scholarly journals Hemin and Zinc Protoporphyrin IX Affect Granisetron Constipating Effects In Vitro and In Vivo

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Addolorata Zigrino ◽  
Valentina Leo ◽  
Giuseppe Renna ◽  
Monica Montagnani ◽  
Maria Antonietta De Salvia
Keyword(s):  
Protoporphyrin Ix ◽  
Electrical Field Stimulation ◽  
Zinc Protoporphyrin ◽  
Electrical Field ◽  
Anticancer Chemotherapy ◽  
Protein Levels ◽  
Basal Activity ◽  
Per Se

Granisetron is a 5-HT3 receptors antagonist used in the management of emesis associated with anticancer chemotherapy. It affects intestinal motility with constipating effect. Since the pathway heme oxygenase/carbon monoxide (HO/CO) is involved in gastrointestinal motility, we evaluated the possible interplay between granisetron and agents affecting HO/CO pathways such as zinc protoporphyrin IX (ZnPPIX), an HO inhibitor, or hemin, an HO-1 inducer. ZnPPIX (10 µM) or hemin (10 µM), but not granisetron (0.1, 0.3, 1 µM), affected spontaneous basal activity recorded in rat duodenal strips, in noncholinergic nonadrenergic conditions. Granisetron restored spontaneous basal activity after ZnPPIX, but not after hemin. ZnPPIX decreased and hemin increased the inhibition of activity after electrical field stimulation (EFS), but they did not affect the contraction that follows the relaxation induced by EFS called off contraction. Granisetron did not alter the response to EFS per se but abolished both ZnPPIX and hemin effect when coadministered. In vivo study showed constipating effect of granisetron (25, 50, 75 µg/kg/sc) but no effect of either ZnPPIX (50 µg/kg/i.p.) or hemin (50 µM/kg/i.p.). When coadministered, granisetron effect was abolished by ZnPPIX and increased by hemin. Specimens from rats treated in vivo with hemin (50 µM/kg/i.p.) showed increased HO-1 protein levels. In conclusion, granisetron seems to interact with agents affecting HO/CO pathway both in vitro and in vivo.

Release of epithelium-derived PGE2 from canine trachea after antigen inhalation

1998 ◽  
Vol 274 (2) ◽  
pp. L220-L225 ◽  
Author(s):  
I. McGrogan ◽  
L. J. Janssen ◽  
J. Wattie ◽  
P. M. O’Byrne ◽  
E. E. Daniel
Keyword(s):  
Smooth Muscle ◽  
Electrical Field Stimulation ◽  
Tracheal Smooth Muscle ◽  
Organ Bath ◽  
Field Stimulation ◽  
Electrical Field ◽  
Concentration Response Curve

To investigate the role of prostaglandin (PG) E2 in allergen-induced hyperresponsiveness, dogs inhaled either the allergen Ascaris suum or vehicle (Sham). Twenty-four hours after inhalation, some animals exposed to allergen demonstrated an increased responsiveness to acetylcholine challenge in vivo (Hyp-Resp), whereas others did not (Non-Resp). Strips of tracheal smooth muscle, either epithelium intact or epithelium denuded, were suspended on stimulating electrodes, and a concentration-response curve to carbachol (10−9 to 10−5 M) was generated. Tissues received electrical field stimulation, and organ bath fluid was collected to determine PGE2content. With the epithelium present, all three groups contracted similarly to 10−5 M carbachol, whereas epithelium-denuded tissues from animals that inhaled allergen contracted more than tissues from Sham dogs. In response to electrical field stimulation, Hyp-Resp tissues contracted less than Sham tissues in the presence of epithelium and more than Sham tissues in the absence of epithelium. PGE2release in the muscle bath was greater in Non-Resp tissues than in Sham or Hyp-Resp tissues when the epithelium was present. Removal of the epithelium greatly inhibited PGE2release. We conclude that tracheal smooth muscle is hyperresponsive in vitro after in vivo allergen exposure only when the modulatory effect of the epithelium, largely through PGE2 release, is removed.

Airway smooth muscle responsiveness from dogs with airway hyperresponsiveness after O3 inhalation

1988 ◽  
Vol 65 (1) ◽  
pp. 57-64 ◽  
Author(s):  
G. L. Jones ◽  
P. M. O'Byrne ◽  
M. Pashley ◽  
R. Serio ◽  
J. Jury ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Potassium Chloride ◽  
Airway Smooth Muscle ◽  
Airway Hyperresponsiveness ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Electrical Field ◽  
Trachealis Muscle

Airway hyperresponsiveness occurs after inhalation of O3 in dogs. The purpose of this study was to examine the responsiveness of trachealis smooth muscle in vitro to electrical field stimulation, exogenous acetylcholine, and potassium chloride from dogs with airway hyperresponsiveness after inhaled O3 in vivo and to compare this with the responsiveness of trachealis muscle from control dogs. In addition, excitatory junction potentials were measured with the use of single and double sucrose gap techniques in both groups of dogs to determine whether inhaled O3 affects the release of acetylcholine from parasympathetic nerves in trachealis muscle. Airway hyperresponsiveness developed in all dogs after inhaled O3 (3 ppm for 30 min). The acetylcholine provocative concentration decreased from 4.11 mg/ml before O3 inhalation to 0.66 mg/ml after O3 (P less than 0.0001). The acetylcholine provocative concentration increased slightly after control inhalation of dry room air. Airway smooth muscle showed increased responses to both electrical field stimulation and exogenous acetylcholine but not to potassium chloride in preparations from dogs with airway hyperresponsiveness in vivo. The increased response to electrical field stimulation was not associated with a change in excitatory junctional potentials. These results suggest that a postjunctional alteration in trachealis muscle function occurs after inhaled O3 in dogs, which may account for airway hyperresponsiveness after O3 in vivo.

Mechanism underlying ozone-induced in vitro hyperresponsiveness in canine bronchi

1991 ◽  
Vol 261 (2) ◽  
pp. L55-L62
Author(s):  
L. J. Janssen ◽  
P. M. O'Byrne ◽  
E. E. Daniel
Keyword(s):  
Airway Hyperresponsiveness ◽  
Electrical Field Stimulation ◽  
Progressive Decrease ◽  
Electrical Field ◽  
Thromboxane Receptor ◽  
Direct Measurements ◽  
Thromboxane Receptor Antagonist ◽  
Over Time

The effects of ozone inhalation on the contractility of canine bronchi and the mechanisms underlying any changes observed were investigated. Ozone inhalation caused acetylcholine airway hyperresponsiveness in vivo. Isolated segments of bronchi (3rd to 5th order) from dogs previously exposed to ozone (or normal air) were mounted in organ baths. Contractile responses to electrical field stimulation (FS) in all tissues decreased in magnitude over time (measured at 10, 120, 210, and 300 min after mounting tissues in the organ baths); responses to 150 mM KCl did not show such a progressive decrease. Ozone inhalation produced a dramatic enhancement of FS responses, a smaller enhancement of responses to carbachol (10(-8)-10(-4) M), and no change in responses to KCl (150 mM). In the presence of 10(-5) M indomethacin, all responses were enhanced and tended to increase in magnitude over time; indomethacin also abolished the differences in responsiveness between the control and ozone-exposed tissues. In the presence of the thromboxane receptor antagonist L-670,596 (10(-8) M), the magnitudes of all FS responses showed a progressive decrease over time while KCl responses did not; again, the differences in FS responses between control and ozone-exposed tissues were decreased or made insignificant. In conclusion, ozone produced airway hyperresponsiveness in vivo and hyperresponsiveness in canine bronchi in vitro via decreased prejunctional and postjunctional inhibition (likely mediated by prostaglandin E2) and increased prejunctional excitation mediated by thromboxane A2. However, direct measurements of mediator release should be carried out to reach a firm conclusion.

Allergen-induced airway hyperresponsiveness in Brown-Norway rat: role of parasympathetic mechanisms

1993 ◽  
Vol 75 (1) ◽  
pp. 279-284 ◽  
Author(s):  
W. Elwood ◽  
T. Sakamoto ◽  
P. J. Barnes ◽  
K. F. Chung
Keyword(s):  
Airway Hyperresponsiveness ◽  
Allergen Challenge ◽  
Electrical Field Stimulation ◽  
Airway Responsiveness ◽  
Brown Norway ◽  
Field Stimulation ◽  
Electrical Field ◽  
Norway Rat

Enhanced parasympathetic mechanisms may contribute to airway hyperresponsiveness. The present study examined whether the in vivo increase in airway responsiveness seen 18–24 h after either a single or chronic aerosolized allergen challenge protocol in actively sensitized Brown-Norway rats was due to altered parasympathetic mechanisms. The roles of central and reflex vagal mechanisms were studied by performing bilateral cervical vagotomy before measurement of airway responsiveness. Bilateral vagotomy failed to reduce the increase in airway responsiveness after either a single or chronic allergen challenge. The roles of increased neural release of acetylcholine (ACh) and increased end organ responsiveness were studied in vitro. The isometric responses of tracheal and bronchial strips to both electrical field stimulation and exogenously applied ACh from rats exposed both to single and chronic allergen challenges were compared with those from saline-exposed rats. The responses to electrical field stimulation and to exogenous ACh were not significantly enhanced 18–24 h after either protocol. We conclude that the airway hyperresponsiveness observed in this allergic rat model is not mediated through an enhancement of parasympathetic mechanisms.

Enteric locus of action of prokinetics: ABT-229, motilin, and erythromycin

2000 ◽  
Vol 278 (5) ◽  
pp. G744-G752 ◽  
Author(s):  
Sushil K. Sarna ◽  
Asensio Gonzalez ◽  
Robert P. Ryan
Keyword(s):  
Single Cells ◽  
Circular Muscle ◽  
Electrical Field Stimulation ◽  
Conscious State ◽  
Presynaptic Neuron ◽  
Electrical Field ◽  
Neuroeffector Junction ◽  
Presynaptic Neurons

We investigated the in vivo and in vitro locus of actions of prokinetics: motilin, erythromycin, and ABT-229. The test substances were infused close intra-arterially in short segments of the jejunum in the intact conscious state. Each prokinetic acted on a presynaptic neuron and utilized at least one nicotinic synapse to stimulate circular muscle contractions. The final neurotransmitter at the neuroeffector junction was ACh. Motilin and erythromycin, but not ABT-229, also released nitric oxide. Each prokinetic utilized somewhat different subtypes of muscarinic, serotonergic, tachykininergic, and histaminergic receptors, except for the M3 receptor, which was common to all of them. In contrast, none of the prokinetics stimulated contractions in mucosa-free or mucosa-attached muscle strips, or rings, even though methacholine or electrical field stimulation induced phasic contractions in all of them. The prokinetics also did not release ACh in longitudinal muscle-myenteric plexus preparations. Each prokinetic, however, decreased the length of enzymatically dispersed single cells. In conclusion, each prokinetic may act on a different subset of presynaptic neurons that converge on the postsynaptic cholinergic and nonadrenergic noncholinergic motoneurons. The presynaptic neurons may be impaired in the muscle bath environment.

Multiple responses to electrical field stimulation in circular muscle of canine gastric corpus

1984 ◽  
Vol 62 (8) ◽  
pp. 912-918 ◽  
Author(s):  
Yasushi Sakai ◽  
Edwin E. Daniel
Keyword(s):  
Substance P ◽  
Circular Muscle ◽  
Electrical Field Stimulation ◽  
Scorpion Venom ◽  
Adrenergic Blockade ◽  
Field Stimulation ◽  
Electrical Field ◽  
Gastric Corpus

Innervation of circular muscle of the canine stomach studied in vitro was investigated by subjecting muscle strips to electrical field stimulation. Strips were cut from the lesser curvature of the gastric corpus and stimulated with 10-s trains of 0.5-ms pulses at 0.5–20 Hz, 40 V. Most responses were classified into one of three types. In general, field stimulation tended to elicit sequences of varying magnitudes of transient on-contraction, on-relaxation, off-relaxation, off-contraction. Responses were abolished by tetrodotoxin. On-contraction was almost abolished by atropine plus desensitization by 5-hydroxytryptamine (5-HT) or substance P. On-relaxation and off-relaxation were not affected by adrenergic blockade, methysergide, apamin, or 4-aminopyridine. ATP usually caused contraction and slightly diminished relaxation to field stimulation. Vasoactive intestinal polypeptide (VIP) had little effect on tone and response to field stimulation. Relaxation disappeared after scorpion venom treatment. This probably resulted from depletion of the transmitter which mediates relaxation. Off-contraction was reduced by atropine, desensitization by 5-HT or substance P, cromoglycate, indomethacin or ATP, but was not affected by adrenergic blockade, hexamethonium, methysergide, mepyramine, or VIP. The findings suggest that innervation of gastric corpus circular muscle included excitatory cholinergic and both excitatory and inhibitory noncholinergic, nonadrenergic innervation. However, the responses of circular muscle to field stimulation in vitro were drastically different from those obtained previously in vivo, suggesting damage or altered inputs to circular muscle when strips of circular muscle are studied.

scholarly journals Switching metalloporphyrin binding specificity of a b-type cytochrome to fluorogenic zinc by design

2019 ◽  
Author(s):  
B. J. Bowen ◽  
A. R. McGarrity ◽  
J-Y. A. Szeto ◽  
C. R. Pudney ◽  
D. D. Jones
Keyword(s):  
Design Process ◽  
Protoporphyrin Ix ◽  
Binding Specificity ◽  
Zinc Protoporphyrin ◽  
Iterative Design ◽  
New Variant

AbstractMetalloporphyrins play important roles in areas ranging from biology to nanoscience. Biology uses a narrow set of metal centres comprising mainly of iron and magnesium. Here, we convert metalloporphyrin specificity of cytochrome b562 from iron (haem) to fluorogenic zinc protoporphyrin IX (ZnPP). Through a computationally guided iterative design process, a variant with a near total preference for ZnPP was generated representing a switch in specificity. The new variant greatly enhanced (≥60 fold) the negligible aqueous fluorescence of free ZnPP in vitro and in vivo.Abstract Figure

Myogenic and neurogenic mechanisms and arachidonate metabolites in bronchial muscle response to allergen

1997 ◽  
Vol 273 (6) ◽  
pp. L1118-L1125 ◽  
Author(s):  
L. J. Janssen ◽  
I. McGrogan ◽  
J. Wattie ◽  
P. M. O’Byrne ◽  
E. E. Daniel
Keyword(s):  
Airway Hyperresponsiveness ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Electrical Field ◽  
Muscle Response ◽  
Arachidonate Metabolites ◽  
Evoked Contractions ◽  
Bathing Fluid

We investigated allergen-induced airway hyperresponsiveness (AH) in bronchial tissues obtained from dogs that inhaled Ascaris suum leading to AH (RESP) in vivo or that exhibited no change (NON-RESP) as well as from dogs that inhaled saline (SHAM). RESP tissues were not hyperresponsive to KCl or to carbachol, whereas contractions to electrical field stimulation (EFS) were reduced. This reduction was reversed partially by indomethacin and completely by replacement of the bathing fluid. Radioimmunoassay revealed marked elevation of prostaglandin (PG) E2 generation in RESP tissues compared with SHAM and NON-RESP tissues. EFS-evoked contractions were often followed by a slowly developing secondary contraction in RESP tissues but not in SHAM or NON-RESP tissues. However, indomethacin unmasked such secondary contractions in many SHAM and NON-RESP tissues and markedly enhanced those in RESP tissues, whereas L-655,240 (thromboxane A2/PGD2receptor antagonist) abolished such contractions in all groups. We were unable to detect thromboxane using radioimmunoassay. We conclude that allergen-induced AH involves altered generation of cyclooxygenase metabolites of arachidonic acid (particularly PGE2) as well as of a nonprostanoid inhibitory factor; as such, the responsiveness of the tissue in vitro is dependent on the relative levels of inhibitory and excitatory metabolites.

Immune sensitization augments epithelium-dependent spontaneous tone in guinea pig trachealis

1994 ◽  
Vol 266 (5) ◽  
pp. L485-L492 ◽  
Author(s):  
I. M. Ndukwu ◽  
J. Solway ◽  
K. Arbetter ◽  
K. Uzendoski ◽  
A. R. Leff ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Electrical Field Stimulation ◽  
Field Stimulation ◽  
Active Tension ◽  
Electrical Field ◽  
Spontaneous Tone ◽  
Comparable Magnitude ◽  
All Treatment

We examined epithelial modulation of tracheal smooth muscle (TSM) responsiveness in vitro from guinea pigs receiving active immune sensitization in vivo. Initially, guinea pigs were either ovalbumin sensitized (by aerosol) or sham sensitized with normal saline; TSM responsiveness was assessed isometrically as active tension (AT) after equilibration by electrical field stimulation in vitro. For epithelium-intact (Epi+) tissues, sensitization caused an increase in baseline active spontaneous tone (1.89 +/- 0.20 g AT) vs. sham-sensitized tissues (1.18 +/- 0.28 g AT; P = 0.02). Spontaneous tone in sensitized TSM in which the epithelium was removed (Epi-) (1.01 +/- 0.14 g AT) was substantially less than from Epi+ tissues (P = 0.01) and did not differ from sham-sensitized epithelium-denuded tissues (0.82 +/- 0.24 g AT; P > 0.05). Indomethacin caused a reduction in spontaneous tone to comparable magnitude for all treatment paradigms. Immune sensitization caused physiological reduction in the ability to relax in response to isoproterenol; the concentration of isoproterenol eliciting 50% relaxation of spontaneous tone was 7.10 +/- 0.13 (-log M) for TSM from sensitized guinea pigs compared with 8.20 +/- 0.27 (-log M) for sham-sensitized tissues (P = 0.006). However, after precontraction with exogenous acetylcholine, relaxation caused by isoproterenol was not affected by either indomethacin or epithelial removal. Muscarinic responsiveness to acetylcholine was augmented by immune sensitization; however, the increase in response to acetylcholine was attenuated by epithelium removal or cyclooxygenase blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

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