bluuebunny/crossref_metadata_2025_split huggingface dataset:
β2‐Adrenoceptor blockade is the basis of guinea‐pig bronchial hyper‐responsiveness to leukotriene C4 and other agonists
Authors: Bongrani S. , Folco G.C. , Razzetti R. , Schiantarelli P. 
Published: July 2012

Four β‐adrenoceptor antagonists, namely (−)‐propranolol, (+)‐propranolol, ICI‐118551 and (±)‐practolol, were investigated for their effects on leukotriene C4 (LTC4)‐induced bronchoconstriction in the anaesthetized guinea‐pig. (−)‐Propranolol was also investigated for its effects on acetylcholine and histamine bronchospasm in the anaesthetized guinea‐pig, and on LTC4‐induced contractions of guinea‐pig isolated trachea and lung parenchyma.
The various β‐adrenoceptor antagonists potentiated, dose‐dependently, the bronchoconstriction induced by threshold doses of LTC4 and the intensity of the potentiation correlated with the β2‐blocking capacity possessed by the drugs.
(−)‐Propranolol potentiated the bronchospasm induced by threshold doses of acetylcholine and histamine but to a lesser degree than the LTC4‐induced bronchospasm.
The airway hyper‐responsiveness induced by (−)‐propranolol was unaffected by pretreatment with mepyramine, cyproheptadine, phenoxybenzamine, atropine or indomethacin.
The airway hyper‐responsiveness induced by (−)‐propranolol persisted even in adrenalectomized or reserpine‐treated guinea‐pigs, although adrenalectomy induced some increase in airway responsiveness.
(−)‐Propranolol had no effect on LTC4, histamine and acetylcholine‐induced contractions of isolated trachea and lung parenchyma.
The results show that the airway hyper‐responsiveness induced by β‐adrenoceptor antagonists generally correlates with their β2‐blocking activity. The possibility remains that some other unknown mechanism(s) may also be implicated.
Effects of drugs on the cerebral circulation of the dog in relation to the cerebral oxygen consumption
Authors: Chin Wan‐Pao , Imai Shoichi , Nakano Ushio , Takeda Keisuke , Tamatsu Hirokuni , Ushijima Toyohiko 
Published: July 2012

Drug effects were studied on the cerebral circulation by measuring the sagittal sinus outflow in the anaesthetized dog following the method of Michenfelder and by monitoring cerebral oxygen consumption. Systemic aortic pressure, heart rate and spinal fluid pressure were also studied.
Since dilatation of cerebral vessels was observed in nearly all the preparations after inhalation of CO2, it was thought that gross extracerebral contamination was virtually eliminated in this preparation. A close correlation was observed between the oxygen consumption of the brain as a whole and the sagittal sinus outflow (r = 0.93, P < 0.001); therefore it became feasible to differentiate the direct effects of drugs on cerebral blood vessels from indirect ones attributable to changes in the cerebral oxidative metabolism.
Sodium pentobarbitone (5 mg kg−1, i.v.), reduced the cerebral venous outflow and caused a decrease in the oxygen consumption. Pentylenetetrazol (30 mg kg−1 i.v.) and bemegride (5 mg kg−1 i.v.) produced an increase in the blood flow and a corresponding increase in the cerebral oxygen consumption. Thus, it was concluded these substances had no direct effects on the cerebral blood vessels.
Acetazolamide (10 mg kg1, i.v.), a carbonic anhydrase inhibitor, produced a marked and sustained vasodilatation after a latent period of 0.5–1 min. There was no increase in the cerebral oxygen consumption. A similar pattern was seen after CO2 had been inhaled. Methylergometrine and dihydroergotamine (20 μg kg−1 i.v.) induced a prolonged vasoconstriction of the cerebral vascular bed without any changes in the oxygen consumption of the brain. Therefore this method can discriminate between indirect or direct effects of drugs on cerebral vascular outflow.
The effect of β‐adrenoceptor blocking agents, with differing ancillary properties, on the arrhythmias resulting from acute coronary artery ligation in anaesthetized rats
Authors: Campbell C. A. , Parratt J.R. 
Published: July 2012

The effects of several β‐adrenoceptor blocking agents, ((+), (−) and (±)‐oxprenolol,p‐oxprenolol, practolol, propranolol and timolol) were investigated on the ventricular arrhythmias occurring within the first 30 min of acutely ligating the main left coronary artery in anaesthetized rats. The degree of cardiac and vascular β‐adrenoceptor blockade was also assessed.All the compounds exhibited antiarrhythmic activity under these conditions. The degree of cardiac β‐adrenoceptor blockade required for this protection was less for the cardioselective agents,p‐oxprenolol and practolol, than for the non‐selective β‐adrenoceptor blocking agents.A comparison of the two isomers of Oxprenolol demonstrated that the (−)‐isomer markedly suppressed ischaemic arrhythmias (ventricular ectopic beats, incidence and duration of ventricular tachycardia and duration of ventricular fibrillation) more effectively than the (+)‐isomer.Compounds possessing intrinsic sympathomimetic activity (ISA) caused less marked haemodynamic changes (in equivalent β‐blocking doses) than those that did not possess this ancillary property.The membrane stabilizing activity of Oxprenolol andp‐oxprenolol did not appear to contribute to the antiarrhythmic activity of these agents; however, the membrane stabilizing activity of propranolol may contribute to its effectiveness.In all the drugs studied, the main pharmacological property required to suppress early post‐ischaemic arrhythmias is blockade of cardiac β‐adrenoceptors.
Microelectrode recording of the effects of agonists and antagonists on α‐adrenoceptors on rat somatic nerve terminals
Authors: Lim Siew Peng , Muir T.C. 
Published: July 2012

The effects of apomorphine, catechol, clonidine, isoprenaline, (‐)‐and (±)‐noradrenaline, phenylephrine, pyrogallol and xylazine were investigated on the frequency and amplitude of miniature endplate potentials (m.e.p.ps) and, with the exception of apomorphine, catechol and pyrogallol, on the amplitude of endplate potentials (e.p.ps) in the rat phrenic nerve diaphragm preparation.
Clonidine, (‐)‐noradrenaline, phenylephrine and xylazine (each at 1.5 × 10−5M) increased m.e.p.p. frequency but not amplitude. The other drugs were ineffective, except isoprenaline (1.5 × 10−5 M) which enhanced m.e.p.p. amplitude but not frequency.
The increase in m.e.p.p. frequency was inhibited by phentolamine, prazosin and yohimbine (each 1.5 × 10−9M). Prazosin and yohimbine alone each reduced m.e.p.p. frequency but failed to abolish m.e.p.ps even at high concentrations (10−3M).
Clonidine, (‐)‐noradrenaline, phenylephrine and xylazine (each 3 × 10−6M) enhanced e.p.p. amplitude; this enhancement was blocked by prazosin and by yohimbine (each 3 × 10−6M).
In preparations fatigued by prolonged continuous nerve stimulation (5 Hz, 0.05 ms for 30 min), (‐)‐noradrenaline (3.3 × 10−4M) restored m.e.p.p. frequency.
The results indicate that adrenoceptors on somatic nerve terminals interact with both α1‐ and α2‐agonists and antagonists and show different characteristics from those at autonomic neuroeffector junctions.
The α‐adrenoceptors on somatic nerve terminals may have an ancilliary physiological role in influencing but not controlling transmitter release.
Effects of a new α‐adrenoceptor blocking agent, ethyl‐7‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]heptanoate dihydrochloride (SGB‐483), on smooth muscle and neuromuscular transmission in guinea‐pig mesenteric artery
Authors: Fujisawa K. 
Published: July 2012

The effects of ethyl‐7‐[4‐(2‐methoxyphenyl)‐l‐piperazinyl] heptanoate dihydrochloride (SGB‐483) on the smooth muscle of the guinea‐pig mesenteric artery were investigated using microelectrodes.
The resting membrane potential was — 70.3 ± 2.1 mV. SGB‐483 (10−8M‐ 10−4M) did not modify the membrane potential or membrane resistance, as estimated from measurement of current‐voltage relationships.
Noradrenaline (NA; above 10−5M) depolarized the membrane. After pretreatment with SBG‐483 10−5M or prazosin 10−6M, the NA‐induced depolarization of the membrane was inhibited; yohimbine (10−5M) was ineffective. Phenylephrine and NA (> 3 × 10−7M) but not clonidine (10−6M) contracted the artery. These contractions were inhibited by SGB‐483.
Following repetitive perivascular nerve stimulation, the amplitude of excitatory junction potentials (e.j.ps) increased to a certain steady state value (e.j.p.(s)). The amplitude of e.j.p.(s) was frequency‐dependent. Application of SGB‐483 (over 10−8M) enhanced the amplitude of e.j.p.(s), dose‐dependently with no change in the amplitude of the first e.j.p. (e.j.p.(f)) evoked by the first stimulus.
After pretreatment with NA, the amplitudes of both e.j.p.(f) and e.j.p.(s) were inhibited, dose‐dependently. Following pretreatment with SGB‐483 (10−6‐10−5M), the NA‐induced reduction in the amplitude of both e.j.p.(f) and e.j.p.(s) were reversed and the control values restored.
Clonidine (10−7M) inhibited the amplitude of e.j.p.(f) and e.j.p.(s), and SGB‐483 (10−7M) partially restored the amplitude of both.
Yohimbine (10−7M) and phentolamine (10−7M) enlarged the amplitude of e.j.p.(s); the amplitude of e.j.p.(f) was inhibited by yohimbine and enlarged by phentolamine. Prazosin (10−6M) had no effect on the amplitude of either e.j.p.(f) or e.j.p.(s), at any given stimulus frequency. SBG‐483 (10−7M) did not enhance the amplitudes of either e.j.p.(f) or e.j.p.(s) following pretreatment with phentolamine (10−7M) or yohimbine (10−7M) but did enhance the amplitude following pretreatment with prazosin (10−7M).
SGB‐483 possesses the property of an α1‐ and α2‐adrenoceptor antagonist. The α‐antagonistic action was apparent on post‐junctional smooth muscle cells. The α2‐antagonistic action on neuromuscular transmission was mediated at pre‐junctional nerve terminals to enhance the release of NA. The prejunctional actions of SGB‐483 were more selective than those of yohimbine or phentolamine.
Selectivity of 4‐methylhistamine at H1‐ and H2‐receptors in the guinea‐pig isolated ileum
Authors: Barker L.A. , Hough L.B. 
Published: July 2012

The selectivity of 4‐methylhistamine (4‐MH) as an agonist at histamine H1‐ and H2‐receptors has been evaluated in the guinea‐pig isolated ileum.
The EC50 values of 4‐MH on H1‐ and H2‐receptors that mediate contractile responses were determined. The EC50 at H1‐receptors was estimated after selective blockade of H2‐receptors by tiotidine and the EC50 at H2‐receptors estimated after selective blockade of H1‐receptors by mepyramine.
The ‐log EC50 values at H1‐ and at H2‐receptors were 4.57 and 5.23, respectively.
The dissociation constants for the interaction of 4‐MH with H1‐ and H2‐receptors were determined.
The ‐log KD values at H1‐ and H2‐receptors were 3.55 and 4.27, respectively.
These results suggest that 4‐MH is only about 5 times as potent at H2‐ as it is at H1‐receptors in the guinea‐pig ileum and that 4‐MH should be used with caution to discriminate between H1‐ and H2‐receptors.
The actions of Paf‐acether (platelet‐activating factor) on guinea‐pig isolated heart preparations
Authors: Benveniste Jacques , Boullet Cécile , Brink Charles , Labat Carlos 
Published: July 2012

Paf‐acether (platelet‐activating factor) is a phospholipid capable of stimulating platelets to release their granular contents and cause platelet aggregation. When Paf‐acether was administered to isolated heart preparations from normal guinea‐pigs there was a significant concentration‐dependent reduction in coronary flow and contractile force. The high concentration of Paf‐acether was equally effective in reducing these cardiac parameters in the presence of atropine.
The non‐acetylated Paf‐acether analogue, 2‐lyso Paf‐acether, the enantiomer, and a closely related phospholipid 1,α‐lysophosphatidylcholine palmitoyl, did not affect coronary flow and contractile force, indicating the specificity of Paf‐acether.
These data demonstrate a potent effect of Paf‐acether on cardiac function. Whether or not these effects are direct or mediated through generation of endogenous mediators remains to be established.
Correlations between pharmacological responses and structure of human lung parenchyma strips
Authors: Bertram John F. , Goldie Roy G. , PapadimitriouM John M. , Paterson James W. 
Published: July 2012

Correlations were sought between responses of human lung parenchyma strip to 5‐hydroxytryptamine (5‐HT) and (‐)‐noradrenaline (NA) and the proportions of the three major, potentially contractile components within the strip, namely smooth muscle in airways proximal to alveolar ducts, vascular smooth muscle and contractile cells in alveolar septa.
After the isometric measurement of responses to 5‐HT or to NA, lung strips were processed for stereological examination at the light microscopic level. On average, approximately 46% of the total volume of the lung strip was tissue and the remainder was air space. Tissue contained blood vessels (16.8%), airways proximal to alveolar ducts (4.8%) and alveolar parenchyma (78.4%).
Human lung parenchyma strips relaxed, contracted or failed to respond to 5‐HT or NA. Results indicated that these agonists caused simultaneous contraction of blood vessels and relaxation of airways proximal to alveolar ducts. The size and type of responses to 5‐HT or NA was significantly correlated with the ratio of the volume of blood vessels and larger airways.
Conversely, the proportion of alveolar tissue in lung strips was not significantly correlated with responses to 5‐HT or NA.
Substance P modulates the sensitivity of the nicotinic receptor in amphibian cholinergic transmission
Authors: Akasu T. , Kojima M. , Koketsu K. 
Published: July 2012

The effect of substance P on the sensitivity of nicotinic acetylcholine (ACh) receptors of bullfrog sympathetic ganglion cells and frog skeletal muscle endplate was examined electrophysiologically.
The amplitude of ACh‐induced postsynaptic potential (ACh potential) and current (ACh current) were reversibly and dose‐dependently reduced by substance P at low concentrations (0.42–42 μM).
The mean amplitude of the miniature endplate potential (m.e.p.p.) was also reduced by substance P (4.2 μM).
Substance P (4.2 μM) shifted the S‐shaped dose‐response curve of the ACh current downward. A Lineweaver‐Burk plot constructed from the dose‐response curve revealed that substance P depressed the maximum response without changing the apparent affinity (Km) of ACh for the receptor.
Substance P (0.42–42 μM) did not alter the reversal potential of the ACh current of the endplate. The half‐decay time of endplate current (e.p.c.) and its voltage‐dependency were not altered by substance P in these concentrations.
The depression of the ACh current by substance P may not be due to a blockade of the opened channel which has been activated by the preceding combination of ACh with the receptor.
These results suggest that substance P suppresses the sensitivity of nicotinic ACh‐receptors of the sympathetic ganglion cell and skeletal muscle endplate, acting on a certain allosteric site but not the recognition site of ACh in the receptor‐ionic channel complex.
Non‐specific, time‐dependent desensitization of the vas deferens and anococcygeus preparations of the rat to α1‐adrenoceptor antagonists and atropine
Authors: Onnen Igor 
Published: July 2012

Rat vas deferens preparations became desensitized to the α1‐adrenoceptor antagonist thymox‐amine: after 6 h in vitro, the t1/2 value (time to attain half the occupancy of receptors occupied at equilibrium) of the response to this drug was 1.50 fold greater in control strips (strips exposed to thymoxamine at 6 h) than in test strips (strips exposed to thymoxamine at 1 h).
The rate of action of the α1‐adrenoceptor antagonist AR‐C239 on the rat anococcygeus preparation was correlated with the rate of action of atropine. There was also a significant correlation between the t1/2 ratios (1.37 and 1.30 for AR‐C 239 and atropine respectively) observed in the control muscles at 6 h. The in vitro slowing is thus due to some change in the longitudinal muscle and not to a change in the receptors.
The in vitro slowing occured when either phenylephrine or methoxamine was the α1‐adrenoceptor agonist used.
The most likely mechanism of desensitization is a non‐specific slowing of the access of drugs to receptors.
In vivo and in vitro studies of bacterial endotoxin‐membrane interactions and the effects of membrane‐active agents
Authors: Garnett Maureen E. , Godin David V. , Tuchek John M. 
Published: July 2012

The characteristics of 51Cr‐labelled E. coli endotoxin binding to human erythrocyte membranes in vitro have been investigated. A saturable component of binding was apparent at low endotoxin concentrations (<50 μg ml−1) relevant to its in vivo actions, while at higher concentrations binding was non‐saturable and increased in linear fashion. Experiments examining the ability of unlabelled endotoxin to antagonize the binding of labelled toxin provided further evidence for these specific and non‐specific modes of endotoxin‐membrane interaction.
Membrane‐active agents previously shown to reduce endotoxin toxicity in vivo decreased endotoxin binding to erythrocyte membranes in vitro, with propranolol and pranolium being the most effective in this regard.
Tissue distribution studies following administration of radiolabeled endotoxin to guinea‐pigs showed a positive correlation between the accumulation of 51Cr‐endotoxin in lung and elevations in plasma acid phosphatase activity, a measure of in vivo endotoxin toxicity.
The in vivo accumulation of 51Cr‐endotoxin in guinea‐pig lung was reduced by prior treatment with (+)‐propranolol or pranolium, paralleling the results of the in vitro binding studies.
Our results suggest that membrane‐active agents such as (+)‐propranolol may be useful adjuncts to antimicrobial drugs in the therapy of gram‐negative endotoxaemia.
Alteration of the fast excitatory postsynaptic current by barium in voltage‐clamped amphibian sympathetic ganglion cells
Authors: Connor E.A. , Parsons R.L. 
Published: July 2012

Barium‐induced alterations in fast excitatory postsynaptic currents (e.p.s.cs) have been studied in voltage‐clamped bullfrog sympathetic ganglion B cells.
In the presence of 2–8 mm barium, e.p.s.c. decay was prolonged and in many cells the e.p.s.c. decay phase deviated from a single exponential function. The decay phase in these cases was more accurately described as the sum of two exponential functions. The frequency of occurrence of a complex decay increased both with increasing barium concentration and with hyperpolarization.
Miniature e.p.s.c. decay also was prolonged in barium‐treated cells.
E.p.s.c. amplitude was not markedly affected by barium (2–8 mm) in cells voltage‐clamped to — 50 mV whereas at — 90 mV there was a progressive increase in peak size with increasing barium concentration.
In control cells the e.p.s.c.‐voltage relationship was linear between −20 and −100 mV; however, this relationship became progressively non‐linear with membrane hyperpolarization in barium‐treated cells. The e.p.s.c. reversal potential was shifted to a more negative value in the presence of barium.
There was a voltage‐dependent increase in charge movement during the e.p.s.c. in barium‐treated cells which was not present in control cells.
We conclude that the voltage‐dependent alteration in e.p.s.c. decay time course, peak amplitude and charge movement in barium‐treated cells is due to a direct postsynaptic action of barium on the kinetics of receptor‐channel gating in postganglionic sympathetic neurones.
Structure‐antinociceptive activity studies with neurotensin
Authors: Furuta Seiichi , Kisara Kensuke , Sakurada Shinobu , Sakurada Tsukasa , Sasaki Yusuke , Suzuki Kenji 
Published: July 2012

The antinociceptive effects of synthetic neurotensin (NT), its fragments and analogues administered into the lateral cerebroventricle have been compared in the conscious mouse.
Intracerebroventricular (i.c.v.) administration of NT produced a dose‐dependent antinociceptive effect in the tail pressure test.
The NT fragments and analogues, NT(8–13), NT(8–10), NT(9–13), NT(9–11), NT(8–11) NHEt and NT(9–11) NHEt were also effective antinociceptive peptides.
The potency of NT(8–13) and the duration of its effects were found to be approximately equal to those of NT.
The antinociceptive effects produced by NT, NT(8–13) and NT(9–13) were significantly reversed by the opioid antagonist naloxone but not by thyrotropin releasing hormone.
It is concluded that NT(8–13) is required for the full expression of the antinociceptive effects of NT which may be mediated in part through the brain opioid system.
Effects of SCH 32651 on resting and stimulated acid secretion in guinea‐pig isolated fundic mucosa
Authors: Barnett Allen , Chiu Peter J.S. , Tetzloff Glen 
Published: July 2012

Effects of SCH 32651, a novel antisecretory and cytoprotective agent, on resting and stimulated acid secretion by the guinea‐pig isolated fundic mucosa were studied.
SCH 32651 inhibited resting acid secretion in proportion to concentrations in serosal solution (0.1–10 μm), the IC50 being 4.4 μm. Cimetidine and atropine at concentrations up to 100 μm were inactive.
Serosal application of SCH 32651 inhibited acid secretory responses to histamine (10 μm), methacholine (1 μm) or dibutyryl cyclic AMP (0.5 mm) plus theophylline (1 mm) in a concentration‐dependent manner. The IC50s against histamine, methacholine and db cyclic AMP plus theophylline were 4.2 μm, 0.71 μm and 2.9 μm, respectively. In contrast, atropine and cimetidine each at 100 μm, a concentration that entirely abolished responses to methacholine and histamine, respectively, did not affect acid responses to db cyclic AMP plus theophylline.
The inhibitory effects of SCH 32651 on resting and histamine‐stimulated acid secretion were readily reversible upon washing.
SCH 32651 0.1 mm in the mucosal solution also greatly suppressed the resting and stimulated acid secretion.
In the presence of histamine treatment, SCH 32651 concomitantly caused a marked rise in K+ entry into the mucosal solution in parallel to a decline in the appearance of H + in the same solution.
The various events demonstrated by SCH 32651 in the present study are shared by omeprazole, a potent antisecretory agent working through inhibition of gastric H+/K+‐ATPase. We conclude that SCH 32651 as a potent antisecretory agent seems to act directly on the parietal cell, near or at the site of H+/K+‐ATPase which is a final step in the acid secretory process triggered by various stimuli.
Evidence that ethylenediamine acts in the isolated ileum of the guinea‐pig by releasing endogenous GABA
Authors: Kerr D.I.B. , Ong Jennifer 
Published: July 2012

Ethylenediamine (EDA) released [3H]‐γ‐aminobutyric acid ([3H]‐GABA) in a dose‐dependent manner from the isolated preloaded ileum of the guinea‐pig maintained in Krebs‐bicarbonate solution (pH 7.4, 37°C), in the presence of β‐alanine and amino‐oxyacetic acid (AOAA) to prevent GABA uptake into glial cells and catabolism. This release was reversibly prevented by 3‐mercaptopropionic acid (3‐MPA), also in a dose‐dependent manner.
In the isolated ileal preparations of the guinea‐pig maintained in Krebs‐bicarbonate solution, EDA induced a dose‐dependent transient, cholinergic contractile response (GABAA‐receptor‐mediated effect), followed by an ‘after‐relaxation’ (GABAB‐receptor‐mediated effect). EDA also induced a transient contraction superimposed on repetitive twitch responses to electrical transmural stimulation of the cholinergic neurones, followed by a depression of the twitch contractions.
This GABAA‐receptor‐mediated contraction was antagonized by bicuculline methochloride and picrotoxinin, whilst the GABAB‐receptor‐mediated ‘after‐relaxation’, and depression of cholinergic twitch contractions, was susceptible to antagonism by δ‐aminovaleric acid. The pA2 value for bicuculline methochloride antagonism of EDA was estimated to be 5.8, identical with that for GABA.
3‐Mercaptopropionic acid also prevented these pharmacological actions induced by EDA without affecting responses to GABA, 3‐aminopropranesulphonic acid, muscimol, baclofen or the twitch responses to transmural stimulation.
It is concluded that EDA releases both [3H]‐GABA and endogenous GABA in the guinea‐pig ileum, thus providing further evidence that GABA is a transmitter in the enteric nervous system.