bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fade and tachyphylaxis of gastric acid secretory response to pentagastrin in rat isolated gastric mucosa
Authors: Hirst Barry H. , Holland Joy , Parsons Michael E. , Price Carolyn A. 
Published: July 2012

Gastric acid secretory responses to pentagastrin were characterized in the rat isolated gastric mucosa. In particular, the mechanisms underlying fade, declining response upon continued stimulation, and tachyphylaxis, progressively reduced responses upon repeated stimulation, were investigated.
Pentagastrin, 10−9‐10−7m, resulted in concentration‐related increases in acid secretion, with a mean maximum of 2.65 μmolcm−2h−1 in response to pentagastrin, 10−7m. Higher concentrations of pentagastrin produced sub‐maximal secretory rates; we define this as auto‐inhibition. The responses to all concentrations of pentagastrin demonstrated fade. The rate of fade was correlated with the maximum acid secretory rate, declining at about 36% of the peak over the first 16min.
The Po2, Pco2, [HCO3−], pH, [glucose], [lactate], [Na+] and [K+] did not decline during the fade of the acid secretory response to pentagastrin, 10−7 m. Addition of a second aliquot of pentagastrin was not able to reverse fade, but these tissues were responsive to histamine. Replacement of the serosal solution, before addition of a second aliquot of pentagastrin, increased the acid response from 3% to 24% of the first response.
Serosal solution from donor tissues, allowed to respond to pentagastrin and then the acid secretion to fade, was able to stimulate secretion in fresh recipient tissues, although at lower rates.
Acid secretory responses to a second dose of pentagastrin were not significantly different, whether the tissues were previously unstimulated, or stimulated with pentagastrin washed out after attaining its peak secretory response (after 10–20 min). The second response was significantly reduced if the first response was allowed to fade with the pentagastrin in contact for 100min; i.e. fade significantly influenced the extent of tachyphylaxis.
Proglumide, 10−2m, a gastrin receptor antagonist, and omeprazole, 10−5 m, an inhibitor of the gastric (H+ + K+)‐ATPase, both inhibited pentagastrin‐stimulated acid secretion to similar extents. The second response to pentagastrin after pentagastrin alone, or pentagastrin plus omeprazole were both reduced compared to responses after no stimulation or omeprazole alone, respectively. After pentagastrin plus proglumide, the second response to pentagastrin was not lower than after proglumide alone. Proglumide, but not omeprazole, therefore, prevented pentagastrin tachyphylaxis.
It is concluded that gastrin fade and tachyphylaxis are related phenomena. Part of the fade may be due to release of an inhibitor(s). The major proportion of tachyphylaxis is a result of specific interaction of gastrin with its receptors.
Receptors for ATP in rat sensory neurones: the structure‐function relationship for ligands
Authors: Krishtal Oleg A. , Marchenko Sergey M. , Obukhov Alexander G. , Volkova Tatyana M. 
Published: July 2012

The pharmacological properties of the ATP‐activated conductance in isolated sensory neurones of the rat were investigated by use of voltage clamp and concentration clamp techniques.
Adenosine 5′‐triphosphate (ATP), adenosine 5′‐diphosphate (ADP), cytidine 5′‐triphosphate (CTP), cytidine 5′‐diphosphate (CDP) and some derivatives activate these receptors, whereas adenosine 5′‐monophosphate (AMP), cytidine 5′‐monophosphate (CMP) and other naturally‐occurring nucleotides are competitive blockers.
In the sequence of substances, adenosine 5′‐(β,γ‐methylene)‐triphosphonate (APPCP), adenosine 5′‐(β,γ‐difluoromethylene)− triphosphonate (APPCF2P), adenosine 5′‐(β,γ‐dichloromethylene)‐triphosphonate (APPCC12P) and adenosine 5′‐(β,γ‐dibromomethylene)triphosphonate (APPCBr2P), the properties of ligands depend on the radius of the atom linked to the carbon of the diphosphonate group. Thus, APPCP is an agonist, APPCF2P is a partial agonist, while dichloromethylene and dibromomethylene analogues of adenosine 5′‐(β,γ‐methylene)triphosphonate demonstrate features of competitive blockers. APPCC12P is the most effective blocker of ATP‐receptors (inhibition constant Ki = 21 ± 4μm). An adenosyl or adenylyl radical, when connected to the terminal phosphate of ATP, converts the agonist into a partial agonist.
Two especially important parts of the ATP molecule are crucial for the interactions with receptors. They are: (1) the vicinity of C6 of the purine ring and (2) the polyphosphate chain. Some modifications in these regions of the molecule result in the transformation of an agonist into an antagonist.
Detergent and methylene blue affect endothelium‐dependent vasorelaxation and pressure/flow relations in rat blood perfused mesenteric arterial bed
Authors: Randall Michael D. , Hiley C. Robin 
Published: July 2012

The autoperfused superior mesenteric arterial bed of the rat was used to study the opposition by carbachol of pressor responses to noradrenaline and the effects of methylene blue, the detergent CHAPS and indomethacin on pressure/flow relations.
Carbachol (1 ng‐3 μg) reduced the pressor response to 1μg noradrenaline in a dose‐dependent manner with an ED50 = 25.5 ± 6.0 ng and a maximum inhibition of 51.8 ± 1.9%. Perfusion of the mesenteric bed with 0.3% CHAPS in saline for 150 s abolished the reduction by carbachol of the noradrenaline pressor response. The effect of carbachol was also abolished by infusion of 1% methylene blue into the mesenteric vacular bed. Indomethacin (5mgkg−1) was without significant effect on the carbachol opposition of noradrenaline pressor responses. None of the 3 treatments had any effect on the response to 1 μg noradrenaline.
Perfusion with CHAPS before determination of pressure/flow relations, or infusion of methylene blue during their determination, steepened the regression of pressure upon flow to the same extent; at all the flow rates used (0.4–3.54 ml min−1) pressure was greater as a result of the treatment than in control animals. Pretreatment with indomethacin had no effect on pressure/flow relations.
It is concluded that carbachol opposition to noradrenaline pressor responses in the blood perfused superior mesenteric arterial bed of the rat shows the characteristics of being mediated by endothelium‐dependent relaxing factor (EDRF). Since vascular resistance increases more rapidly than in controls when the endothelium is functionally inhibited by treatment with CHAPS or perfusion with methylene blue, it appears that EDRF has a role in vivo in the modulation of myogenic vascular tone.
Complex interactions of agonists with α1‐adrenoceptors in intact cells
Authors: Sladeczek Fritz , Schmidt Bernard H. , Cory Robert N. , el Moatassim Chakib , Alonso Richard , Kirk Kenneth L. , Kirk Christopher J. , Rouot Bruno , Bockaert Joël 
Published: July 2012

The apparent Ki values of (−)noradrenaline (NA), (+)− and (−)‐adrenaline (Ad), phenylephrine and the mono‐fluorinated NAs (in position 2, 5 or 6) for α1‐adrenoceptors of intact BC3H1 cells labelled with [3H]‐prazosin were greatly dependent on the incubation temperature.
The EC50 values of these compounds for stimulation of the inositol phosphate (IP) accumulation at 37°C were intermediate between their apparent dissociation constants at 2°C (Ki2°) and at 37°C (Ki37°).
The fact that an irreversible blockade of 46% ± 6% (n = 3) of the [3H]‐prazosin binding sites by phenoxybenzamine reduced the maximal IP‐formation induced by NA by 57% ± 5% (n = 3) shows that there is a direct coupling between α1‐adrenoceptors and phospholipase C in BC3H1 cells.
The Ki37°s of all agonists tested were in the same range (0.1 to 1mm) and showed no simple correlation with their EC50 values.
The Ki2° values for all the agonist correlated linearly with their EC50 values but were about 20–100 times lower than the respective EC50 values (except for the partial agonist methoxamine). In order to explain this difference, we propose that the apparent high affinity in the cold could be due to an [3H]‐prazosin‐induced alteration of the active site of the α1‐adrenoceptor, increasing its apparent affinity for catecholamines.
Acetylcholine releases endothelium‐derived hyperpolarizing factor and EDRF from rat blood vessels
Authors: Chen Guifa , Suzuki Hikaru , Weston Arthur H. 
Published: July 2012

The effects of haemoglobin and methylene blue on the acetylcholine (ACh)‐induced electrical and mechanical responses of smooth muscle cells were investigated in rat aorta and rat main pulmonary artery.
When the endothelium was intact, ACh induced a transient hyperpolarization and sustained relaxation of tissues precontracted with noradrenaline. Both hyperpolarization and relaxation were absent in preparations without endothelium.
Haemoglobin and methylene blue inhibited the ACh‐induced relaxation, but not the transient hyperpolarization.
In aorta with an intact endothelium, ACh produced an increase in both the rate of 86Rb efflux and tissue cyclic GMP levels. The changes in ion flux were unaffected by either haemoglobin or methylene blue in concentrations which almost abolished the increase in cyclic GMP concentrations.
In arteries with an intact endothelium, indomethacin had no effect on the ACh‐induced electrical and mechanical responses or on the increase in 86Rb efflux and tissue cyclic GMP levels.
It is concluded that in the rat aorta and rat main pulmonary artery, ACh releases two different substances, an endothelium‐derived relaxing factor (EDRF) and a hyperpolarizing factor (EDHF), from the endothelial cells. Neither substance appears to be derived from a pathway dependent on cyclo‐oxygenase. EDHF seems to play a minor role in the relaxation of noradrenaline‐induced contractions.
Effects of neuropeptides and capsaicin on the canine tracheal vasculature in vivo
Authors: Salonen R.O. , Webber S.E. , Widdicombe J.G. 
Published: July 2012

The nonadrenergic, noncholinergic nervous system may control the airway vasculature via various neuropeptides. We have perfused the cranial tracheal arteries of the anaesthetized dog and investigated the effects of neuropeptides and capsaicin (which is supposed to release neuropeptides from sensory nerve endings) on the tracheal vasculature by injecting them locally into the perfusion system.
Neurokinin A (NKA, 0.02–20 pmol), calcitonin gene‐related peptide (CGRP, 2–200 pmol) and peptide histidine isoleucine (PHI, 0.02–2 nmol) dose‐dependently decreased tracheal vascular resistance (Rtv). NKA was 10 and 100 times more potent than CGRP and PHI, respectively. The duration of the response to CGRP was greatly prolonged with larger doses. Galanin (0.2–2 nmol) had no appreciable effect on Rtv.
Neuropeptide Y (NPY 0.02–2 nmol) and bombesin (0.02–10 nmol) dose‐dependently increased Rtv. However, the dose‐response curve for bombesin was bell‐shaped suggesting the development of tachyphylaxis with larger doses. In smaller doses, bombesin was twice as potent as NPY. The duration of the response to NPY was prolonged with larger doses.
With the exception of PHI no neuropeptide altered tracheal smooth muscle tone; PHI (1 and 2 nmol) caused small dilatations of the trachea.
The effects of capsaicin (2–100 nmol) were complex. Usually, the vascular response had two dose‐dependent phases: a rapid vasoconstriction followed by a small, longer‐lasting vasodilatation. The tracheal smooth muscle response was usually biphasic, a contraction followed by a relaxation.
According to previous and present data, the order of potency of the neuropeptides on the canine tracheal vasculature is for the vasodilators: NKA > vasoactive intestinal peptide (VIP) > CGRP ≥ substance P > PHI, and for the vasoconstrictors: bombesin > NPY. The longer‐acting neuropeptides (VIP, CGRP and NPY) may be more important than the shorter‐acting neuropeptides (substance P, NKA, PHI and bombesin) as regulators of the airway wall blood flow.
Comparison between effects of caffeine and ryanodine on electromechanical coupling in myocardium of hibernating chipmunks: role of internal Ca stores
Authors: Kondo Noriaki 
Published: July 2012

To clarify the cause of uncoupling of Ca influx through Ca channels and the contractility of the myocardium in hibernating chipmunks, the electromechanical effects of two different internal Ca store inhibitors, caffeine and ryanodine, and a cardiotonic agent, isoprenaline, were investigated in papillary muscles of hibernating animals.
Ryanodine (10−6 m), an inhibitor of internal Ca release, abolished the contraction with a marked inhibition of the action potential plateau (APp). In such preparations, an increase in Ca influx induced by isoprenaline (5 × 10−8 m) failed to augment the contraction, indicating uncoupling of Ca influx and contraction.
In ryanodine pretreated preparations, 10mM caffeine produced an early phase of APp, but did not affect the contraction abolished by ryanodine, while a higher concentration of caffeine (25 mm) markedly increased the contraction with an augmentation of the electrical response.
In the absence of ryanodine, caffeine (5mm) almost abolished the contraction with a greater inhibition of APp. In such preparations, isoprenaline greatly increased the contraction with an augmentation of the early phase of APp.
These effects were not significantly affected by additional application of ryanodine, but were inhibited by nifedipine, a Ca channel blocker.
These observations suggest that in cardiac muscles of hibernating animals, lack of the positive inotropic effect of isoprenaline may be attributed to a rapid and effective sequestration of increased cytoplasmic Ca through Ca influx by internal stores, probably by enhancement of their ability to take up Ca.
The stereospecificity of LY253352 for α1‐adrenoceptor binding sites in the brain and prostate
Authors: Lepor Herbert , Baumann Mary , Shapiro Ellen 
Published: July 2012

The stereospecificity of the enantiomers of LY253352, a potent and selective α1‐adrenoceptor antagonist, were studied in the human prostate and canine brain using radioligand receptor binding methods.
The mean equilibrium dissociation constant (KD) in the canine brain and human prostatic adenoma was 84.4 pM and 65.4 pM, respectively.
The α1‐adrenoceptor density in the canine brain was approximately eight fold greater than in the human prostatic adenoma.
The mean Ki values of (−)‐LY253352 and (+)‐LY253352 in the prostate were 0.19 nM and 5.79 nM, respectively.
The mean Ki values of (−)‐LY253352 and (+)‐LY253352 in the brain were 0.29 nM and 34.7 nM, respectively.
This study indicates that the stereochemical specificity of the optical isomers of LY253352 is a manifestation of differential affinities of the enantiomers for α1‐adrenoceptor binding sites.
The differential affinities of (+)‐LY253352 in the brain and prostate are suggestive of subtle unique properties of adrenoceptor binding sites in these tissues.
A comparison of the effects of the calcium entry blockers, verapamil, diltiazem and flunarizine against contractions of the rat isolated aorta and portal vein
Authors: Marriott J.F. 
Published: July 2012

The actions of the chemically distinct calcium entry blockers, verapamil (Ver), diltiazem (Dlz) and flunarizine (Flu) have been compared in rat isolated aorta and portal vein.
KCl‐induced contractions of the rat aorta depend exclusively upon extracellular Ca2+, whereas, those induced by noradrenaline (NA) rely upon Ca2+ from intra‐ and extracellular sources. The NA‐induced contraction was pharmacologically dissected under Ca2+‐free conditions revealing a contraction dependent upon intracellular Ca2+ (EGTA‐resistant response) or a low concentration of prazosin which left a contraction which was mediated by extracellular Ca2+ (prazosin‐resistant response).
The portal vein produced spontaneous rhythmic contractions and a sustained contraction to NA and KCl; however, all responses appeared to depend exclusively upon extracellular Ca2+.
In the aorta, contractions which might be expected to depend upon Ca2+‐entry through voltage‐operated channels (KCl‐induced contraction) showed similar sensitivities to Ver, Dlz and Flu whereas, marked differences in the sensitivity to these agents was noted against contractions which appear to depend upon Ca2+‐entry through receptor‐operated channels (prazosin‐resistant response). Only Dlz reduced contractions mediated by intracellular Ca2+ (EGTA‐resistant response).
In the portal vein, Ver and Dlz caused similar pronounced reductions of spontaneous and NA or KCl‐induced contractions. In contrast, these contractions of the portal vein were unaffected by Flu except at a concentration of 10 μM. However, contractions induced by addition of Ca2+ (0–14 mM) to previously depolarized portal veins could be reduced by Flu (100 nμ‐10 μM).
The present study indicates that in the rat aorta, contractions mediated by intracellular Ca2+ and depolarization or receptor‐activated Ca2+ entry can be pharmacologically dissected and that these processes show different sensitivities to calcium entry blockade. Of the agents tested, Ver displays the properties most commonly associated with an ideal calcium entry blocker. Ca2+‐activation mechanisms in the portal vein differ from those in the aorta resulting in a different spectrum of selectivity of the calcium entry blockers studied.
Failure of the inhibition of rat gastric mucosal 5‐lipoxygenase by novel acetohydroxamic acids to prevent ethanol‐induced damage
Authors: Boughton‐Smith N.K. , Whittle B.J.R. 
Published: July 2012

The role of leukotriene B4 (LTB4) and LTC4 as mediators of gastric mucosal damage following ethanol challenge in vivo has been investigated using two selective 5‐lipoxygenase inhibitors, BW A4C and BW A137C.
Oral administration of ethanol to rats in vivo, induced macroscopic damage to the gastric mucosa and markedly increased the formation of the 5‐lipoxygenase products, LTB4 and LTC4, from the mucosa ex vivo.
Pretreatment with the acetohydroxamic acids BW A4C and BW A137C (5–50 mg kg−1 p.o.) dose‐dependently reduced ethanol‐stimulated LTB4 and LTC4 formation by the gastric mucosa, with an ID50 of approximately 5 mg kg−1 p.o.
A single oral dose of BW A4C (20 mg kg−1) induced near‐maximal inhibition of mucosal LTB4 formation within 30 min, which was well maintained for 5h, whereas BW A137C (20 mg kg−1 p.o.) induced maximal inhibition between 30 and 60 min after administration, which then diminished over the subsequent 5 h.
The mucosal formation of the cyclo‐oxygenase product, 6‐keto‐prostaglandin F1α, which was unaltered following ethanol challenge, was not inhibited by the acetohydroxamic acids. Likewise, the small increase in mucosal thromboxane B2 formation following challenge was not inhibited by BW A4C.
Neither BW A4C nor BW A137C, at doses that almost completely inhibited the mucosal synthesis of LTB4 or LTC4, reduced the macroscopic gastric mucosal damage induced by ethanol.
Pretreatment with the lipoxygenase inhibitor BW 755C (5–50 mg kg−1 p.o.) did reduce mucosal damage, but there was a dissociation between the degree of protection and the inhibition of leukotriene biosynthesis.
Oral administration of high doses of either BW A4C or BW A137C (300 mg kg−1) did not induce macroscopic gastric damage over a 3 h period.
These findings suggest that the leukotrienes, LTB4 and LTC4 are not the primary mediators of ethanol‐induced acute mucosal damage, but do not exclude their role in more chronic gastric damage and inflammation.
GABAA‐receptor‐mediated inhibition of the delayed increase in intragastric pressure to stimulation of vagal afferent fibres in cats
Authors: Okamoto Toshihiro , Kurahashi Kazuyoshi , Fujiwara Motohatsu , Oikawa Hiroshi 
Published: July 2012

The possible involvement of γ‐aminobutyric acidA (GABAA)‐ and GABAB‐receptors in the inhibitory effects of GABA on the delayed increase in intragastric pressure of the stomach to stimulation of vagal afferent fibres in cats was studied.
Cats were anaesthetized with pentobarbitone‐gallamine and pretreated with hexamethonium. GABA inhibited the hexamethonium‐resistant delayed contraction of the stomach in a dose‐dependent manner. Such effects of GABA were antagonized by both bicuculline and picrotoxin.
Muscimol, a GABAA‐receptor agonist, mimicked the inhibitory effects of GABA and the effects of muscimol were antagonized by bicuculline and picrotoxin. The ID50 of muscimol was 10 times less than that of GABA.
In contrast to muscimol, baclofen, a GABAB‐receptor agonist did not mimic the inhibitory effects of GABA.
The present experiments demonstrate that GABAA‐receptors are involved in the inhibitory action of GABA on the delayed contraction of the stomach to vagal afferent stimulation.
Palytoxin‐induced contraction and release of endogenous noradrenaline in rat tail artery
Authors: Karaki H. , Nagase H. , Ohizumi Y. , Satake N. , Shibata S. 
Published: July 2012

The mechanism of the contractile effect of a potent marine toxin, palytoxin (PTX) on the rat isolated tail artery was examined.
PTX (10−7 M) induced a contraction in the tail artery which was dependent on external Ca2+. This contraction was inhibited (by 75% or more) by 10−6 M prazosin, 2.4 × 10−5 M bretylium and 10−4 M 6‐hydroxydopamine (6‐OHDA), and partially (by 40%) by 10−5 M indomethacin. However, this contraction was not affected by 10−6 m tetrodotoxin (TTX), 10−6 M nifedipine or reserpine treatment. The PTX‐induced contraction in reserpine‐treated artery was partially inhibited by nifedipine and indomethacin but not by prazosin.
Transmural electrical stimulation induced a transient contraction which was dependent on external Ca2+. The contraction induced by electrical stimulation was inhibited by TTX, prazosin, bretylium, reserpine treatment and 6‐OHDA but not by nifedipine or indomethacin.
PTX increased the release of noradrenaline from this artery. However PTX did not release noradrenaline from reserpine‐treated arteries. PTX‐induced noradrenaline release was only partially inhibited by TTX or by Ca2+‐free solution.
These results suggest that PTX has pre‐ and postsynaptic effects in the rat tail artery. PTX may stimulate adrenergic nerves and release noradrenaline mainly by a TTX‐insensitive and Ca2+‐independent mechanism and partially by a TTX‐sensitive and Ca2+‐dependent mechanism. Further, PTX may also release prostaglandins and depolarize smooth muscle cell membrane to induce a contraction.