bluuebunny/crossref_metadata_2025 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.
Loss of receptor‐mediated 86Rb efflux from pig aortic endothelial cells in culture
Authors: Ager A. , Martin W.
Published: July 2012

The responsiveness of freshly‐isolated and subcultured pig aortic endothelial cells to adenosine triphosphate (ATP), bradykinin and ionophore A23187 was compared by monitoring agonist‐induced 86Rb efflux. ATP, bradykinin and ionophore A23187 stimulated 86Rb efflux from freshly‐isolated cells. ATP and bradykinin, which act via specific receptors, were less effective at inducing 86Rb efflux from subcultured cells but ionophore A23187 was as effective on subcultured as on freshly‐isolated cells. These results suggest that pig aortic endothelial cells, when subcultured, lose receptors for ATP and bradykinin and/or develop an abnormality in the coupling‐mechanism between receptor‐occupation and calcium‐mobilization.
Anaphylactic contraction (Schultz‐Dale reaction) of the bovine bronchial artery in vitro
Authors: Alexander D.I. , Eyre P. , Gordon V.P.
Published: July 2012

Bronchial arteries from sensitized calves contracted on antigenic challenge in the absence and presence of selected anti‐allergic drugs and autonomic agents in vitro. Anaphylactic reactivity was inhibited by tripelennamine, isoprenaline and aminophylline, and potentiated by indomethacin and dopamine. Disodium cromoglycate, compound FPL 55712 and ketanserin failed to inhibit anaphylactic contraction.
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.
Potassium induces relaxation and hyperpolarization of circular muscles but contraction of longitudinal muscles of pig duodenum
Authors: Kimura I. , Kimura M. , Kimura M.
Published: July 2012

The mechanisms by which K+ relaxes circular muscles of pig duodenum were investigated, and compared with the response of the longitudinal muscles to K+.

Circular muscles were concentration‐dependently relaxed by 8.3–23.6 mm K+, but contracted by 47.2–143.4 mmK+.

Longitudinal muscles were contracted by 11.8–94.4 mm.K+.

The relaxation of circular muscles was correlated with hyperpolarization (4 mV), but evoked Ca2+ spikes were not suppressed.

Neither ouabain (0.14 μm) nor phentolamine (10 μm) blocked the relaxation, but tetrodotoxin (TTX, 0.63 μm) blocked both the relaxation and hyperpolarization. Mesaconitine (0.16 μm) increased the relaxation. Inhibitory junction potentials and concomitant relaxations were also blocked by TTX.

The results suggest that K+‐induced relaxation is caused by the release of a non‐adrenergic inhibitory transmitter.
Inhibition of GABA uptake potentiates the conductance increase produced by GABA‐mimetic compounds on single neurones in isolated olfactory cortex slices of the guinea‐pig
Authors: Brown D.A. , Scholfield C.N.
Published: July 2012

Membrane potential and input conductance were recorded in single neurones in slices of guinea‐pig olfactory cortex in vitro. γ‐Aminobutyric acid (GABA) and GABA‐mimetic compounds were applied by bath‐perfusion. Potency was measured as the concentration required to double the input conductance.

The potency of GABA was increased (i.e. the equi‐effective concentrations were reduced) by 15.5 ± 2.3 times (mean ± s.e.mean) on reducing external [Na+] from 144 to 20 mmol l−1, by replacement with Mg2+. Corresponding potency changes for other agonists were + 10.8 ± 2.5 for 3‐aminopropanesulphonic acid (3‐APS); 3.25 ± 1.06 for isoguvacine and 2.43 ± 0.69 for muscimol.

Nipecotic acid (0.5 mm) produced the following increases in potency: GABA 2.68 ± 0.82; 3‐aminopropanesulphonic acid, 3.11 ± 0.07; isoguvacine, 1.92 ± 0.34; muscimol, 2.24 ± 0.17.

The concentration of GABA in the bathing fluid necessary to double input conductance increased with increasing depth of the recording site from the cut surface. The apparent potency fell 10 times for each 60 μm depth increment up to 150 μm. The recording depth also affected the apparent potency of muscimol and 3‐APS but to a lesser extent. Reduction of external [Na+] reduced the depth‐dependence of both GABA and 3‐APS potency.

No clear change in the duration of the recurrent inhibitory postsynaptic conductance could be detected in the presence of 0.5 mmol l−1 nipecotic acid.

It is suggested that agonist uptake by a Na+‐dependent, nipecotic acid‐sensitive mechanism severely attenuates the responses of olfactory neurones to exogenous GABA and to its analogues 3‐APS, muscimol and isoguvacine, but has little immediate influence on the duration of the GABA‐mediated inhibitory postsynaptic conductance.
Influence of heart rate on the effects of prenalterol on regional myocardial blood flow and function during coronary stenosis in dogs
Authors: Berdeaux A. , Bonhenry C. , Duhazé P. , Giudicelli J.F. , Thuillez C.
Published: July 2012

The effects of prenalterol, a selective β1‐adrenoceptor agonist with potent cardiac positive inotropic properties have been investigated on regional myocardial blood flow (RMBF) (microspheres) and contractile function (ultrasonic crystals) during partial circumflex coronary artery stenosis in 8 open‐chest anaesthetized dogs.

Prenalterol was investigated at two intravenous doses: 5 μg kg−1, which increased myocardial contractility (dP/dt max: +29%) more than heart rate (+ 12%, up to 150 beats min−1) and 20 μg kg−1 which induced almost similar increases in contractility (+35%) and heart rate (+31% up to 175 beats min−1). The induced modifications of regional flow and function were then compared to those produced in another series of 6 dogs by atrial pacing at 150 and 175 beats min−1 respectively.

Prenalterol significantly increased RMBF and segment length (SL)‐shortening in a dose‐dependent manner in the nonischaemic zone. In the ischaemic zone, RMBF was maintained and SL‐shortening increased with prenalterol, 5 μg kg−1 whereas both RMBF and contractile function were severely decreased with prenalterol, 20 μg kg−1.

Atrial pacing had almost no effect on RMBF and SL‐shortening in the nonischaemic zone. In the ischaemic zone, atrial pacing rate‐dependently decreased both RMBF and SL‐shortening.

Thus, a significant increase in contractility, associated with little tachycardia (prenalterol, 5 μg kg−1), induces beneficial effects on RMBF and function in both the nonischaemic and ischaemic myocardium. In contrast, a strong tachycardia, whether accompanied by positive inotropic effects (prenalterol, 20 μg kg−1) or not (atrial pacing at 175 beats min−1) induces deleterious effects on RMBF and cardiac function in the ischaemic myocardium.
A direct protective effect of sulphinpyrazone on ischaemic and reperfused rat hearts
Authors: Karmazyn Morris
Published: July 2012

Initiation of 60 min ischaemia to rat isolated hearts produced a depression in developed tension and heart rate. Subsequent reperfusion caused a greatly exacerbated creatine phosphokinase (CPK) efflux and limited functional recovery.

Sulphinpyrazone (100 ng ml−1 and 1 μg ml−1) significantly reduced CPK release, particularly after reperfusion, the lower concentration being more effective.

A reduction in the mechanical depression during ischaemia and enhanced recovery after reperfusion were seen only with 100 ng ml−1 sulphinpyrazone. Heart rate and coronary perfusion pressure were unaffected by drug treatment.

The reduction in reperfusion‐induced CPK efflux by 100 ng ml−1 sulphinpyrazone was maximal when the drug was present throughout the perfusion period although some protection was evident when sulphinpyrazone was present either during ischaemia or reperfusion only. An enhanced recovery in contractility was seen only when the drug was present throughout all phases of perfusion.

It is suggested that sulphinpyrazone exerts a direct protective effect on the heart particularly during reperfusion. The degree of protection is critically dependent on the concentration of sulphinpyrazone.
Effects of the antagonists MDL 72222 and ketanserin on responses of cat carotid body chemoreceptors to 5‐hydroxytiyptamine
Authors: Kirby G.C. , McQueen D.S.
Published: July 2012

The effects of intracarotid (i.c.) injections of 5‐hydroxytryptamine (5‐HT; 1–50 μg) on carotid chemoreceptor activity recorded from the carotid sinus nerve have been studied in anaesthetized cats.

Three separate components in the complex response of the chemoreceptors to injected 5‐HT were identified. Firstly, a transient burst of activity was obtained during the injection period in 56% of the recordings. Secondly, in all the recordings a period of chemodepression commenced a few seconds after completing the injection and was usually dose‐related. Thirdly, a delayed longer‐lasting chemoexcitation occurred in many experiments, concomitant with a fall in systemic blood pressure.

The neuronal 5‐HT receptor antagonist MDL 72222 (10–100 μg kg−1, i.c.) virtually abolished the transient chemoexcitation evoked during 5‐HT injections and also significantly increased the mean ID50 for 5‐HT‐induced chemodepression; in 37% of recordings 5‐HT caused a dose‐related chemoexcitation after the high dose of MDL 72222. Neither the delayed chemoexcitation nor the hypotension caused by 5‐HT were much affected by the antagonist. MDL 72222 itself had a biphasic effect on chemosensory discharge, causing depression followed by a delayed excitation.

The 5‐HT2‐receptor antagonist ketanserin (100 μg kg−1, i.c.) had no appreciable effect on the transient chemoexcitation evoked during 5‐HT injections and caused a slight but significant increase in the mean ID50 for 5‐HT‐induced chemodepression. The delayed chemoexcitation and accompanying hypotension associated with 5‐HT were both substantially reduced or abolished by the antagonist. Ketanserin itself caused a short‐lasting period of chemoexcitation.

All the effects of injected 5‐HT on chemosensory discharge could be abolished by the combination of MDL 72222 and ketanserin (100 μg kg−1, i.c.).

Neither MDL 72222 nor ketanserin had any significant effect upon the response of the carotid chemoreceptors to hypoxia. The rate at which discharge increased, and also the steady‐state discharge before and during hypoxia, were unaffected by the antagonists, alone or in combination.

At least two types of 5‐HT receptor appeared to be involved in the response of carotid body chemoreceptors to 5‐HT. Transient excitation and chemodepression wer*** mediated via MDL 72222‐sensitive (peripheral neuronal) receptors whereas the delayed chemoexcitation and associated hypotension involved a ketanserin‐sensitive, presumably 5‐HT2‐, receptor. It appears unlikely that 5‐HT plays a crucial role in chemoreception.
Interactions between receptors that increase cytosolic calcium and cyclic AMP in guinea‐pig liver cells
Authors: Cocks T.M. , Jenkinson D.H. , Koller Karin
Published: July 2012

The action of agonists which increase the K+ permeability of liver cells was studied by using a K+‐sensitive electrode to record the net movement of K+ between guinea‐pig isolated hepatocytes and their suspension medium.

Two types of agonist were examined. Type 1 comprised angiotensin II, ATP, noradrenaline and amidephrine, all of which are thought to raise cytosolic Ca2+ in hepatocytes. The Type 2 agonists were isoprenaline and glucagon, which activate adenylate cyclase.

Each type of agonist initiated K+ loss from the hepatocytes though the response to Type 2 agonists was more variable than that to Type 1, and sometimes absent.

Simultaneous application of a small concentration of an agonist from each class caused a loss of K+ which was much larger than the sum of that seen with each agonist alone, i.e. potentiation occurred.

The α‐adrenoceptor antagonist, WB 4101, abolished potentiation if applied after an α‐agonist, and before a Type 2 agonist, showing that both receptors have to be active for potentiation to occur.

Simultaneous application of a maximal concentration of each type of agonist caused a larger loss of K+ (˜ 17% of the cell total within 45 s) than did a maximal concentration of a Type 1 agonist alone (˜ 10%).

Since the K+ loss caused by these agonists is thought to be a consequence of a rise in cytosolic Ca2+, the influence of both types of agonist on 45Ca and 42K efflux from guinea‐pig liver slices was studied.

The effect of isoprenaline on 45Ca and 42K efflux became much greater following a previous application of the α‐adrenoceptor agonist, amidephrine.

In the presence of apamin, the potentiated effect of isoprenaline on 42K efflux was greatly reduced whereas that on 45Ca efflux was little affected.

The effects of Type 1 and Type 2 agonists separately and together on the cyclic AMP content of isolated hepatocytes were examined. Type 2 agonists increased cyclic AMP in the expected way. The increase became slightly smaller, if anything, when a Type 1 agonist was applied at the same time. Hence potentiation could not be ascribed to changes in cyclic AMP formation.

Possible mechanisms for potentiation are discussed. Our evidence suggests, albeit indirectly, that it is a consequence of an interaction between the effects of the two types of agonist on cytosolic Ca2+.
A comparison of dimaprit, nordimaprit, methylamine and chloroquine as inhibitors of mitogen‐induced lymphocyte activation
Authors: Dale M. Maureen , Ladd R.
Published: July 2012

Methylamine and chloroquine both ‘lysosomotropic’ agents (i.e. agents which sequester in lysosomes) caused a dose‐related inhibition of mitogen‐induced lymphocyte activation in the concentrations which have previously been shown to increase the pH of lysosomes.

The dose‐response curves of inhibition of mitogen‐induced lymphocyte activation for chloroquine and methylamine are very steep and are similar to the dose‐response curves obtained with dimaprit and nordimaprit, but very different from the flat dose‐response curves previously described for histamine. Approximate IC50 values were methylamine 6.4 mm, dimaprit 0.13 mm, nordimaprit 0.03 mm and chloroquine 18 μm.

It is suggested that the mechanism of action of methylamine and chloroquine may be related to their lysosomotropic action and consequent interference with ligand‐receptor processing, and that dimaprit and nordimaprit but not histamine may act by a similar mechanism.
The effect of prostaglandin D2 on the blood vessels of the perfused isolated cotyledon of the human placenta
Authors: Abramovich D. R. , Page K.R. , Parkin A.M.L.
Published: July 2012

Prostaglandin D2 was shown to constrict the blood vessels of the isolated perfused cotyledon of the human placenta. Its potency was less than that of prostaglandin F2α but similar to prostaglandin E2. As it is known to dilate uterine blood vessels it may, by its differential action on the foetal and maternal vascular beds, play a role in the local regulation of utero‐placental blood flow.
In vivo platelet aggregation in the rat: dependence on extracellular divalent cation and inhibition by nonsteroidal anti‐inflammatory drugs
Authors: Mallarkey G. , Smith G.M.
Published: July 2012

Using the Technicon Autocounter, the mechanisms involved in collagen‐induced platelet aggregation in vivo have been studied without the interference of an anticoagulant.

Extracellular divalent cation was essential for in vivo platelet aggregation.

Non‐steroidal anti‐inflammatory drugs completely inhibited the aggregation induced by collagen in platelet‐rich plasma in in vitro or ex vivo studies. In vivo only a maximum of 50% inhibition was achieved when release of thromboxane A2 (TXA2) was completely inhibited. Therefore in vivo, collagen causes aggregation through more than one pathway which operate independently of each other and which are all dependent on extracellular divalent cation.

In vivo, when different doses of collagen were compared, aggregation produced by low doses of collagen was more dependent upon prostaglandin endoperoxide/TXA2 formation.
Electromechanical effects of bepridil on rabbit isolated hearts
Authors: Anno Takafumi , Furuta Tatsuji , Itoh Masanori , Kodama Itsuo , Toyama Junji , Yamada Kazuo
Published: July 2012

Electromechanical effects of a new antianginal agent, bepridil, on Langendorff‐perfused rabbit hearts were compared with those of verapamil and lidocaine.

Bepridil at concentrations above 2 × 10−7m caused a dose‐related decrease in heart rate (HR), a prolongation of the atrio‐His bundle conduction time (A‐H interval) and a prolongation of the functional refractory period (FRP) of the atrioventricular (A‐V) node. Similar changes in HR, A‐H interval and the FRP of the A‐V node were observed with verapamil at concentrations above 2 × 10−8m. Lidocaine at above 4 × 10−5m prolonged slightly the A‐H interval and the FRP of the A‐V node but did not decrease the HR.

Bepridil at concentrations above 10−6m prolonged both the His bundle‐ventricular conduction time (H‐V interval) and the effective refractory period (ERP) of ventricular muscles. Similar changes in the H‐V interval and in the ERP of ventricular muscles were observed with lidocaine at above 10−5m. Verapamil ranging between 5 × 10−8m and 8 × 10−7m had no effect on the H‐V interval and appreciably shortened the ERP of ventricular muscles.

Bepridil at concentrations above 2 × 10−6m reduced the developed tension as did verapamil at above 10−7m.

On a molar basis, the depressant effect of bepridil on HR and the A‐V nodal conduction, which may reflect inhibitory action on the slow channels, was less than one tenth that of verapamil. Bepridil was more potent than lidocaine in prolonging the H‐V interval and the ERP of ventricular muscles indicating a possible inhibition of the fast sodium channels. Both of these electrophysiological effects of bepridil may afford significant bases for the antiarrhythmic action of the drug.
Androgenic repression of hexobarbitone metabolism and action in Crl:CD‐1 (ICR)BR mice
Authors: Shapiro Bernard H. , Szczotka Susan M.
Published: July 2012

Mice of the Crl:CD‐1 (ICR)BR strain exhibit a sexual dimorphism in hexobarbitone metabolism and action. Compared to females, males have a lower Vmax and a higher Km for hepatic microsomal hexobarbitone hydroxylase. In agreement with the enzyme studies, hexobarbitone‐induced sleeping times were greater for males than for females.

Results from experiments measuring hexobarbitone metabolism and action in castrate, testosterone and gonadotropin‐treated mice indicate that the sexual differences in drug metabolism and action found in Crl:CD‐1 (ICR)BR mice are due to the normally repressive effects of testicular androgens on the activities of the hepatic mono‐oxygenases. These findings are in dramatic contrast to studies with rats where it has been shown that androgens induce mono‐oxygenases. Furthermore, in the case of the mouse, changes in the activity of hexobarbitone hydroxylase in response to alterations in androgen levels require weeks, while in the rat, androgenic‐induced changes are apparent within a matter of days.
Vascular reactivity in rats with glycerol‐induced acute renal failure
Authors: Bowmer C. J. , Clarke Colette A. , Comer M. B. , Yates M. S.
Published: July 2012

The vascular reactivity of rats with glycerol‐induced acute renal failure was assessed in vitro and in vivo.

The contractile responses to noradrenaline, angiotensin and potassium chloride of aortic strips and portal vein segments from uraemic rats were significantly smaller than the responses obtained in vessels from control animals.

The pressor responses to angiotensin were reduced significantly in rats with acute renal failure when compared to those in control rats.

The reduced vascular responses to a range of spasmogens suggests that in this model of renal failure there is a defect in some mechanism of vascular contraction common to all three constrictor agents.
Contractile responses to substance P and related peptides of the isolated muscularis mucosae of the guinea‐pig oesophagus
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: July 2012

The site of action of substance P and related tachykinins with respect to isotonic contractions was examined on the isolated muscularis mucosae attached to the submucous plexus of the guinea‐pig oesophagus.

Substance P (> 30 nm) produced a concentration‐dependent contraction of the muscularis mucosae (EC50 1.9 ± 0.5 μm, n = 10). The contractions were rapid in onset (2 min or less), sustained, reversible by washing and the preparation did not show tachyphylaxis.

Eledoisin and physalaemin produced similar sustained contraction of the muscularis mucosae. The order of sensitivity was eledoisin > substance P > physalaemin. Contractions induced by 1 μm of each tachykinin were not significantly modified by incubation of the tissue with substance P or eledoisin (10 μm for 30 min).

The contractile responses to tachykinins were unaffected by tetrodotoxin (0.3 μm), atropine (0.3 μm), phentolamine (1 μm), chlorpheniramine (1 μM), methysergide (1 μM) baclofen (100 μm) and verapamil (10 μm), but were abolished by the incubation of the tissue with calcium‐free, EGTA (0.1 mm)‐containing Tyrode solution.

A substance P antagonist, [d‐Pro2, d‐Trp7,9]‐substance P (>0.1 μm), produced a transient contraction of the muscularis mucosae and the smooth muscle regained its original tone within 6 to 10 min. Contractions to the tachykinins were now inhibited by the antagonist (0.1–10 μm) in a concentration‐dependent manner, the order of sensitivity being physalaemin > substance P = eledoisin.

The cholinergically mediated electrically (0.1 Hz, 0.5 ms, supramaximal voltage)‐induced twitch contractions of the muscularis mucosae were not significantly modified by substance P (0.01–0.3 μm).

The present results indicate that substance P and related tachykinins contract the isolated muscularis mucosae of the guinea‐pig oesophagus by a direct action on the smooth muscle, probably by stimulating SP‐E receptors.
The response of cat spinal motoneurones to the intracellular application of agents with local anaesthetic action
Authors: Engberg I. , Flatman J.A. , Lambert J.D.C.
Published: July 2012

QX‐222 (the trimethyl analogue of lignocaine), methylxylocholine, lignocaine and pentobarbitone were iontophoresed intracellularly into cat lumbosacral motoneurones. Iontophoresis and recording was either from a triple‐barrelled microelectrode unit or from two separately advanced microelectrodes.

QX‐222 and methylxylocholine caused a very slow reversible block of the current‐evoked and antidromic action potentials (AP) with no significant change of membrane potential (EM). Lignocaine had a minimal blocking effect on the AP.

No change, or only a small decrease, of membrane slope conductance (GM) was seen when the APs had been totally abolished.

QX‐222 and methylxylocholine reduced the massive Gm increase evoked by the passage of large depolarizing currents and converted the post‐current hyperpolarization (time constant 120–150 ms) into a depolarization of similar time course. It is suggested that the quaternary local anaesthetics can reduce the fast and slow voltage‐dependent potassium conductances.

Both agents totally blocked AP generation without decreasing the magnitude of the Ia e.p.s.p.

It is suggested that intracellularly iontophoresed QX‐222 (on account of its low lipid solubility) could be used as a pharmacological tool to block specifically the active Na and K channels in only the cell impaled by the microelectrodes.