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Biomedical subjects

E E Daniel

Publications and source records attributed to E E Daniel.

At least 127 records · Page 7Linked to original sources
PubMed1993

Subcellular-membrane characterization of [3H]ryanodine-binding sites in smooth muscle.

The plant alkaloid ryanodine, known to interact selectively with the intracellular Ca(2+)-release channel in skeletal and cardiac muscles, has been repeatedly reported to affect smooth-muscle contractile functions that are consistent with its intracellular action at the Ca(2+)-release channel sites. Direct evidence for the binding of [3H]ryanodine to smooth-muscle membranes is sparse. Following our recent detailed characterization of functional effects of ryanodine and a preliminary report on the presence of [3H]ryanodine binding sites in rat vas deferens smooth muscle, we now report in this study a detailed characterization of binding of [3H]ryanodine to smooth muscle at the subcellular-membrane level. The ryanodine receptor in rat vas deferens muscle layer is primarily of smooth-muscle origin and is localized at the subcellular membrane site that is consistent with its role as a Ca(2+)-release channel in the sarcoplasmic reticulum (SR). Ryanodine binding to its receptor is Ca(2+)-dependent, with half-maximal binding occurring within the physiologically relevant cytosolic Ca2+ concentration. It is also sensitive to many factors, including change in Mg2+ concentration, ionic strength and osmolarity across the membrane vesicles. Agents known to inhibit (Ruthenium Red, Mg2+) or enhance (caffeine, Na+, K+) the Ca(2+)-induced Ca2+ release also inhibit or enhance the binding of ryanodine. Quantitative differences in ryanodine receptors exist among smooth muscles and do not seem to parallel their SR contents. Results from the present study indicate both the need and the basis for future investigations of the functional role of the ryanodine receptor in different smooth muscles.

Animals↗
PubMed1993

Effects of thapsigargin and ryanodine on vascular contractility: cross-talk between sarcoplasmic reticulum and plasmalemma.

Thapsigargin and ryanodine are proposed to interfere with Ca2+ storage in sarcoplasmic reticulum by different mechanisms. Thapsigargin inhibits Ca2+ transport into and ryanodine enhances Ca2+ out of the sarcoplasmic reticulum. Contractility studies were performed in the rat aorta and dog mesenteric artery. Ryanodine was found to reduce phenylephrine-induced (10 microM) contraction in Ca(2+)-free medium of rat aorta and dog mesenteric artery in a concentration-dependent manner. Each agent alone caused a slow contraction in the rat aorta. In this tissue, the tension caused by ryanodine (30 microM) but not that by thapsigargin (1 microM) was found to be dependent on the status of the sarcoplasmic reticulum: prior stimulation with K+ (60 mM) enhanced the rate of development of ryanodine-induced tension compared with when the sarcoplasmic reticulum was previously depleted with phenylephrine stimulation in Ca(2+)-free medium. Sodium nitroprusside (1 microM) or isoproterenol (1 microM) fully antagonized the contraction induced by ryanodine or phenylephrine. However, thapsigargin-induced contraction was antagonized fully by sodium nitroprusside and only partially by isoproterenol. This result suggests that cAMP elevation by isoproterenol required a functioning sarcoplasmic reticulum Ca2+ pump for its relaxant effect while cGMP elevation by sodium nitroprusside did not. These findings are consistent with the view that ryanodine promotes Ca2+ release from the sarcoplasmic reticulum and that thapsigargin inhibits the ability of cAMP to stimulate Ca2+ uptake into the store by blocking its Ca2+ pump. In the dog mesenteric artery, when the phenylephrine-sensitive Ca2+ pool was emptied and thapsigargin was added to block Ca2+ uptake into the store, restoration of Ca2+ in the Ca(2+)-free medium caused a transient contraction (absent in controls). This contraction was replaced by a significantly larger amplitude and more sustained contraction in low Na+ medium indicating the involvement of the Na+/Ca2+ exchanger in the homeostasis of cytosolic [Ca2+]. In the presence of nifedipine (2 microM), repletion of the phenylephrine-sensitive store was inhibited. It is possible that refilling occurs in part through L-type Ca2+ channels.

Animals↗
PubMed1993

Distribution and characterization of vasoactive intestinal polypeptide binding in canine lower esophageal sphincter.

BACKGROUND: Vasoactive intestinal polypeptide (VIP) may be a nonadrenergic, noncholinergic inhibitory transmitter in the lower esophageal sphincter (LES). There is no biochemical evidence of VIP receptors in the LES. METHODS: Using membranes from canine LES, VIP receptor distribution and characterization were analyzed by radioligand binding and cross-linking experiments. RESULTS: High densities of saturable VIP receptors were found (maximum bound [Bmax], 539.2 fmol/mg in the synaptosome-enriched fraction [P2] and 732.7 fmol/mg in the smooth muscle, plasma membrane-enriched fraction [Mic II]), with high affinity for 125I-VIP (dissociation constant [Kd], 1.38 nmol/L in P2 and 1.40 nmol/L in Mic II). Competition binding studies suggested the presence of two binding sites, a high-affinity (inhibitor constant [Ki1], 0.064 nmol/L) and a low-affinity (Ki2, 2.68 nmol/L) binding site in P2 membranes, but only one binding site (Ki, 1.18 nmol/L) in Mic II membranes. Guanosine triphosphate-gamma-s pretreatment eliminated high-affinity binding in P2 membranes by conversion to binding sites of lower affinity (Ki, 2.82 nmol/L). Studies with a cross-linking agent identified VIP receptors in synaptosomal and smooth muscle plasma membrane fractions; a single polypeptide of approximately 60 kilodaltons was found in each membrane. CONCLUSIONS: Specific VIP receptors exist in both synaptosomal and smooth muscle plasma membrane of canine LES.

Animals↗
PubMed1993

LP-805, a releaser of endothelium-derived nitric oxide, activates an endothelial calcium permeable non-specific cation channel.

The actions of LP-805, a releaser of endothelium-derived nitric oxide, on Ca2+ permeable non-specific cation channel in cultured bovine pulmonary artery endothelial cells (BPAECs) were investigated using patch-clamp technique. In Ca2+ saline bath solution, 10 microM LP-805 increased inward and outward currents. LP-805 evoked currents were reversibly blocked by 50 microM La3+, an inorganic Ca2+ influx blocker. In Ca2+ and Na+ free saline bath solution, 10 microM LP-805 did not evoke these currents, when 2 mM Ca2+ was then added to the bath the inward current increased. Furthermore, in the Na+ saline bath solution (Ca2+ free), 10 microM LP-805 increased similar inward and outward currents, which were blocked by 50 microM La3+. LP-805 evoked currents were carried by either Ca2+ or Na+. With the pipette solution containing 11 mM EGTA, 10 microM LP-805 activated the inward and outward currents. The increase of inward and outward currents by 10 microM LP-805 was inhibited by 1 mM Ni2+ but not by 1 microM nicardipine or 50 microM SKF 96365. In conclusion, LP-805 increases Ca2+ influx into vascular endothelial cells through Ca2+ permeable non-specific cation channels. This may explain the release of endothelium-derived nitric oxide in endothelial cells by LP-805.

Animals↗
PubMed1993

Norepinephrine release in rat vas deferens. Effect of rauwolscine and BHT 920.

Norepinephrine (NE) overflow from field-stimulated rat was deferens preparations was quantified directly by electrochemical detection using high performance liquid chromatography. The effect of agonist (BHT 920) and antagonist (rauwolscine) of prejunctional alpha 2-adrenoceptors on NE overflow was assessed and compared with their effect on the smooth muscle mechanical response to field stimulation. Increasing the stimulation frequency from 2 to 30 Hz resulted in an increase in muscle tension together with an increase in NE overflow. Addition of 1 microM rauwolscine to the medium resulted in a significant increase in muscle contraction to field stimulation which reached a maximum at 5 Hz. On the other hand, NE overflow increased linearly with the frequency of stimulation within the range studied. Addition of 0.1 microM BHT 920 to the medium significantly decreased the amplitude of contractions at lower stimulation frequencies (2 to 10 Hz) but elicited no significant changes at high frequencies. BHT 920 did not significantly affect NE overflow for all range of stimulation frequency. The simultaneous recording of field-stimulation induced contractions and NE overflow indicates that in the rat vas deferens, rauwolscine acts like a pure alpha 2 adrenoceptor antagonist at a prejunctional level. BHT 920 did not appear to affect selectively prejunctional alpha 2 adrenoceptors but also may activate postjunctional alpha 1 adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1993

Nitric oxide as putative nonadrenergic noncholinergic inhibitory transmitter in the opossum sphincter of Oddi.

The sphincter of Oddi has a typical nonadrenergic noncholinergic inhibitory innervation; however, the transmitter of this inhibition has not been identified. The aim of the present study was to evaluate whether metabolites of the L-arginine--nitric oxide synthase pathway mediate neural inhibition in the sphincter of Oddi of the opossum. Electrical field stimulation at various frequencies (3, 5, and 10 pulses/s), performed in the presence of guanethidine (10(-6) M) to exclude adrenergic responses, caused a slight, but significant excitatory response of the sphincter of Oddi. The responses were more pronounced at the duodenal side of the sphincter of Oddi than on the hepatic side. When the electrical field stimulation was repeated after blockading muscarinic receptors, using atropine (10(-6) M), a potent inhibitory response was obtained. The inhibitory response to each of the various stimulation parameters was similar. Addition of L-arginine methyl ester (L-NAME, 2 x 10(-4) M) abolished and reversed the inhibitory effect of electrical field stimulation, resulting in a potent stimulatory effect. Higher frequencies (5 and 10 pulses/s) were more potent in causing a stimulatory response than lower frequencies (3 pulses/s). The excitatory effect of electrical field stimulation was blocked or reversed to inhibition when the amino acid L-arginine (2 x 10(-3) M) was added to the bath. In a second series of experiments, the inhibitory effect of electrical field stimulation in the presence of atropine and guanethidine was not prevented after the addition of methylene blue (5 x 10(-5) M), a substance that, in vascular smooth muscle, has been demonstrated to block cyclic GMP dependent inhibitory responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic Fibers↗
PubMed1993

Distinct pathways to refill ACh-sensitive internal Ca2+ stores in canine airway smooth muscle.

The ability of extracellular Ca2+ to refill internal Ca2+ stores of canine tracheal smooth muscle after a prior depletion by acetylcholine (ACh) was assessed using a novel sarcoplasmic reticulum (SR) Ca2+ pump inhibitor, cyclopiazonic acid (CPA). The transient contraction induced by ACh in a medium free of Ca2+ was used as an index for the content of agonist-sensitive intracellular Ca2+ stores. CPA inhibited in a concentration-dependent manner the refilling of the stores occurring during high KCl stimulation, and this inhibitory effect was independent of the external Ca2+ concentration. On the other hand, CPA was less effective in inhibiting the refilling occurring during prolonged ACh stimulation, especially when external Ca2+ concentration was raised. At 5.0 mM external Ca2+ or when 0.1 microM BAY 8644 was present in the medium, CPA was ineffective in inhibiting the refilling occurring during prolonged ACh stimulation. The maximum ACh-induced contraction in Ca(2+)-containing medium was independent of the extent of internal store Ca2+ load in the absence of L-type Ca2+ channel blocker but was highly dependent on the extent of internal Ca2+ load in the presence of the Ca2+ channel blocker. Hyperpolarization of the plasma membrane with the K+ channel opener cromakalim reduced the amplitude of ACh tonic contraction. Subsequent addition of nifedipine further reduced ACh tonic contraction. It is concluded that two different pathways for external Ca2+ are used to refill ACh-sensitive internal stores. One involves active Ca2+ uptake via a CPA-sensitive Ca2+ pump, and the other involves a CPA-insensitive pathway whose nature remains to be determined.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1993

Selective accumulation of methylene blue by interstitial cells of Cajal in canine colon.

The network of interstitial cells of Cajal (ICC) at the submucosal surface of the canine colon was selectively stained by incubation with 15-50 microM methylene blue for 30-45 min. The network was composed of regularly scattered ICC cell bodies interconnected by long processes. Circular muscle cells were unstained. Staining of neurons was limited to one or two axons within bundles. The ICC network had a thickness of a single cell, since no overlapping of ICC cell bodies was observed. The ICC network connected the circular muscle cells at the submucosal surface across the septa which circumferentially divided the circular muscle into lamellae. Methylene blue at 50 microM slightly decreased the resting membrane potential and increased the duration of slow waves, leading to an increase in the force of phasic contractions, with no significant influence on other slow-wave parameters. Methylene blue produced neither electrophysiological nor mechanical effects on circular muscle preparations from which the submuscular ICC network was removed, indicating that the excitatory effects of methylene blue on the full-thickness circular muscle layer were mediated by ICC. In summary, the three-dimensional aspects of the submuscular ICC network can be visualized after selective staining by methylene blue. This staining does not affect physiological characteristics of smooth muscle cells.

Animals↗
PubMed1993

Expression of gap junction connexin 43 and connexin 43 mRNA in different regional tissues of intestine in dog.

To determine the distribution of gap junction protein connexin 43 (Cx43) and the expression of Cx43 mRNA in different regions of canine small intestine and colon, modified Western blot and Northern blot techniques were used with a site-directed antibody raised against a synthetic peptide of Cx43 Anti-Cx43 (252-271) and a probe of 1.3-kb Cx43 cDNA. Equal amounts of plasma membrane enriched fraction (10 micrograms protein) from small intestinal and colonic circular muscle, longitudinal muscle, and colonic submucous plexus border of circular muscle (interstitial cells of Cajal rich layer, ICC) of the dog were resolved by 12% sodium dodecyl sulfate-polyacrylamide gel electrophoresis, transferred onto nitrocellulose, and blotted by chemiluminescent assay. Different yet characteristic ratios of the immunoreactive gap junction proteins located at 43 and 40 kDa were found in membranes from small intestinal and colonic circular smooth muscle, and ICC. These results suggest that gap junction Cx43 in dog heart, dog small intestinal and colonic circular muscle, and ICC is homologous to rat heart. Furthermore, with the use of Northern blot hybridization with a 1.3-kb Cx43 cDNA, a 3.0-kb message was observed in small intestinal and colonic circular muscles, longitudinal muscles, and ICC. However, the mRNA signal of small intestinal circular muscle was the strongest and that of longitudinal muscle was weakest, especially from colon longitudinal muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1993

Differential effects of putative protein kinase C inhibitors on contraction of rat aortic smooth muscle.

We investigated effects of three kinds of putative protein kinase C (PKC) inhibitors, calphostin C, 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7), and stauro-sporine, on aortic muscle contractions induced by KCl, phenylephrine, 12-O-tetradecanoylphorbol-13-acetate (TPA), and phorbol 12, 13-dibutyrate (PDBu). Calphostin C noncompetitively inhibited TPA-induced contractions in a concentration-dependent manner. At 10(-6) M, calphostin C completely abolished responses to TPA and also effectively inhibited PDBu-induced contractions. Such a concentration of calphostin C had no effect on KCl-induced contractions but decreased the maximal tension of phenylephrine-induced response curve by 35.3 +/- 6.6% H-7 (10(-5) M had little effect on TPA-induced contraction but significantly inhibited contractile responses to phenylephrine and KCl. Staurosporine (10(-8) M, 3 x 10(-8) M) inhibited contractile responses to KCl, phenylephrine, and TPA. We suggest that staurosporine and H-7, which are known to act on the catalytic domain of PKC carrying high degree of sequence homology with other protein kinases, are relatively nonselective for PKC. On the other hand, calphostin C acting on the regulatory domain of PKC, which is distinct from other protein kinases, may serve as a relatively more selective PKC inhibitor.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1993

Effect of ozone exposure in vivo on response of bronchial rings in vitro: role of intracellular Ca2+.

In this study we investigated the role of intracellular Ca2+ in ozone- (O3) induced airway hyperresponsiveness. Acetylcholine-induced airway responses were measured before and after inhalation of O3 (3 ppm, 30 min) or dry air. In vitro experiments were performed with intact ring segments of third- to fifth-order bronchi. Bronchial responses to carbachol (CCh) were evaluated in Krebs solution (2.5 mM Ca2+) and in Ca(2+)-free [0.1 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)] Krebs solution with or without indomethacin (IDM, 10(-5) M) and were expressed as percentage of the maximal KCl response (60 mM). Inhalation of O3, but not dry air, caused airway hyperresponsiveness to acetylcholine in vivo. Responses to 50% effective concentrations of CCh were similar in bronchial preparations from O3 and control animals (with or without IDM) in normal Krebs solution. In Ca(2+)-free solution, CCh induced a sustained (20-min) bronchial contraction. These contractions relaxed immediately when nifedipine or a high EGTA concentration was added to the organ bath. The sustained contraction was abolished when the tissues had been incubated with cyclopiazonic acid (10(-5) M), a novel inhibitor of the sarcoplasmic reticulum Ca2+ pump. After O3 exposure, responses of the bronchial smooth muscle (in Ca(2+)-free medium without IDM) were increased (P < 0.05) compared with controls during the first and second CCh stimulations. This O3-induced increase in response to CCh in Ca(2+)-free solution was abolished when the tissues were incubated with IDM.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Functional alterations in the aorta of the spontaneously hypertensive rat: pharmacological assessment with cyclopiazonic acid.

One of the changes in vascular smooth muscle membranes associated with hypertension is an alteration in Ca2+ handling. It has been unclear as to whether changes occurred at the plasma membrane or at the endoplasmic reticulum (ER) or both. Recently, cyclopiazonic acid (CPA) has been reported to inhibit selectively the ER Ca2+ pump. We aimed at determining the effect of ER Ca2+ pump inhibition by CPA on the contractility of aortic smooth muscle from 4- to 5-month-old SHR and age- and weight-matched WKY control rats. The responsiveness of the SHR tissues to phenylephrine or K+ was significantly reduced as compared with controls, although the sensitivity was not altered. Stimulation with phenylephrine (10 mumol/l) in Ca2(2+)-free medium caused a significantly reduced transient contraction in SHR as compared with control tissues. After pretreatment with CPA (30 mumol/l), this contraction was suppressed in SHR and WKY tissues. On the restoration of Ca2+, CPA induced a nifedipine (5 mumol/l) sensitive contraction, significantly larger in SHR than in WKY tissues. The relaxation rate to nifedipine of K(+)-induced contraction in CPA-treated SHR tissue was also reduced. We conclude that the ER Ca2+ pump in SHR aorta is less effective as compared with WKY tissue. The significantly greater CPA-induced contraction together with the reduced relaxation rate in the presence of CPA in SHR tissues as compared with controls suggests that Ca2+ handling was also altered at the plasma membrane.

Animals↗
PubMed1993

Nitric oxide synthase in the autonomic nervous system of canine ileum.

The synaptosomes from canine ileal deep muscular plexus possess a nitric oxide (NO)-sensitive soluble guanylate cyclase, as demonstrated by approximately 3- to 4-fold elevation of synaptosomal cyclic GMP levels in the presence of either 1 mM sodium nitroprusside or L-arginine (20-1,000 microM) plus 1 mM NADPH. The activating effect of L-arginine on synaptosomal soluble guanylate cyclase was related to its enzymatic conversion to citrulline by NO synthase. The synaptosomal NO synthase was found to exhibit both calcium-independent and calcium/calmodulin-dependent components accounting for approximately 2- to 2.5-fold and 7- to 8-fold increases in the basal activity, respectively. The absolute magnitude of these activities was several-fold greater compared to the activities observed in the isolated cells of circular smooth muscle. The synaptosomal Ca-independent and Ca/calmodulin-dependent NO synthase activities were inhibited by methylene blue and L-NG-arginine methyl ester. The NO synthase activity was also attenuated in the presence of cyclic AMP (10 microM). Such an inhibition was related primarily to the suppression of Ca-independent activity. The ability of enteric nerves to generate NO from L-arginine strongly suggests the involvement of this process in the biochemical mechanisms underlying the neurogenic control of intestinal motility.

Amino Acid Oxidoreductases↗
PubMed1993

Rauwolscine induces contraction in the dog mesenteric artery precontracted with KCl and endothelin-1: mediation via 5-hydroxytryptamine1-like receptors.

Rauwolscine, a selective alpha-2 adrenoceptor antagonist, elicited a sustained contraction in the dog mesenteric artery precontracted with 20 mM KCl or 10(-9) M endothelin-1. Cumulative concentration-response curves to rauwolscine were not shifted by spiperone, propranolol, pindolol, mianserin, ketanserin, prazosin or phenoxybenzamine at the concentration of 10(-6) M. The pA2 values against rauwolscine were 8.34 +/- 0.32 for methysergide, 8.52 +/- 0.22 for methiothepin and 5.84 +/- 0.27 for phentolamine, which were in good agreement with the pA2 values for those antagonists against 5-hydroxytryptamine (5-HT) in the dog mesenteric artery precontracted with 20 mM KCl. Contractile responses to 5-HT after pretreatment with 20 mM KCl were antagonized in an apparently competitive manner by 10(-5) M rauwolscine. In the absence of precontraction, rauwolscine also shifted 5-HT-induced contractions in a parallel manner. These data suggest that rauwolscine is a partial agonist with a lower intrinsic activity than 5-HT and acts at the same 5-HT1-like receptors as 5-HT, most probably 5-HT1D receptors, in the dog mesenteric artery precontracted with KCl.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1992

Pharmacological assessment of Ca2+ dependence of endothelin-1-induced response in rat aorta.

In rat aorta, endothelin-1 (ET-1) induced a slowly developing and sustained contraction in Ca(2+)-containing normal Krebs, nominally Ca(2+)-free Krebs, and Ca(2+)-free Krebs containing EGTA with a decreasing level of contraction. When ET-1-precontracted tissues were washed with Ca(2+)-free Krebs +50 microM EGTA, the tissues spontaneously and slowly relaxed. Readministration of Ca2+ during the early spontaneous relaxation phase caused a rapidly developing tonic contraction. When added during the late spontaneous relaxation phase, Ca2+ evoked slowly developing or, sometimes, biphasic contractions. In the presence of sarcoplasmic reticulum Ca(2+)-pump inhibitor, cyclopiazonic acid, the above biphasic contraction brought about by readministration of Ca2+ converted to a rapidly developing monophasic response. Thus, the first component of the biphasic contraction may be due to refilling of ET-1-sensitive Ca2+ store via the internal membrane Ca(2+)-pump. Furthermore, the ability of the phenylephrine-sensitive pool of internal Ca2+ to refill in the presence of 10(-8) M ET-1 suggests that the phenylephrine-sensitive pool differs from ET-1-sensitive pool and cannot be depleted by ET-1.

Animals↗
PubMed1992

An endothelial cell-line contains functional vasoactive intestinal polypeptide receptors: they control inwardly rectifying K+ channels.

Bovine endothelial cells cultured from pulmonary artery (ATCC cell line No. 209) were found to contain a high density of 125I-VIP (vasoactive intestinal polypeptide) binding sites. These were found to be saturable and to be fit by a single binding site model (Kd 1.8 nM; Bmax 534 fmol/mg protein). Studies of association and dissociation of 125I-VIP to this site revealed that binding was fully reversible and yielded a Kd value similar to that from equilibrium binding. However competition studies showed that VIP competed for binding at two sites (Ki1 1.2 x 10(-11) M, Ki2 4.7 x 10(-9) M; N1 = 21%, N2 = 77%; Ki a dissociation constant for inhibitor; N percentage of occupied receptors). [Phe1]VIP also competed at two sites, but VIP-(10-28), PHM, [4-Cl-D-Phe6,Leu17]VIP and [D-Ala4]VIP displaced all specific VIP binding in a simple competitive manner. These VIP binding sites were shown to be functional. In patch clamp studies VIP 10(-8)-10(-7) M inhibited opening of inwardly rectifying K+ channels on hyperpolarization. These channels were affected appropriately by alteration in the K(+)-gradient and by Ba2+ or Cs+. The VIP antagonist [4-Cl-D-Phe6, Leu17]VIP prevented or reversed the effects of VIP. These results show that functional VIP receptors are present in high density in a endothelial cell line and provide a possible model for analysis of the molecular biology of these receptors.

Animals↗
PubMed1992

The internal calcium store in airway muscle: emptying, refilling and chloride. Possible new directions for drug development.

This review examines the ionic mechanisms underlying acetylcholine (Ach) depolarization of airway smooth muscle and suggests that multiple mechanisms are involved. Increased chloride and nonspecific cation conductance, and decreased or rapidly inactivating potassium conductances seem to be involved. Chloride ions also seem to play an important role in determining whether Ca2+ remains inside or is replenished in the sarcoplasmic reticulum (SR). The physiological role of Ach-induced depolarization is analysed and is suggested to be the promotion of the refilling of Ca2+ stores, partly through a direct refilling of SR-Ca2+ stores by way of an L-type Ca2+ channel. This refilling is promoted by Ca2+ channel agonists and is independent of the transmembrane potential. Ca(2+)-release by a variety of agonists leads to depolarization and stable membrane oscillations which depend on the action of the Ca(2+)-store uptake mechanisms in order to function. These oscillations may play a role in prolonged bronchoconstriction. Better knowledge of the control mechanisms of Cai2+ is likely to reveal new targets for the therapy of asthma and provide a better understanding of the function of airway smooth muscle.

Acetylcholine↗