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Biomedical subjects

J Jury

Publications and source records attributed to J Jury.

14 recordsLinked to original sources
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↗
PubMed1992

K(+)-channel blockers do not decrease acetylcholine depolarizations in canine trachealis.

Using the double sucrose gap, we have examined the role of K+ channels in the cholinergic depolarizations in response to field stimulation and acetylcholine (Ach) in canine trachealis. Acetylcholine-like depolarization per se decreased electrotonic potentials from hyperpolarizing currents. The net effect of acetylcholine (10(-6) M) depolarization on membrane conductance was a small increase after the depolarization was compensated by current clamp. Reversal potentials for acetylcholine depolarization and for the excitatory junction potential (EJP) were determined by extrapolation to be 20-30 mV positive to the resting potential, previously shown to be approximately -55 mV. They were shifted positively by tetraethylammonium ion (TEA) at 20 mM or Ba2+ at 1 mM. TEA or Ba2+ initially depolarized the membrane and increased membrane resistance. Repolarization of the membrane restored any reductions in EJP amplitudes associated with depolarization. After 15 min, the membrane potential partially repolarized, and acetylcholine-induced depolarization and contractions were then increased by TEA. 4-Aminopyridine depolarized the membrane but decreased membrane resistance. Apamin (10(-6) M), charybdotoxin (10(-7) M), and glybenclamide (10(-5) M) each failed to significantly depolarize membranes, increase membrane resistance, or reduce EJP amplitudes or depolarization to 10(-6) M Ach. Glybenclamide reduced depolarizations to added acetylcholine slightly. TEA occasionally reduced the EJP markedly, but this was shown to be most likely a prejunctional effect mediated by norepinephrine release. TEA alone among K(+)-channel blockers slowed the onset and the time courses of the EJP as well as the acetylcholine-induced depolarization. K(+)-channel closure cannot be a complete explanation of acetylcholine-induced membrane effects on this tissue. Acetylcholine must have increased the conductance of an ion with a reversal potential positive to the resting potential in addition to any effect to close K+ channels.

Acetylcholine↗
PubMed1992

A mediator derived from arginine mediates inhibitory junction potentials and relaxations in lower esophageal sphincter: an independent role for vasoactive intestinal peptide.

This study provides mechanical and electrophysiological evidence to show that a metabolite of arginine, not vasoactive intestinal peptide (VIP), is the putative nonadrenergic noncholinergic (NANC) inhibitory mediator in canine and opossum lower esophageal sphincters (LES). Relaxations of spontaneous active tension by electrical field stimulation (FS) at parameters that induced tetrodotoxin (TTX)-sensitive responses were abolished by L-N omega-arginine methyl ester (L-NAME) at 10(-4) M and restored by L-arginine (10(-3) M) but not D-arginine (10(-3) M). TTX-insensitive relaxations to 5-ms pulses were unaffected by L-NAME, L- or D-arginine. VIP (10(-6) M) caused maximum relaxations of basal tension in both the opossum and canine LES. However these relaxations, unlike those from FS were unaffected by L-NAME. Methylene blue (5 x 10(-5)M) increased basal tension of the LES in each species, and did not inhibit the relaxation to FS or VIP, but often increased the amplitudes of these responses due to the increase in basal tension. In parallel experiments NANC inhibition of body circular muscle from opossum esophagus was abolished by methylene blue. Electrophysiological studies using micro-electrodes revealed that NANC inhibition was associated with inhibitory junction potentials in the canine LES. These were inhibited by L-NAME and restored by L-arginine but not D-arginine. In contrast, 10(-6) M VIP in canine LES did not induce any change in membrane potential during a 20-min superfusion. Sodium nitroprusside also hyperpolarized sphincteric muscle and its effects were not affected by L-NAME.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cromakalim and K+ channels in canine trachealis.

The effects of cromakalim and glibenclamide on membrane properties and responses to acetylcholine of canine trachea were studied in the double sucrose gap to evaluate the presence and function of ATP-sensitive K+ channels. Cromakalim produced a concentration-dependent hyperpolarization of muscle membrane potential which at maximum brought the membrane potential near the potassium equilibrium potential. Current clamping by hyperpolarizing current to this equilibrium potential abolished the hyperpolarization but not the membrane resistance decrease to cromakalim. Glibenclamide had no effect on resting membrane properties but reduced or abolished effects of cromakalim. Another K+ channel antagonist, tetraethylammonium at 20 mM, also reduced the effects of cromakalim, but 4-aminopyridine (5 mM), Ba2+ (1 mM), and apamin (10(-6) M) had no antagonistic effect. The EJP produced on stimulation of cholinergic nerves sometimes increased just after cromakalim-induced hyperpolarization, but within 5-10 min as membrane resistance dramatically fell it was reduced, as was the depolarization to infused acetylcholine. Initially the reduction in EJP amplitude could be partially overcome by applying hyperpolarizing currents or by applying a second field stimulation; later the EJP was reduced further and was unaffected by these procedures. Even when depolarization to acetylcholine was markedly reduced, the contraction was not. Glibenclamide had no effects alone but antagonized all the effects of cromakalim. These results suggest that ATP-sensitive cromakalim activated K+ channels are present in canine trachea but are usually closed during resting conditions under our experimental conditions. When they are opened by cromakalim, they hyperpolarize to near EK, markedly decrease membrane resistance and reduce the depolarization response to acetylcholine, probably by short circuiting the acetylcholine-induced current.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Role of depolarization and calcium in contractions of canine trachealis from endogenous or exogenous acetylcholine.

The relationships of the electrical to the mechanical responses of the canine trachealis muscle during stimulation of its cholinergic nerves or exposure to exogenous acetylcholine were recorded in the single or the double sucrose gap. At 27 degrees C, the responses to a train of stimuli consisted of a transient depolarization excitatory junction potential of 10-30 mV followed by fading oscillations and contractions. When stimulus parameters were varied in the single sucrose gap, contractions were more closely associated with the occurrence of and varied in duration with the oscillations rather than with the amplitude of the EJP. Acetylcholine superfused at a concentration of 10(-6) M for 30 s caused a prolonged depolarization of 10-20 mV, but a much larger contraction than could be elicited by nerve stimulation. None of the responses to acetylcholine was significantly affected by the Ca channel antagonists, nifedipine, nitrendipine, or verapamil in Ca channel blocking concentrations. When tissues were exposed to a Ca-free medium, the excitatory junction potentials and oscillations rapidly disappeared, but the electrical and mechanical responses to acetylcholine persisted and only gradually disappeared with repetitive exposures. Furthermore, in a medium with normal Ca2+ in the double sucrose gap, depolarization by 10-15 mV with an applied current caused no contraction, and repolarization to the normal membrane potential during acetylcholine-induced contraction caused no relaxation. Tetraethylammonium ion (20 mM) depolarized the membrane, increased membrane resistance, and enhanced the secondary oscillations and contractions after field stimulation. No other K(+)-channel blocker tested (Ba2+, apamin, 4-aminopyridine, glibenclamide, charybdotoxin) had the effect of prolonging secondary oscillations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Nitric oxide may be the final mediator of nonadrenergic, noncholinergic inhibitory junction potentials in the gut.

This study tested the hypothesis that the final mediator of nonadrenergic, noncholinergic (NANC) inhibitory junction potentials (ijps) and associated relaxation responses was nitric oxide (NO) or a related substance and not vasoactive intestinal polypeptide (VIP). We used opossum esophagus body circular muscle and canine intestine circular muscle. In both these tissues, ijps had reversal potentials near the potassium equilibrium potential, (EK); in esophagus the ijps were apamin insensitive, but in the intestine they were partially apamin sensitive. N omega-Nitro-L-arginine methyl ester (NAME) (10(-5) to 5 x 10(-4) M) abolished ijps in both tissues, an effect overcome by 10(-3) M L-arginine but not D-arginine. NAME increased input resistance of esophagus tissues in the double sucrose gap but caused no significant depolarization in the sucrose gap or in studies with microelectrodes. Contractions and basal tension were increased in both tissues by NAME. The apamin sensitive and insensitive ijp components in canine muscle were both abolished by NAME, but the time course of this abolition was different for the two components. Methylene blue (10-50 microM) with variable rapidity and extent inhibited ijps in both tissues, but L-arginine could not overcome this effect. Methylene blue, like NAME, did not depolarize detectably but enhanced the contractile activity. VIP (10(-6) M) had very small effects in both tissues, little or no hyperpolarization and increased input resistance in esophagus, these effects were not changed by NAME, and VIP did not affect ijps. We conclude that NO may be the final mediator of NANC-initiated inhibitory junction potentials in gastrointestinal circular smooth muscle.

Animals↗
PubMed1989

Vasoactive intestinal polypeptide and non-adrenergic, non-cholinergic inhibition in lower oesophageal sphincter of opossum.

1. Field stimulation or vasoactive intestinal polypeptide (VIP) relaxed lower oesophageal sphincter (LOS) from North American opossum. Pretreatment with carbachol in Cl-ion-containing or Cl-ion-free Krebs solution or with 10(-3) M 9-aminoacridine abolished or markedly reduced relaxation due to VIP applied exogenously but not that elicited by field stimulation of non-adrenergic, non-cholinergic nerves. 2. Inhibitory junction potentials (7.5 +/- 1.2 mV, n = 5) could be recorded in LOS strips with the sucrose gap technique. They lacked significant after-depolarizations but were accompanied by decreased membrane resistance (61 +/- 6%, n = 3). In these strips, VIP (10(-6) M) produced small hyperpolarizations (2.1 +/- 1.1 mV, n = 5) sometimes followed by membrane potential oscillations but no change in conductance. 3. Removal of external chloride depolarized the membranes (7.6 +/- 1.7 mV) but did not prevent the hyperpolarization to VIP or the occurrence of inhibitory junction potentials. Restoration of external chloride repolarized the cells. It appears that an appreciable chloride conductance may be present in sphincter muscle cells and this may cause them to be more depolarized than non-sphincter muscle. 4. We conclude that it is very unlikely that VIP is the inhibitory NANC neurotransmitter since it does not mimic the inhibitory junction potential.

Animals↗
PubMed1987

Muscarinic receptors on nerves and muscles in opossum esophagus muscularis mucosa.

The muscarinic receptors of muscularis mucosa have some recognition properties that suggest they resemble receptors of the M1 subtype. The nerves of these tissues also contain muscarinic receptors which inhibit tonic contractions caused by release of a substance-P-like material by field stimulation. These receptors also appear to be M1 in type as they are maximally activated by McNeil A343 as well as by carbachol (pD2, 5.5 and 7.5, respectively). They are also inhibited by pirenzepine, as well as by atropine (negative logarithms of the required dose for 50% inhibition or potentiation, 6.6-6.7 compared with 8.2-8.3). Hexahydrosiladifenidol, an antagonist selective or M2 receptors of guinea pig ileum, had a low (approximately 7.1) pA2 value for antagonism of both agonists in smooth muscle in this tissue. However, it was closer to atropine in potency with respect to potentiating tonic responses to field stimulation or to inhibiting phasic responses to field stimulation than it was to antagonizing smooth muscle contractions. Thus, atropine was about 40 times more potent than pirenzepine and 2-5 times more potent than hexahydrosilafenidol. There were some quantitative differences in the effectiveness of these three antagonists in blocking the phasic (acetylcholine-mediated) response to field stimulation. Atropine was 70-100 times more potent than pirenzepine and 8-25 times more potent than hexahydrosiladifenidol. This greater potency difference for inhibition of phasic contractions compared with potentiation of tonic contractions was discussed. This tissue appears to be one of the first smooth muscles in which both nerves and muscles contain muscarinic receptors with some recognition properties resembling those of the M1 subtype.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1986

Receptors for neurotransmitters in opossum oesophagus muscularis mucosa.

Muscularis mucosa of the distal oesophagus of the opossum contains nerves which release acetylcholine and substance P(SP)-like material on field stimulation. The release of SP-like material appeared to be inhibited by the presence of exogenous muscarinic agonists and potentiated by muscarinic antagonists. Analysis of the postjunctional receptors involved using carbachol, McNeil A-343 (McN A-343), atropine and pirenzepine suggested that the receptors were not typical M2-muscarinic receptors. The potency of agonists and antagonists were consistent with some receptor properties resembling M1-muscarinic receptors. Prejunctional receptors to opiates, adenosine, agonists at alpha 2-adrenoceptors and prostaglandins were not detected. Receptors for tachykinins were present on the muscle in this tissue, but did not resemble clearly either SP-E or SP-P type receptors. They appear to be undifferentiated since most tachykinins were of similar potency. These results suggest that not all postjunctional muscarinic receptors in intestinal smooth muscle are M2 in type. There may be a gradation of types between M1 and M2.

Animals↗
PubMed1985

Unusual potassium channels mediate nonadrenergic noncholinergic nerve-mediated inhibition in opossum esophagus.

Field stimulation of the circular muscle of the opossum esophagus produces a transient hyperpolarization (inhibitory junction potential, IJP) followed by an "off" depolarization. A similar nonadrenergic, noncholinergic (NANC) response in guinea pig taenia caecum has been shown to be due to an increase in the potassium ion permeability of the smooth muscle cell membrane. Double sucrose gap studies showed a decrease in resistance during the IJP, and a reversal at an estimated membrane potential of about -90 mV (4 mM K+). The reversal potential was dependent on the extracellular potassium concentration, shifting to -75 mV when the potassium in the superfusion medium was increased to 10 mM. The IJP in the opossum esophageal circular smooth muscle is therefore like the IJP of the guinea pig taenia caecum in that it is probably due to a selective increase in potassium ion permeability. Potassium conductance blocking agents, tetraethylammonium chloride (TEA, 20 mM) and 4-aminopyridine (4-AP, 5 mM) both caused a depolarization of the smooth muscle cell membrane, but TEA increased the membrane resistance, whereas 4-AP did not affect the membrane conductance in a consistent way. A decrease in IJP amplitude owing to these agents was not apparent. Apamin (10 microM) did not affect the membrane potential, the membrane resistance, or the IJP. Quinine (0.1 mM) produced effects quantitatively similar to those of TEA. Quinine (1 mM) did abolish the IJP, however, this was likely due to a blockade of impulse transmission of the intramural nerves.(ABSTRACT TRUNCATED AT 250 WORDS)

4-Aminopyridine↗
PubMed1985

Muscarinic inhibition of canine small intestinal motility in vivo.

The quiescent canine gastrointestinal tract responsed to close intraarterial acetylcholine with an atropine-sensitive, hexamethonium, and tetrodotoxin-insensitive contraction, thus suggesting acetylcholine interacts with a muscarinic receptor located on the muscle. When the gut is actively contracting (spontaneously, in response to field stimulation or to motilin), acetylcholine caused a contraction followed by prolonged inhibition of contractions. No such inhibition was apparent after tetrodotoxin; therefore, the receptor for acetylcholine-induced inhibition was apparently on nerves. Neither the acetylcholine-induced excitation nor the inhibition was altered by hexamethonium or reserpine treatment. Both inhibitory and excitatory responses were greatly reduced by atropine, suggesting that both receptors were muscarinic in nature. McNeil A343 produced inhibition but no excitation. Tetrodotoxin, hexamethonium, reserpine, and pirenzepine all increased the concentration of McNeil A343 required for production of 50% inhibition, suggesting it acts via multiple mechanisms. Furthermore, pirenzepine reduced both the inhibitory and excitatory response to acetylcholine, suggesting that it is nonselective in its action on the neural inhibitory or muscular excitatory receptors. We suggest that the presynaptic muscarinic receptor responsible for inhibitory effects of acetylcholine is on the postganglionic cholinergic neuron itself and constitutes an important negative-feedback loop to reduce excessive cholinergic output. Although such a mechanism has been found in vitro previously, this is the first report in vivo in canine small intestine.

(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethy↗
PubMed1985

Capsaicin effects on muscularis mucosa of opossum esophagus: substance P release from afferent nerves?

The effects of capsaicin on the function and structure of muscularis mucosa of opossum esophagus were studied. In this tissue there are numerous nerves containing a substance P-like immunoreactive substance (SPLS), and electrical field stimulation (EFS) leads to a phasic response that appears to be due to release of acetylcholine, followed by a tonic response at higher frequencies of stimulation that appears to be due to release of a SPLS. The acetylcholine released by EFS and exogenous muscarinic agonists inhibits release of this SPLS (8). In the present study capsaicin (5 X 10(-5) M) was shown to cause a tonic submaximal contraction in most cases. This was prevented by substance P tachyphylaxis and by pretreatment with the partial agonist [D-Pro2, D-Trp7,9]substance P, the antagonist [D-Arg1, D-Trp7, Leu11]substance P, and tetrodotoxin. This response to capsaicin could not be repeated even after 2 h. Capsaicin also abolished the tonic response to high-frequency EFS without affecting phasic responses and reduced markedly the enhanced tonic response after atropine had abolished the phasic response. This occurred with or without a preliminary contraction to capsaicin. This tonic response to high-frequency EFS recovered completely 1-2 h after washing out capsaicin. Then, a further administration of capsaicin had no direct effect but again abolished tonic responses to EFS. Capsaicin reduced responses to exogenous substance P or carbachol only partially. When tissues were fixed and studied after capsaicin had abolished tonic responses to EFS, specific damage to nerve varicosities or synaptic vesicles in nerve varicosities could not be demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗