects of high concentrations of Mg2+ on Ca2+ waves in isolated rat ventricular myocytes. [Ca2+]i was estimated using the Ca(2+)-indicating probe indo 1. Ca2+ waves in myocytes, stimulated at 0.2 Hz, were induced by perfusion of isoproterenol (10(-7) M). High Mg2+ concentration suppressed Ca2+ waves in a concentration-dependent manner (36% at 4 mM, 70% at 8 mM, and 82% at 12 mM). The Ca2+ channel blocker verapamil also suppressed Ca2+ waves in a similar way. In contrast with marked depression of Ca2+ transients by verapamil, Ca2+ transients were not affected by high Mg2+ concentration (8 mM). High Mg2+ concentration also reduced frequencies of Ca2+ waves in the absence of electrical stimulation, whereas verapamil failed to reduce frequencies of Ca2+ waves. Reduction in frequency of Ca2+ waves by high Mg2+ concentration was associated with slowing of propagation velocity of Ca2+ waves. To examine whether suppressive effects of high Mg2+ concentration on Ca2+ waves were related to an increase in intracellular Mg2+ concentration ([Mg2+]i), the effect of high-Mg2+ solution on [Mg2+]i was examined in myocytes loaded with mag-fura 2. An increase in extracellular Mg2+ concentration from 1 to 12 mM increased [Mg2+]i from 1.06 +/- 0.16 to 1.87 +/- 0.22 mM (P < 0.01) in 30 min. To examine the effect of high Mg2+ concentration on amount of releasable Ca2+ in the sarcoplasmic reticulum, the effect of high Mg2+ concentration on the Ca2+ transient induced by a rapid application of caffeine was examined. High-Mg2+ solution increased the peak of the caffeine-induced Ca2+ transient. These results suggest that the inhibitory effect of Mg2+ on Ca2+ waves was not due to inhibition of the sarcolemmal Ca2+ channel but could be due to a decreased propensity for the sarcoplasmic reticulum to divest itself of excess Ca2+.

Presynaptic β2-adrenoceptors mediate nicotine-induced NOergic neurogenic dilation in porcine basilar arteries

2000 ◽  
Vol 279 (2) ◽  
pp. H808-H816 ◽  
Author(s):  
Tony J. F. Lee ◽  
W. Zhang ◽  
S. Sarwinski
Keyword(s):  
Sympathetic Innervation ◽  
Nerve Fibers ◽  
Facilitatory Effect ◽  
Nerve Terminals ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Double Labeling ◽  
Adrenoceptor Antagonist ◽  
Basilar Arteries

We previously reported that nicotine-induced nitric oxide (NO)-mediated cerebral neurogenic vasodilation was dependent on intact sympathetic innervation. We hypothesized that nicotine acted on sympathetic nerve terminals to release norepinephrine (NE), which then acted on adrenoceptors located on the neighboring nitric oxidergic (NOergic) nerve terminals to release NO, resulting in vasodilation. The adrenoceptor subtype in mediating nicotine-induced vasodilation in isolated porcine basilar arterial rings denuded of endothelium was therefore examined pharmacologically and immunohistochemically. Results from using an in vitro tissue bath technique indicated that propranolol and preferential β2-adrenoceptor antagonists (ICI-118,551 and butoxamine), in a concentration-dependent manner, blocked the relaxation induced by nicotine (100 μM) without affecting the relaxation elicited by transmural nerve stimulation (TNS, 8 Hz). In contrast, preferential β1-adrenoceptor antagonists (atenolol and CGP-20712A) did not affect either nicotine- or TNS-induced relaxation. Results of double-labeling studies indicated that β2-adrenoceptor immunoreactivities and NADPH diaphorase reactivities were colocalized in the same nerve fibers in basilar and middle cerebral arteries. These findings suggest that NE, which is released from sympathetic nerves upon application of nicotine, acts on presynaptic β2-adrenoceptors located on the NOergic nerve terminals to release NO, resulting in vasodilation. In addition, nicotine-induced relaxation was enhanced by yohimbine, an α2-adrenoceptor antagonist, which, however, did not affect the relaxation elicited by TNS. Prazosin, an α1-adrenoceptor antagonist, on the other hand, did not have any effect on relaxation induced by either nicotine or TNS. The predominant facilitatory effect of β2-adrenoceptors in releasing NO may be compromised by presynaptic α2-adrenoceptors.

Sarcolemmal cation channels and exchangers modify the increase in intracellular calcium in cardiomyocytes on inhibiting Na+-K+-ATPase

2007 ◽  
Vol 293 (1) ◽  
pp. H169-H181 ◽  
Author(s):  
Harjot K. Saini ◽  
Naranjan S. Dhalla
Keyword(s):  
Intracellular Calcium ◽  
Channel Blocker ◽  
Critical Role ◽  
Cation Channels ◽  
Dependent Manner ◽  
Additive Effects ◽  
Concentration Dependent Manner ◽  
Rat Cardiomyocytes ◽  
Induced Changes ◽  
Isolated Rat

Although inhibition of the sarcolemmal (SL) Na+-K+-ATPase is known to cause an increase in the intracellular concentration of Ca2+ ([Ca2+]i) by stimulating the SL Na+/Ca2+ exchanger (NCX), the involvement of other SL sites in inducing this increase in [Ca2+]i is not fully understood. Isolated rat cardiomyocytes were treated with or without different agents that modify Ca2+ movements by affecting various SL sites and were then exposed to ouabain. Ouabain was observed to increase the basal levels of both [Ca2+]i and intracellular Na+ concentration ([Na+]i) as well as to augment the KCl-induced increases in both [Ca2+]i and [Na+]i in a concentration-dependent manner. The ouabain-induced changes in [Na+]i and [Ca2+]i were attenuated by treatment with inhibitors of SL Na+/H+ exchanger and SL Na+ channels. Both the ouabain-induced increase in basal [Ca2+]i and augmentation of the KCl response were markedly decreased when cardiomyocytes were exposed to 0–10 mM Na+. Inhibitors of SL NCX depressed but decreasing extracellular Na+ from 105–35 mM augmented the ouabain-induced increase in basal [Ca2+]i and the KCl response. Not only was the increase in [Ca2+]i by ouabain dependent on the extracellular Ca2+ concentration, but it was also attenuated by inhibitors of SL L-type Ca2+ channels and store-operated Ca2+ channels (SOC). Unlike the SL L-type Ca2+-channel blocker, the blockers of SL Na+ channel and SL SOC, when used in combination with SL NCX inhibitor, showed additive effects in reducing the ouabain-induced increase in basal [Ca2+]i. These results support the view that in addition to SL NCX, SL L-type Ca2+ channels and SL SOC may be involved in raising [Ca2+]i on inhibition of the SL Na+-K+-ATPase by ouabain. Furthermore, both SL Na+/H+ exchanger and Na+ channels play a critical role in the ouabain-induced Ca2+ increase in cardiomyocytes.

scholarly journals Inhibition of apolipoprotein B net synthesis and secretion from cultured rat hepatocytes by the calcium-channel blocker diltiazem

1989 ◽  
Vol 263 (2) ◽  
pp. 411-415 ◽  
Author(s):  
T C Kwong ◽  
J D Sparks ◽  
D J Pryce ◽  
J F Cianci ◽  
C E Sparks
Keyword(s):  
Molecular Mass ◽  
Apolipoprotein B ◽  
Channel Blocker ◽  
Rat Hepatocytes ◽  
Acetate Incorporation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Apo B ◽  
Cellular Lipids ◽  
Mass Form

1. The effect of the Ca2+-channel blocker diltiazem on hepatic apolipoprotein B (apo B) synthesis and secretion was studied in 12-18 h cultures of collagenase-dispersed rat hepatocytes. 2. The presence of diltiazem in the medium decreased apo B secretion by hepatocytes in a concentration-dependent manner. At 25 microM, diltiazem inhibited apo B secretion by approx. 36%, but there was no evidence of intracellular accumulation of apo B. 3. The inhibition of apo B secretion by hepatocytes was significantly correlated with cell-associated diltiazem (r = 0.72, P less than 0.01). 4. The rate of apo B secretion remained linear over 16 h even in the presence of 50 microM-diltiazem. 5. At diltiazem concentrations in the medium which were inhibitory for apo B secretion, [14C]acetate incorporation into cellular lipids and [35S]methionine incorporation into protein were enhanced. 6. Diltiazem inhibited the secretion of the apo B variants with a preferential inhibition of the higher-molecular-mass form of apo B (apo BH) over the lower-molecular-mass form (apo BL) at diltiazem concentrations in the medium greater than 25 microM. 7. Together, these results suggest that Ca2+ may play an important role in the synthesis and secretion of apo B-containing lipoproteins.

Statins prevent cholinesterase inhibitor blockade of sympathetic α7-nAChR-mediated currents in rat superior cervical ganglion neurons

2007 ◽  
Vol 293 (3) ◽  
pp. H1737-H1744 ◽  
Author(s):  
Mansoor Mozayan ◽  
Tony J. F. Lee
Keyword(s):  
Superior Cervical Ganglion ◽  
Vascular Function ◽  
Cerebral Arteries ◽  
Neuronal Cultures ◽  
Nerve Terminals ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Α7 Nachr ◽  
Cervical Ganglion ◽  
Ganglion Neurons

Statins are reported to be beneficial in treating a multitude of disorders including dementia due to Alzheimer disease (AD) and vascular dementia (VaD) with varying, yet-to-be determined mechanisms of actions. Although cholinesterase inhibitors (ChEIs) are still recommended as the primary drug of choice for AD and related diseases, their efficacy is frequently questioned. We recently reported that α7-neuronal acetylcholine nicotinic receptor (α7-nAChR)-mediated neurogenic vasodilation of porcine cerebral arteries was blocked by ChEIs, and this blockade was prevented by statin pretreatment. The exact mechanism of interaction between ChEIs and statins remains unclear. Activation of α7-nAChRs located on perivascular postganglionic sympathetic nerve terminals releases norepinephrine, which then acts on presynaptic β2-adrenoceptors located on neighboring nitrergic nerve terminals, resulting in nitric oxide release and vasodilation. The present study, therefore, was designed to determine whether interaction of ChEIs and statins occurs at the α7-nAChR level. We examined effects of concurrent application of ChEIs and statins on α7-nAChR-mediated inward currents in primary neuronal cultures of rat superior cervical ganglion cells, the origin of the perivascular sympathetic innervation to the cerebral arteries. The results indicated that physostigmine, neostigmine, and galantamine inhibited choline- and nicotine-induced whole cell currents in a concentration-dependent manner. This inhibition, which was noncompetitive in nature, was prevented by concurrent application of mevastatin and lovastatin in a concentration-dependent manner. These results suggest that statins protect α7-nAChR function directly at the receptor level. Since α7-nAChR is neuroprotective, having beneficial effects on memory and cerebral vascular function, its functional inhibition by ChEIs may explain in part the limitation of its effectiveness in AD and VaD therapy. Protection of α7-nAChR function from ChEI inhibition by concurrent administration of statins may provide an alternative strategy in improving the efficacy of AD and VaD therapy.

scholarly journals Effect of Conantokin G on NMDA Receptor–Mediated Spontaneous EPSCs in Cultured Cortical Neurons

2006 ◽  
Vol 96 (3) ◽  
pp. 1084-1092 ◽  
Author(s):  
Anitha B. Alex ◽  
Anthony J. Baucum ◽  
Karen S. Wilcox
Keyword(s):  
Nmda Receptor ◽  
Nmda Receptors ◽  
Binding Site ◽  
Cortical Neurons ◽  
Dependent Manner ◽  
Patch Clamp Technique ◽  
Concentration Dependent Manner ◽  
Whole Cell ◽  
Cultured Cortical Neurons

Conantokin G (Con G), derived from the venom of Conus geographus, is the most characterized natural peptide antagonist targeted to N-methyl-d-aspartate (NMDA) receptors. Although Con G is known to bind to the glutamate binding site on the NR2 subunit of the receptor, it is unclear whether it can allosterically modulate the function of the receptor through the glycine binding site on the NR1 subunit. This study was designed to evaluate the action of Con G on NMDA receptor–mediated spontaneous excitatory postsynaptic currents (sEPSCs) and its modulation by glycine in cultured cortical neurons (13–19 days in vitro) using the whole cell patch-clamp technique. Con G inhibited NMDA receptor–mediated sEPSCs in a concentration-dependent manner. Also, the potency of Con G decreased as a function of time in culture. The inhibition of EPSCs observed after application of Con G in the presence of high (10 μM) and nominal (no added) concentrations of glycine was not different at 13 days in vitro (DIV). Furthermore, similar results were obtained with experiments on Con G–induced inhibition of NMDA-evoked whole cell currents. These results indicate that glycine concentrations do not have a direct effect on Con G–induced inhibition of NMDA currents. In addition, age dependency in the action of Con G on cortical neurons in vitro suggests that this model system would be useful in examining the effects of different agonists/antagonists on native synaptic NMDA receptors.

scholarly journals Swelling-Induced, Cftr-Independent Atp Release from a Human Epithelial Cell Line

1999 ◽  
Vol 114 (4) ◽  
pp. 525-533 ◽  
Author(s):  
Akihiro Hazama ◽  
Takahiro Shimizu ◽  
Yuhko Ando-Akatsuka ◽  
Seiji Hayashi ◽  
Shoko Tanaka ◽  
...  
Keyword(s):  
Epithelial Cell ◽  
Cell Line ◽  
Channel Blocker ◽  
Atp Release ◽  
Epithelial Cell Line ◽  
Dependent Manner ◽  
Human Epithelial Cell ◽  
Osmotic Swelling ◽  
Concentration Dependent Manner ◽  
Cl Channel

To examine a possible relation between the swelling-induced ATP release pathway and the volume-sensitive Cl− channel, we measured the extracellular concentration of ATP released upon osmotic swelling and whole-cell volume-sensitive Cl− currents in a human epithelial cell line, Intestine 407, which lacks expression of cystic fibrosis transmembrane conductance regulator (CFTR). Significant release of ATP was observed within several minutes after a hypotonic challenge (56–80% osmolality) by the luciferin/luciferase assay. A carboxylate analogue Cl− channel blocker, 5-nitro-2-(3-phenylpropylamino)-benzoate, suppressed ATP release in a concentration-dependent manner with a half-maximal inhibition concentration of 6.3 μM. However, swelling-induced ATP release was not affected by a stilbene-derivative Cl− channel blocker, 4-acetamido-4′-isothiocyanostilbene at 100 μM. Glibenclamide (500 μM) and arachidonic acid (100 μM), which are known to block volume-sensitive outwardly rectifying (VSOR) Cl− channels, were also ineffective in inhibiting the swelling-induced ATP release. Gd3+, a putative blocker of stretch-activated channels, inhibited swelling-induced ATP release in a concentration-dependent manner, whereas the trivalent lanthanide failed to inhibit VSOR Cl− currents. Upon osmotic swelling, the local ATP concentration in the immediate vicinity of the cell surface was found to reach ∼13 μM by a biosensor technique using P2X2 receptors expressed in PC12 cells. We have raised antibodies that inhibit swelling-induced ATP release from Intestine 407 cells. Earlier treatment with the antibodies almost completely suppressed swelling-induced ATP release, whereas the activity of VSOR Cl− channel was not affected by pretreatment with the antibodies. Taking the above results together, the following conclusions were reached: first, in a CFTR-lacking human epithelial cell line, osmotic swelling induces ATP release and increases the cell surface ATP concentration over 10 μM, which is high enough to stimulate purinergic receptors; second, the pathway of ATP release is distinct from the pore of the volume-sensitive outwardly rectifying Cl− channel; and third, the ATP release is not a prerequisite to activation of the Cl− channel.

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