bluuebunny/crossref_metadata_2025 huggingface dataset:
Reversals of the neostigmine‐induced tetanic fade and endplate potential run‐down with respect to the autoregulation of transmitter release
Authors: Chang C.C. , Chen S.M. , Hong S.J.
Published: July 2012

In order to shed more light on the role of presynaptic cholinoceptors in the modulation of transmitter release, the effects of tubocurarine, choline and hexamethonium on neostigmine‐induced tetanic fade and run‐down of endplate potentials (e.p.ps) in response to indirect stimulation with trains of pulses were studied in the intact and cut isolated phrenic nerve‐diaphragm preparation of the mouse, respectively.

Tubocurarine, choline and hexamethonium reduced both the tetanic fade and e.p.p. run‐down caused by neostigmine, despite the fact that they themselves also induced these two effects.

At a given degree of postsynaptic inhibition, choline and hexamethonium caused less e.p.p. run‐down and reversed the neostigmine‐induced tetanic fade and e.p.p. run‐down better than tubocurarine. Moreover, the e.p.p. run‐down caused by choline or hexamethonium, but not that induced by tubocurarine, was reciprocally reversed by neostigmine.

Tubocurarine, choline and hexamethonium significantly decreased the endplate depolarization induced by repetitive nerve stimulation in the presence of neostigmine. The remaining depolarization continued to grow during repetitive stimulation in the presence of choline or hexamethonium, but not, however, in the presence of tubocurarine; a finding which suggests that choline and hexamethonium but not tubocurarine may be displaced from the receptor by the accumulated acetylcholine.

The mutual reversal by neostigmine and cholinoceptor antagonists of e.p.p. run‐down may implicate the presence of a positive (physiological) and a negative (pharmacological) feedback regulation for evoked transmitter release via nicotinic cholinoceptors in the mammalian motor nerve, depending on the concentration of acetylcholine within the synaptic cleft.
Effect of the ‘antidementia drug’ pantoyl‐GABA on high affinity transport of choline and on the contents of choline and acetylcholine in rat brain
Authors: Nakahiro Masanobu , Mochizuki Daisuke , Uchida Shuji , Yoshida Hiroshi
Published: July 2012

Effect of pantoyl‐γ‐aminobutyric acid (pantoyl‐GABA) on high affinity transport of choline into synaptosomes and on the choline (Ch) and acetylcholine (ACh) concentrations of rat brain were studied.

Pantoyl‐GABA was injected intraperitoneally four times at a dose of 500mgkg−1 at intervals of 30min. One hour after the last injection, rats were killed by decapitation for measurement of high affinity transport of Ch into synaptosomes or by microwave irradiation for the measurement of Ch and ACh concentrations.

Transport of Ch was increased into synaptosomes prepared from the cerebral cortex and hippocampus, but not into those from the striatum.

In the cerebral cortex and hippocampus, Ch concentration was increased and ACh concentration decreased.

Since treatments that enhance the activity of cholinergic neurones in vivo are reported to increase high affinity transport of Ch measured in vitro, the present results suggest that pantoyl‐GABA may increase cholinergic activity in vivo. This action of the drug may be related to changes in the Ch and ACh concentrations.
Platelet inhibition by endothelium‐derived relaxing factor from the rabbit perfused aorta
Authors: Bult Hidde , Fret Hermine R.L. , Van den Bossche Rita M. , Herman Arnold G.
Published: July 2012

The platelet inhibiting activity of endothelium‐derived relaxing factor (EDRF) released by the perfused thoracic aorta of the rabbit was investigated.

The aortic effluent superfused a ring of the abdominal aorta without endothelium in order to bioassay EDRF. Aliquots of effluent were collected on rabbit washed platelets and aggregation induced by U‐46619 was measured after 1 min. Prostacyclin (PGI2) was monitored by radioimmunoassay of 6‐oxo‐prostaglandin F1α.

Acetylcholine (ACh) caused a dose‐dependent secretion of EDRF, PGI2 and anti‐aggregating activity. Plasma and methylene blue suppressed the platelet inhibition by the effluent.

The PGI2 content of the effluent was not sufficient to account for all the anti‐aggregating activity. However, the platelet inhibition disappeared when PGI2 formation was blocked with indo‐methacin.

Compression of the thoracic aorta increased the EDRF content in the effluent. A transient secretion of anti‐aggregating activity was then observed in aortic effluent in the absence of PGI2. This activity coincided with the presumed EDRF peak in the effluent.

Superoxide dismutase enhanced the ACh‐induced EDRF content and revealed secretion of an anti‐aggregating substance when PGI2 formation was blocked. Pretreatment of the platelets with subthreshold concentrations of PGI2, or the cyclic GMP phosphodiesterase inhibitor RX‐RE 56, also revealed the release of a labile platelet inhibitor in response to ACh.

The results indicate that EDRF released by fresh aortic endothelium may suppress platelet aggregation, particularly when PGI2 is present.
The effects of peptide histidine isoleucine and neuropeptide Y on mucus volume output from the ferret trachea
Authors: Webber S.E.
Published: July 2012

The effects of peptide histidine isoleucine (PHI) and neuropeptide Y (NPY) were examined on the mucus volume output produced by methacholine and phenylephrine in the ferret whole trachea in vitro.

Sustained application of methacholine (5 μM) or phenylephrine (20 μM) produced a maintained volume output of mucus from the trachea. Both these agonists also increased the output of lysozyme (a marker for serous cell secretion).

PHI inhibited the maintained mucus volume output produced by methacholine but had no effect on that due to phenylephrine. The output of lysozyme produced by methacholine or phenylephrine was not significantly changed by PHI.

NPY enhanced the volume output of mucus produced by methacholine or phenylephrine; however, the rate of output of lysozyme in mucus produced by both agonists was reduced by NPY.

We suggest that PHI has no effect on serous cell secretion but inhibits secretion from another source, possibly mucous cells. NPY inhibits serous cell secretion but has a stronger stimulant action on secretion from another source, again possibly mucous cells.

PHI and NPY may be important physiological modulators of mucus volume output in the ferret trachea.
Amiloride analogues cause endothelium‐dependent relaxation in the canine coronary artery in vitro: possible role of Na+/Ca2+ exchange
Authors: Cocks T.M. , Little P.J. , Angus J.A. , Cragoe E.J.
Published: July 2012

A number of amiloride analogues were used to test the proposal that Na+/Ca2+ exchange may play a role in the secretion of endothelium‐derived relaxing factor (EDRF). The analogues used were those substituted on either the 5‐amino group or the terminal guanidino nitrogen atom. The former block both Na+ /Ca2+ and Na+ /H+ exchange whilst the latter block the Na+ channel and the Na+ /Ca2+ exchange.

Both series of compounds caused relaxation in isolated rings of dog coronary artery (EC50 values, 1–10 μM) presumably due to release of EDRF since removal of endothelium greatly attenuated the response.

Amiloride (1–100 μM) had little effect on either endothelium‐intact or denuded arteries.

The guanidino substituted analogues also appeared to block selectively the relaxation response to acetylcholine in the coronary artery, independently of their EDRF‐releasing activity.

It is proposed that endothelial cells have an active Na+ /Ca2+ exchange operating in the forward mode to extrude Ca2+. This mechanism may be important in the control of EDRF release.
Effects of ethanol and pantothenic acid on brain acetylcholine synthesis
Authors: Rivera‐Calimlim Leonor , Hartley Donna , Osterhout Donna
Published: July 2012

Measurements of brain acetylcholine (ACh) synthesis from precursor [14 C]‐pyruvate, pantothenic acid (PA) concentration in the brain, and blood ethanol (EtOH) concentration were made in rats treated with either ethanol (5–6 g kg−1 body wt daily) alone or ethanol with PA supplementation (100–200 mg kg−1 body wt daily). EtOH with or without PA was administered orally by either Lieber‐Decarli liquid diet for 4 weeks and 4 months or by oral intubation for 1 and 4 days. Matched controls were given either ethanol‐free liquid diet or saline.

ACh synthesis in the brain of rats treated with ethanol alone for 4 months was significantly (P < 0.01) inhibited. PA concentration of the brain was diminished to 7.0% of the control value.

PA concentration in the brain of rats treated with ethanol plus PA for 4 months was three times that of rats treated with ethanol alone. ACh synthesis in rats with ethanol and PA supplementation was also significantly (P <0.01) higher.

There was no difference in blood EtOH concentration between rats treated with ethanol with or without PA supplement.

The EtOH effect on ACh synthesis and PA concentration in the brain was observed in the chronic treatments but not in the acute treatments.

Data suggest that chronic ethanol exposure may decrease ACh synthesis by depleting PA, a precursor for the synthesis of acetyl CoA. Acetyl CoA is an essential substrate for ACh synthesis.
Characterization of neuropeptide‐induced histamine release from human dispersed skin mast cells
Authors: Lowman Mark A. , Benyon R. Christopher , Church Martin K.
Published: July 2012

Human skin mast cells, unlike other human mast cells so far studied, released histamine in a concentration‐related manner in response to substance P, vasoactive intestinal peptide (VIP) and somatostatin (1 μM to 30 μM). In contrast, eledoisin, physalaemin, neurokinin A, neurokinin B, calcitonin gene‐related peptide (CGRP), neurotensin, bradykinin and Lys‐bradykinin induced negligible histamine release.

The low histamine releasing activity of physalaemin, eledoisin, neurokinin A and neurokinin B relative to substance P suggests that the human skin mast cell activation site is distinct from the tachykinin NK‐1, NK‐2 or NK‐3 receptors described in smooth muscle.

The relative potencies of substance P and its fragments SP2–11, SP3–11, SP4–11 and SP1–4 in releasing histamine from human skin mast cells suggests that both the basic N‐terminal amino acids and the lipophilic C‐terminal portion of substance P are essential for activity.

Peptide‐induced histamine release, like that induced by compound 48/80, morphine and poly‐L‐lysine, is rapid, reaching completion in 10–20 s, is largely independent of extracellular calcium but requires intact glycolysis and oxidative phosphorylation.

The substance P analogue, [D‐Pro4, D‐Trp7,9,10] SP4–11 (SPA), not only reduced substance P‐induced histamine release in a concentration‐related manner but also inhibited that induced by VIP, somatostatin, compound 48/80, poly‐L‐lysine and morphine but not anti‐IgE.

The similar characteristics of histamine release induced by substance P, VIP, somatostatin, compound 48/80, poly‐L‐lysine and morphine suggest that they share a common pathway of activation‐secretion coupling distinct from that of IgE‐dependent activation. Furthermore, the ability of human skin mast cells to respond to basic non‐immunological stimuli including neuropeptides may reflect a specialised function for these cells.
Regional haemodynamic effects of depressor neuropeptides in conscious, unrestrained, Long Evans and Brattleboro rats
Authors: Gardiner Sheila M. , Compton Alix M. , Bennett Terence
Published: July 2012

The regional haemodynamic effects of i.v. bolus doses of atrial natriuretic peptide (ANP, 1 and 10 nmol), calcitonin gene‐related peptide (CGRP, 0.05 and 0.5 nmol) and corticotropin‐releasing factor (CRF, 1 and 5 nmol) were assessed in conscious Long Evans and Brattleboro rats chronically instrumented with miniaturized, pulsed Doppler probes.

The low dose of ANP was without effect on mean arterial pressure (MAP), but caused tachycardia and hindquarters vasodilatation with vasoconstriction in renal and mesenteric beds in Long Evans rats. With the high doses of ANP these effects were more pronounced and MAP fell. In Brattleboro rats there was a primary renal vasodilatation.

The low dose of CGRP caused a slight fall in MAP in Long Evans rats, tachycardia and a renal vasodilatation. The high dose of CGRP caused marked hypotension, tachycardia and renal, mesenteric and hindquarters vasodilatation in both strains of rat. However, only in Long Evans rats were there secondary renal and mesenteric vasoconstrictions.

The low dose of CRF caused falls in MAP in both strains of rat, accompanied by renal and, particularly, mesenteric vasodilatation. Administration of the high dose of CRF caused profound, prolonged hypotension, tachycardia and mesenteric vasodilatation. There was also (late onset) hindquarters vasodilatation accompanying renal vasoconstriction that followed the initial vasodilatation in this vascular bed.

These results indicate that appropriate doses of particular peptides may be capable of promoting flow through individual peripheral vascular beds.
The action of volatile anaesthetics on stimulus‐secretion coupling in bovine adrenal chromaffin cells
Authors: Pocock G. , Richards C.D.
Published: July 2012

The action of four volatile anaesthetics, ethrane, halothane, isoflurane and methoxyflurane on stimulus‐secretion coupling has been studied in isolated bovine adrenal medullary cells. All four agents inhibited the secretion of adrenaline and noradrenaline evoked by 500 μM carbachol at concentrations within the anaesthetic range. Total catecholamine secretion induced by stimulation with 77 mM potassium was also inhibited but at higher concentrations. All four agents inhibited the45 Ca influx evoked by stimulation with 500 μM carbachol and the45 Ca influx in response to K+‐depolarization.

When total catecholamine secretion in response to potassium or carbachol was modulated by varying extracellular calcium or by adding halothane or methoxyflurane to the incubation medium, the amount of catecholamine secretion for a given Ca2+ entry was the same.

The action of methoxyflurane on the relationship between intracellular free Ca and exocytosis was examined using electropermeabilised cells, which were suspended in solutions containing a range of concentrations of ionised calcium between 10−8 and 10−4 M. The anaesthetic had no effect on the activation of exocytosis by intracellular free calcium.

Halothane and methoxyflurane inhibited the carbachol‐induced secretion of catecholamines in a non‐competitive manner.

Halothane and methoxyflurane inhibited the increase in22 Na influx evoked by carbachol. For halothane and methoxyflurane this inhibition of Na influx appears to be sufficient to account for the inhibition of the evoked catecholamine secretion.

We conclude that the volatile anaesthetics ethrane, halothane, isoflurane and methoxyflurane inhibit the secretion of adrenaline and noradrenaline induced by carbachol at concentrations that lie within the range encountered during general anaesthesia. In addition all four also inhibit the secretion of catecholamines induced by depolarization with 77 mM K+ but at much higher concentrations. The decrease in Ca influx caused by methoxyflurane accounts fully for the decrease in secretion in response to depolarization with potassium. Similar actions at synapses within the CNS may underlie the general anaesthetic effects of these agents.
Autoradiographic localization and function of β‐adrenoceptors on the human internal mammary artery and saphenous vein
Authors: Molenaar P. , Malta E. , Jones C.R. , Buxton B.F. , Summers R.J.
Published: July 2012

Receptor autoradiography with (−)‐[125 I]‐cyanopindolol (CYP) was used to study the distribution of β1 and β2‐adrenoceptor subtypes in the human internal mammary artery and saphenous vein.

Images from X‐ray film and nuclear emulsion coated coverslips, exposed to [125 I]‐CYP labelled sections, showed a high density of β2‐adrenoceptors localized to the endothelium of the internal mammary artery and fewer β2‐adrenoceptors on the smooth muscle.

The function of β‐adrenoceptors in ring preparations of the internal mammary artery was investigated in organ bath studies. (−)‐Isoprenaline produced concentration‐dependent relaxation of phenylephrine contracted rings. The potency and maximal effects of (−)‐isoprenaline were not influenced by the presence of the endothelium.

Images of [125 I]‐CYP binding to the saphenous vein, from X‐ray film and nuclear emulsion coated coverslips, showed localization of β2‐adrenoceptors to the outer smooth muscle and not to the endothelium.

Relaxation of mammary artery and saphenous vein to (−)‐isoprenaline is mediated via β2‐adrenoceptors located on the smooth muscle. Endothelial β2‐adrenoceptors, although present on the internal mammary artery, mediate other functions.
Pre‐ and post‐junctional actions of procaterol, a β2‐adrenoceptor stimulant, on dog tracheal tissue
Authors: Ito Yushi
Published: July 2012

The effects of procaterol, a β2‐adrenoceptor agonist, on excitatory neuro‐effector transmission in the dog trachea were investigated and the findings were compared to those seen with isoprenaline, with microelectrode, double sucrose gap and tension recording methods.

Procaterol (10−10‐ 10‐9 M) and isoprenaline (10−9 M) had no effect on the resting membrane potential or on the input resistance of the smooth muscle cells of dog trachea. However with increased concentrations (>10−8 M), these agents hyperpolarized the membrane and decreased the input resistance of the membrane.

Procaterol (10−10‐10−7 M) and isoprenaline (10−9‐10−7 M) dose‐dependently reduced the amplitude of the twitch contractions evoked by field stimulation in the combined presence of indomethacin (10−5 M) and guanethidine (10−6 m). In parallel with actions on twitch contractions, procaterol (10−10‐10−7 m) and isoprenaline (10−9‐10−7 M) reduced the amplitude of the excitatory junction potentials (e.j.ps), evoked by single pulse field stimulation in the dog trachea.

Procaterol (10−8 M) had no effect on the post‐junctional response of smooth muscle cells to exogenous acetylcholine (ACh) (10−7‐10−6 M).

Pretreatment with ICI‐118551, aβ2‐adrenoceptor blocking agent, reduced the inhibitory action of procaterol on the amplitude of twitch contractions evoked by field stimulations in the dog trachea.

These results indicate that procaterol in low concentrations has a prejunctional action inhibiting the excitatory neuro‐effector transmission in addition to a postsynaptic action, presumably by suppressing transmitter release from the vagus nerve terminals through β2‐adrenoceptors in the dog tracheal tissue. The pre‐ and post‐junctional actions of procaterol explain its potent bronchodilator effects in clinical use.
Antigen‐induced contraction of guinea‐pig isolated trachea: studies with novel inhibitors and antagonists of arachidonic acid metabolites
Authors: Jones T.R. , Charette L. , Denis D.
Published: July 2012

Responses of antigen‐challenged isolated trachea from sensitized guinea‐pigs were pharmacologically characterized by use of some novel inhibitors and antagonists of arachidonic acid metabolites.

The cyclo‐oxygenase inhibitor, indomethacin, prolonged without altering the maximum response to antigen in the absence of the anti‐muscarinic agent, atropine, and/or the H1receptor blocker, mepyramine. In the presence of mepyramine, indomethacin both prolonged and increased the magnitude of the response. The selective (SQ‐29548) and non‐selective (L‐640, 035) thromboxane A2 (TXA2) antagonist and the TXA2 synthetase inhibitor, OKY‐046, were essentially inactive.

Two novel inhibitors of 5‐lipoxygenase product formation, AA‐861 and L‐651,896 produced complete inhibition of the response to antigen on tissues treated with atropine and mepyramine, with or without indomethacin.

Equimolar concentrations of the leukotriene D4 (LTD4) receptor antagonists LY‐171883 > L‐649,923 ≧ L‐648,051 ≧ FPL‐55712 blocked part of the response to antigen on tissues treated with atropine, mepyramine and indomethacin. All compounds tended to block a larger component of the response in the absence of indomethacin. A similar tendency was observed with the potent phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) but not the less potent phosphodiesterase inhibitor theophylline.

These results are consistent with the hypothesis that 5‐lipoxygenase products acting on LTD4 receptors play only a minor role in the mediation of the contraction of guinea‐pig trachea to antigen challenge. The nature of the residual contractile mediator is unknown; however, it can be completely blocked by the 5‐lipoxygenase inhibitors AA‐861 and L‐651,896 and non‐selectively blocked by the phosphodiesterase inhibitor, IBMX and non‐selective LTD4 receptor antagonists, such as LY‐171883.
Primary sensory neurones and naloxone‐precipitated morphine withdrawal
Authors: Donnerer Josef
Published: July 2012

The C‐fibre‐evoked depressor reflex following i.a. injection of capsaicin and the wiping movements following chemical irritation of the cornea by capsaicin were both found to be augmented in the naloxone‐precipitated morphine withdrawal phase.

The in vitro capsaicin‐evoked release of substance P from central terminals of C‐fibre afferents in the spinal cord was decreased in morphine‐treated rats. Following naloxone, the release in the morphine‐treated group was as large as in the control group.

The C‐fibre mediated plasma extravasation in the rat paw after naloxone was found to be the same in morphine‐treated and control rats.

It is concluded that C‐fibre‐evoked reflex reactions are augmented during morphine withdrawal, but that the mechanisms responsible are either located postsynaptically to the primary sensory neurone or further centrally.
Reversal of the cardiotonic and action‐potential prolonging effects of DPI 201–106 by BDF 8784, a methyl‐indol derivative
Authors: Armah Benjamin I. , Pfeifer Thomas , Ravens Ursula
Published: July 2012

We studied the interaction of the cardiotonic compound DPI 201–106 (4‐[3′‐(4″‐benzhydryl‐1′‐piperazinyl)−2′‐hydroxypropoxy]‐1H‐indole‐2‐carbonitrile; DPI) and its derivative BDF 8784 (2‐methyl‐4‐[3′‐(4″‐benzhydryl‐1”‐piperazinyl)−2′‐hydroxypropoxy]‐1H‐indole; BDF) in isolated right ventricular papillary muscles of guinea‐pig heart.

In contrast to the cardiotonic DPI, the methyl‐indole derivative lacked a positive inotropic effect and even caused negative inotropic effects in concentrations above 1 μm. At 10 μm BDF significantly reduced the force of contraction and dV/dtmax' but did not affect action potential duration (APD).

Pretreatment of papillary muscles with BDF prevented the positive inotropic action of DPI in a concentration‐dependent, but non‐competitive fashion. At 10 μm, BDF prevented the inotropic effect of racemic DPI and shortened the DPI‐induced prolongation of action potential duration. BDF similarly affected the inotropic and APD‐prolonging effects of the sea anemone polypeptide ATX II.

In cardiac myocytes, DPI induced a tetrodotoxin (TTX)‐sensitive, slowly inactivating inward current. The slow decay of this current was enhanced by BDF. In cells pretreated with BDF, DPI was not effective. BDF alone depressed the sodium and the calcium current.

In conclusion, the non‐inotropic methyl‐indole derivative BDF interacts with DPI non‐competitively at the sodium channels to abolish the inotropic and APD‐prolonging effects of DPI, emphasizing the importance of the substituent in position 2 of the indole moiety for this effect.
The relaxant properties of human calcitonin gene‐related peptide on vascular and extravascular (capsular) smooth muscle of the isolated blood‐perfused spleen of the anaesthetized dog
Authors: Withrington P.G.
Published: July 2012

The 37 amino acid human calcitonin gene‐related peptide (CGRP), was injected intra‐arterially into the isolated, blood perfused spleen of the dog.

The only vascular response observed to CGRP, once threshold had been reached (10–20 fmol), was a dose‐dependent splenic arterial vasodilatation.

The mean intra‐arterial bolus dose of CGRP to reduce the splenic arterial vascular resistance by 50% of maximum response was 0.52 ± 0.12 pmol. This value was significantly lower than the ED50 for the non‐selective β‐adrenoceptor agonist isoprenaline (P < 0.01) in the same experiments. CGRP is the most potent splenic vasodilator yet tested.

The mean maximum vasodilator response to CGRP was significantly less (P < 0.01) than that achieved with isoprenaline.

The time course of the splenic arterial vascular response to CGRP was substantially longer than that to isoprenaline.

The splenic vasodilator response to CGRP was not altered by the prior administration of the selective β2‐adrenoceptor antagonist, ICI 118,551.

At all doses of CGRP that caused splenic vasodilatation there were substantial increases in spleen volume. The time course of the response and slope of the regression line suggested an active capsular relaxation component.

In view of its location within the spleen and high molar potency, CGRP may be considered as a potential factor in the local control of the circulation through the spleen.
8‐OH‐DPAT, flesinoxan and guanfacine: systemic and regional haemodynamic effects of centrally acting antihypertensive agents in anaesthetized rabbits
Authors: Hof R.P. , Fozard J.R.
Published: July 2012

8‐Hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and flesinoxan, agents which show high affinity and selectivity for 5‐HT1A receptors, were administered intravenously in doses of 0.003 to 0.1 and 0.01 to 0.3 mg kg−1 respectively to 5 rabbits each. Their effects were compared with those of the centrally acting agent and α2‐adrenoceptor agonist, guanfacine, 0.01–0.3 mg kg−1, administered to a group of 5 rabbits. Five further rabbits were used as controls and treated with the vehicle of the active agents.

Both flesinoxan and 8‐OH‐DPAT induced similar systemic and regional haemodynamic changes. Both lowered mean arterial pressure and heart rate. The principal blood pressure lowering mechanism was vasodilatation; cardiac output changed minimally despite the falls in heart rate and myocardial contractile force.

With guanfacine the maximal fall of blood pressure was comparable to that obtained with the 5‐HT1A receptor ligands; however, in contrast to the latter, the dose‐response curve was U‐shaped, the highest dose eliciting a pressor effect with reversal of the vasodilatation.

Widespread peripheral vasodilatation was found with all the agents in the splanchnic circulation and also in the brain and skeletal muscle. A weak tendency towards vasodilatation was found in the kidneys where the dose‐response curve was bell‐shaped for guanfacine.

This spectrum of activity is different from that of peripheral vasodilators, such as calcium antagonists, potassium channel activating agents or hydralazine; it is, however, consistent with the putative mechanism of action of these compounds to reduce peripheral sympathetic tone by a central mechanism of action.
Differential antagonism of the negative inotropic effect of gentamicin by calcium ions, Bay K 8644 and isoprenaline in canine ventricular muscle: comparison with cobalt ions
Authors: Hashimoto Hiroo , Yanagisawa Teruyuki , Taira Norio
Published: July 2012

Gentamicin (10−4−10−2 m) and Co2+ (10−4 — 10−2 m) produced a decrease in developed tension of canine isolated ventricular muscles leading to near abolition at 10−2m. Their negative inotropic effects developed rapidly and wore off shortly after wash‐out.

The concentration‐negative inotropic effect curves for gentamicin were shifted to the right in a parallel manner by increasing external Ca2+, or by the presence of Bay K 8644 (10−7−10−5m) or isoprenaline (10−7−10−5m). IC50 values for gentamicin increased about 3‐fold with about a 6 fold increase in external Ca2+. The Schild plot yielded a pA2 of 2.29 for Ca2+ and its slope was −1.17 (r = −0.79).

The concentration‐negative inotropic effect curves for Co2+ were shifted to the right in a parallel manner by increasing external Ca2+, or by the presence of isoprenaline (10−7−10−5m). IC50 values for Co2+ increased about 5 fold with about a 6 fold increase in external Ca2+. The Schild plot gave a pA2 value of 2.60 for Ca2+ and its slope was −1.11 (r = −0.86).

The concentration‐positive inotropic effect curves for Ca2+, which were computer‐fitted to a logistic equation, gave 2.88 × 10−3 m for EC50. This value was very close to the KCa calculated from pA2 values for Ca2+ based on antagonism between gentamicin or Co2+ and Ca2+ (5.13 × 10−3 and 2.51 × 10−3 m).

It is concluded that like Co2+, gentamicin molecules compete with Ca2+ for the same binding sites presumably located at the outer orifice of Ca‐channels in the cardiac sarcolemma.
Electrophysiological effects of E‐3753, a new antiarrhythmic drug, in guinea‐pig ventricular muscle
Authors: Delpón Eva , Valenzuela Carmen , Tamargo Juan
Published: July 2012

The electrophysiological effects of E‐3753, a new antiarrhythmic drug, were studied in guinea‐pig papillary muscles.

E‐3753 (10−7‐10−4m) produced a concentration‐dependent decrease in the action potential amplitude and Vmax of the upstroke, shortened the action potential duration (APD) and shifted the resting membrane potential to less negative values. E‐3753 also shortened the effective refractory period (ERP), lengthening the ERP relative to APD.

E‐3753 (10−5m) shifted the membrane responsiveness curve along the voltage axis to more negative potentials.

In the presence of E‐3753 (10−5m) trains of stimuli at rates between 0.5 and 3 Hz led to an exponential decline in Vmax (onset rate at 3 Hz, 0.05 ± 0.009 per action potential), to a new steady‐state level. This use‐dependent Vmax block was augmented at higher rates of stimulation. The time constant for the recovery of Vmax from the use‐dependent block was 41.1 ± 4.8 s.

E‐3753 (10−5‐10−4 m) had no effect on the characteristics of the slow action potentials elicited by isoprenaline in ventricular fibres depolarized by 27 mm KCl.

The slow onset of use‐dependent block during repetitive activity and the slow offset kinetics of use‐dependent Vmax block suggest that E‐3753 exhibits class Ic antiarrhythmic actions in ventricular muscle fibres but does not exhibit class IV (Ca antagonist) antiarrhythmic actions.
A comparison of the effects of a series of anti‐anginal agents in a novel canine model of transient myocardial ischaemia
Authors: Allely M.C. , Alps B.J.
Published: July 2012

An anaesthetized canine model of transient myocardial ischemia (TMI) has been developed in which reproducible and reversible electrocardiographic (ECG) and haemodynamic responses are exacerbated by electrical pacing.

The model could separate the ECG and haemodynamic effects of compounds with anti‐ischaemic properties.

Compounds known to possess peripheral or coronary vasodilator properties did not necessarily alleviate the ECG consequences of TMI since glyceryl trinitrate was active whereas dipyridamole was not. The effects of verapamil were complicated by its adverse conduction effects while lidoflazine inhibited the ECG changes only during the ischaemic phase and the ‘metabolic modulator’ oxfenicine worsened the ECG response.

In a model considered to lack coronary reserve, improvements observed in the ischaemic ECG and global ventricular function were considered to result from a direct myocardial effect of the drugs examined rather than by a vascular influence. This was provided to the greatest degree by the Ca2+‐entry blockers nifedipine and nicardipine, with flunarizine adopting an intermediate position.
ICI 204448: a κP‐opioid agonist with limited access to the CNS
Authors: Shaw John S. , Carroll Jacqueline A. , Alcock Peter , Main Brian G.
Published: July 2012

A number of compounds were evaluated in an attempt to identify a κ‐opioid receptor agonist with limited access to the central nervous system.

Quaternary derivatives of the κ‐opioid agonists tifluadom, U‐50488H and ethylketocyclazocine were essentially devoid of opioid activity in a range of isolated tissue preparations.

A novel compound — ICI 204448 — is described which produced a potent and naloxone‐reversible inhibition of electrically‐evoked contraction of the guinea‐pig ileum, mouse vas deferens and rabbit vas deferens preparations. ICI 204448 was shown to displace the binding of the κ‐opioid ligand [3H]‐bremazocine from guinea‐pig cerebellum membranes.

Ex vivo binding studies in mice showed ICI 204448 to be well absorbed following subcutaneous administration. The brain levels achieved by ICI 20448 were substantially lower than those produced by κ‐agonists such as U‐50488H and tifluadom.

A good correlation was found for a range of opioids between lipophilicity and degree of CNS penetration.
Histamine H3‐receptors inhibit cholinergic neurotransmission in guinea‐pig airways
Authors: Ichinose M. , Stretton C.D. , Schwartz J.‐C. , Barnes P.J.
Published: July 2012

The histamine H3‐agonist (R)−α‐methylhistamine (α‐MeHA) caused a dose‐dependent inhibition of vagally‐mediated contraction of a guinea‐pig tracheal tube preparation but did not alter tracheal contraction induced by exogenously‐applied acetylcholine. Blockade of H1‐ and H2‐histamine receptors, and α‐ and β‐adrenoceptors failed to prevent the inhibitory effect of α‐MeHA, whereas the specific H3‐antagonist thioperamide prevented the effect of α‐MeHA on tracheal contraction. In the presence of H1‐ and H2‐receptor antagonists, histamine also inhibited vagally‐mediated tracheal contraction. The inhibitory effect of α‐MeHA was greater with preganglionic (vagus nerve) stimulation than with postganglionic stimulation by electrical field stimulation, suggesting that H3‐receptors are localized both to cholinergic ganglia and to post‐ganglionic nerve‐endings. Our results suggest that H3‐receptors exist on the vagus nerve which modulate cholinergic neurotransmission in the airways.
Noradrenaline activates a calcium‐activated chloride conductance and increases the voltage‐dependent calcium current in cultured single cells of rat portal vein
Authors: Pacaud P. , Loirand G. , Mironneau C. , Mironneau J.
Published: July 2012

Membrane responses were recorded by a patch pipette technique in cultured cells isolated from rat portal vein. Using the whole‐cell mode, pressure ejections of noradrenaline evoked depolarization (current clamp) and inward current (voltage clamp) at membrane potentials of −60 to −70 mV. The noradrenaline‐induced response was reversibly blocked by prazosin indicating that the response was mediated by α1‐adrenoceptors.

The ionic mechanism of the noradrenaline‐induced inward current was investigated in potassium‐free caesium‐containing solutions. Alteration of the chloride equilibrium potential produced similar changes in the reversal potential of the noradrenaline‐induced current, indicating that noradrenaline opened chloride‐selective channels. There was no evidence implicating sodium or calcium as the charge‐carrying ion.

Caffeine applied in the bathing solution also induced a transient increase in chloride conductance but the noradrenaline‐induced response was lost after application of caffeine. This is interpreted to mean that the increase in chloride conductance induced by noradrenaline and caffeine can occur as a consequence of a rise in intracellular calcium concentration depending on release of calcium from the same intracellular stores.

In the presence of caffeine, noradrenaline increased both the voltage‐dependent calcium and chloride membrane conductances during application of repetitive depolarizing pulses. It is concluded that in isolated cells of the rat portal vein the depolarization in response to noradrenaline is mediated by an increase in chloride conductance depending on both the calcium release from intracellular stores and the increase of the voltage‐dependent calcium current.
The effects of infusions of arginine vasopressin or 1‐deamino‐8‐D‐arginine vasopressin on common carotid vascular resistance in conscious, Long Evans rats
Authors: Gardiner S.M. , Compton A.M. , Bennett T.
Published: July 2012

Intravenous infusions of arginine vasopressin or 1‐deamino‐8‐d‐arginine vasopressin (DDAVP) were given to conscious, Long Evans rats chronically instrumented with bilateral, common carotid, pulsed Doppler probes and intravascular catheters.

During infusion of vasopressin at 0.3 nmol min−1 there was an increase in common carotid vascular resistance with no change in mean blood pressure or heart rate. Following infusion there was a common carotid vasodilatation.

During infusion of vasopressin at 3.0 nmol min−1 there were increases in mean arterial blood pressure and in common carotid vascular resistances, accompanied by bilateral reductions in flow and in heart rate. Administration of (+)−(CH2)5Tyr(Et)DAVP (a V1‐receptor antagonist), during the continued infusion of vasopressin, reversed the effects of the latter on mean blood pressure and heart rate; under these conditions there were increases in common carotid blood flows above baseline, in company with bilateral vasodilatations. The latter effects persisted after cessation of vasopressin infusion.

Infusions of DDAVP were without significant effects on any measured cardiovascular variable.

The results do not provide straightforward support for the claim that vasopressin acts to promote cerebral perfusion, at least when V1‐receptor effects are unopposed. Furthermore, it seems likely that the vasodilator influence of vasopressin on the common carotid vascular bed is not due to stimulation of V2‐receptors.
Characteristics of oedema formation induced by N‐formyl‐methionyl‐leucyl‐phenylalanine in rabbit skin
Authors: Hellewell Paul G. , Yarwood Helen , Williams Timothy J.
Published: July 2012

The characteristics of N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP)‐induced oedema formation were investigated in vivo in rabbit skin.

FMLP injected intradermally alone induced a small increase in plasma leakage, but marked synergism with prostaglandin E2 (PGE2) in producing oedema responses was observed. In the presence of PGE2, FMLP was equiactive with C5a des Arg and 100–1000 times more active than histamine in terms of permeability‐increasing activity. The response to FMLP was not dependent on endogenous histamine release.

FMLP‐induced responses were of long duration (t1/2 ∼ 40–50 min) when compared with bradykinin (t1/2 ∼ 4–5 min).

The activity of a range of N‐formyl peptides in increasing vascular permeability in skin correlated well with their activity as neutrophil stimulants in vitro.

Intravenous infusion of zymosan‐activated plasma (ZAP) resulted in transient neutropenia and inhibition of oedema formation induced by FMLP and C5a des Arg in the skin. Responses to bradykinin were unaffected by the infusion of ZAP.

Intravenous injection of the non‐steroidal antiinflammatory drug, ibuprofen, resulted in an inhibition of FMLP‐induced, but not histamine‐induced, oedema formation. This effect was independent of cyclo‐oxygenase inhibition and the drug did not induced neutropenia.

Intravenous injection of the microtubule blocking agent colchicine inhibited FMLP‐induced oedema formation. Responses to bradykinin were unaffected. When colchicine was administered after intradermal FMLP, subsequent plasma leakage was abolished.

The inference that receptors have evolved to bacterial secretions (i.e. FMLP) and products of the interaction of bacterial cell walls with tissue fluid (i.e. C5a des Arg), is consistent with the hypothesis that oedema formation is fundamentally a functional process concerned with regulating microbial lysis and opsonisation in an infected tissue.
Characterization of pigment aggregating α2‐adrenoceptors of fish melanophores by use of different agonists after partial irreversible receptor inactivation
Authors: Karlsson Jan Olof G. , Andersson Rolf G.G. , Grundström Nils
Published: July 2012

The affinity for, and the intrinsic efficacy on, postsynaptic melanosome aggregating α2‐adrenoceptors of fish melanophores was studied for B‐HT 920, clonidine, medetomidine, noradrenaline, phenylephrine and UK‐14,304. Investigations were carried out by evaluating the effects of progressive, irreversible inactivation of the α2‐adrenoceptors by benextramine.

The double reciprocal plots of equieffective concentrations of B‐HT 920, clonidine, noradrenaline and phenylephrine were linear, which indicated that these compounds exerted their effects, mainly, through interaction with one receptor site.

The affinity for the α2‐adrenoceptor selective agonist B‐HT 920, was found to be about 1000 times higher than the affinity for the α1‐adrenoceptor selective agonist phenylephrine.

The corresponding plot of equieffective concentrations of medetomidine was not linear, which may indicate that this imidazole compound exerted its effect through more than one receptor site. However, when phenoxybenzamine was used in place of the more selective benextramine, a linear relationship was obtained.
Lipomobilizing effects of procaterol and yohimbine in the conscious dog: comparison of endocrinological, metabolic and cardiovascular effects
Authors: Valet Philippe , Taouis Mohammed , Tran Marie A. , Montastruc Paul , Lafontan Max , Berlan Michel
Published: July 2012

Lipid mobilization during a hypocaloric diet may be enhanced by a pharmacological approach using β2‐adrenoceptor agonists or α2‐adrenoceptor antagonists. Studies were undertaken in the dog, an animal model presenting fat cell antilipolytic α2‐ and lipolytic β‐adrenoceptors, in order, firstly, to demonstrate the presence of β2 subtype adrenoceptors on adipocytes and, secondly, to compare the effects of procaterol (β2‐adrenoceptor agonist) and of yohimbine (α2‐adrenoceptor antagonist) on metabolic, endocrinological and cardiovascular parameters.

Procaterol strongly stimulates lipolysis in dog adipocytes in vitro. The utilisation of selective β1‐ and β2‐adrenoceptor antagonists (bisoprolol and ICI 118,551) in both lipolysis and binding studies (displacement of [3H]‐dihydroalprenolol binding) demonstrated the presence of the two β‐adrenoceptor subtypes in dog fat cells.

Infusion of either yohimbine or procaterol (10 and 0.4 nmol min−1 kg−1, respectively for 30min). provoked an equivalent increase in plasma non‐esterified fatty acids (+100%). Procaterol, but not yohimbine, induced hyperglycaemia (+ 120%). Plasma insulin was weakly enhanced by yohimbine (+ 120%) as compared to the increase given by procaterol (+ 500%).

Both drugs stimulated sympathetic nervous system activity, as indicated by the increased plasma noradrenaline concentration, but only yohimbine increased the plasma adrenaline level.

Cardiovascular measurements indicated that procaterol strongly enhances heart rate and transiently decreases mean blood pressure. Yohimbine exhibits a weaker effect on heart rate and slightly increases mean blood pressure.

The present work clearly indicates that lipid mobilization is enhanced during fasting in the dog by selective β2‐adrenoceptor stimulation or by α2‐adrenoceptor blockade. This enhanced lipolytic effect may result either from a direct action of the drugs on the adrenoceptors of fat cells or from an activation of the sympathetic nervous system. Procaterol suffers major limitations since it strongly increases heart rate, immunoreactive insulin and glycaemia. On the other hand, yohimbine induces only minor modifications both in cardiovascular and endocrinological parameters.
Electrophysiological effects of adenosine and adenosine triphosphate on sheep Purkinje fibres under normal and simulated ischaemic conditions
Authors: Boachie‐Ansah G. , Kane K.A. , Parratt J.R.
Published: July 2012

The electrophysiological effects of adenosine and adenosine triphosphate (ATP) were examined in sheep Purkinje fibres, superfused in vitro with either a normal or a hypoxic, hyperkalaemic and acidotic physiological salt solution (PSS). The ability of adenosine to modify the effects of noradrenaline on action potential characteristics was also investigated.

The only statistically significant effects of adenosine (10−6‐10−4 m) and of ATP (10−6‐10−4 m) on normal action potential characteristics were a slight dose‐dependent shortening of the action potential by adenosine and a depolarization by ATP, 10−4 m.

Superfusion with a hypoxic, hyperkalaemic and acidotic PSS caused marked reductions in resting membrane potential, upstroke and duration of the action potential.

Both adenosine and ATP attenuated the reduction in the rate of rise of the upstroke and the amplitude of the action potential caused by the modified PSS.

Adenosine did not alter the noradrenaline‐induced effects on automaticity or on action potentials of normal or depressed Purkinje fibres.

Adenosine and ATP had electrophysiological effects on Purkinje fibres, exposed to conditions in vitro that mimic mild myocardial ischaemia, that were different from those observed on normally polarized fibres.
The effect of cromakalim on the smooth muscle of the guinea‐pig urinary bladder
Authors: Foster C.D. , Fujii K. , Kingdon J. , Brading A.F.
Published: July 2012

The actions of cromakalim were studied on the detrusor muscle from guinea‐pig urinary bladder. Cromakalim reduced the frequency and amplitude of spontaneous contractile activity of the smooth muscle of the guinea‐pig urinary bladder at 5 × 10−8 m and abolished the activity at concentrations above 5 × 10−7 m.

Electrophysiological experiments demonstrated that cromakalim increased membrane conductance, caused a dose‐dependent hyperpolarization of the cell membrane and loss of spike activity. These events are consistent with the opening of K+ channels.

The effects of 10−6 m and 10−5 m cromakalim on the contractile responses to carbachol, potassium and transmural nerve stimulation were studied. Cromakalim did not prevent the detrusor from responding to these agents, although it significantly reduced the contractile response to K+ at concentrations below 70 mm.

Uptake and efflux experiments using 86Rb+ were unable to demonstrate any significant effect on transmembrane movement produced by cromakalim (10−5 m).

43K+ efflux showed a dose‐dependent increase in the rate constant on addition of cromakalim. The difference in the selectivity for K+ over Rb+ was confirmed in dual label uptake experiments.

Substitution experiments in which the K+ ions in the tissue were gradually replaced by Rb+ demonstrated that cromakalim had a progressively decreasing effect on spontaneous activity as internal K+ was lowered. When all the K+ was replaced by Rb+, cromakalim no longer inhibited spontaneous activity, confirming that the channel opened by cromakalim appears relatively impermeant to Rb+.
Dissipation mechanisms for 5‐hydroxytryptamine in the coronary circulation of the isolated perfused heart of the rat
Authors: Bryan Lesley J. , O'Donnell Stella R. , Williams Adrienne M.
Published: July 2012

The contribution of uptake into vascular endothelial cells, of neuronal uptake and of extraneuronal uptake in the dissipation of 5‐hydroxytryptamine (5‐HT) perfused through the coronary circulation of the rat heart was examined.

Hearts from reserpine‐pretreated rats were isolated and perfused in vitro with 5‐HT, in the absence or presence of inhibitors, and rates of appearance of the deaminated metabolite, 5‐hydroxyindoleacetic acid (5‐HIAA), in the venous effluent were measured using an h.p.l.c. assay.

The steady‐state rates of 5‐HIAA appearance in the venous effluent in hearts perfused with 1 μm 5‐HT (422 ± 8.48 pmol g−1 min−1, n = 12) were reduced by pretreatment of the rats with 6‐hydroxydopamine (22% inhibition), and by inclusion in the perfusion solution of 30 μm cocaine (28% inhibition), 100 μm 3‐O‐methylisoprenaline (64% inhibition), 100 μm corticosterone (58% inhibition), or 30 μm cocaine and 100 μm 3‐O‐methylisoprenaline (87% inhibition).

The extraneuronal deamination of 5‐HT in the heart was saturable (Km = 101 μm, Vmax = 31.2 nmol g−1 min−1). The neuronal deamination of 5‐HT was saturated by about 50 fold lower concentrations of 5‐HT than was extraneuronal deamination, but Km and Vmax values could not be determined.

In the coronary circulation of the rat heart, 5‐HT was dissipated by the uptake processes for catecholamines, extraneuronal uptake (predominantly) and neuronal uptake, and subsequent metabolism by monoamine oxidase. There was no evidence that a cocaine‐sensitive uptake of 5‐HT into vascular endothelial cells made any significant contribution to 5‐HT dissipation in the heart.