bluuebunny/crossref_metadata_2025 huggingface dataset:
Flushing and haemodynamic responses to vasopressin peptides in the rhesus monkey
Authors: Brooks David P. , Koster Paul F. , Stassen Frans L. , Albrightson Christine R. , Huffman William F. , Wasserman Martin A. , Kinter Lewis B.
Published: July 2012

The mechanism of the flushing, hypotension and tachycardia associated with i.v. administration of desGlyd(CH2)5D‐Tyr(Et)VAVP (SK&F 101926; 25 μg kg−1) and the selective V2 antidiuretic agonist, desamino‐8‐D‐arginine vasopressin (dDAVP; 3 μg kg−1) was studied in ketamine‐anaesthetized rhesus monkeys.

The flushing associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer and by repeated administration of peptide (within 2–4 weeks). A similar desensitization to dDAVP‐associated flushing was observed on repeated administration.

Treatment with dDAVP also resulted in reduced SK&F 101926‐associated flushing.

The hypotension associated with SK&F 101926 was not affected by pretreatment with a mast cell stabilizer. A similar degree of hypotension was observed with repeated administration of either SK&F 101926 or dDAVP.

The tachycardia associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer or repeated administration of SK&F 101926. Repeated administration of dDAVP, however, resulted in an enhanced tachycardia.

Indomethacin (5 mg kg−1 i.v.) did not alter the flushing or the hypotension associated with the administration of either SK&F 101926 or dDAVP, but resulted in an enhanced tachycardia to SK&F 101926.

Administration of a selective V1 vasopressor antagonist did not result in flushing, hypotension or tachycardia.

It was concluded that the flushing response to vasopressin‐like peptides in rhesus monkeys may be due to an action on mast cells, whereas the haemodynamic responses are not, but probably involve direct vasodilator actions.
Early induction by crotoxin of biphasic frequency changes and giant miniature endplate potentials in frog muscle
Authors: Hawgood Barbara J. , Smith I. Christopher H. , Strong Peter N.
Published: July 2012

Following the addition of crotoxin (250 nm) at the frog neuromuscular junction, there was an initial fall in frequency of miniature endplate potentials (m.e.p.ps), followed by a secondary rise which was characterized by the appearance of large spontaneous potentials (giants, g.m.e.p.ps) and an occasional large potential of the burst type.

In the presence of 2‐(4‐phenylpiperidino)cyclohexanol (AH5183, vesicamol), an inhibitor of vesicular acetylcholine uptake, the frequency of g.m.e.p.ps induced by crotoxin was reduced.

The characteristic changes in m.e.p.p. frequency and amplitude distribution were absent with crotoxin in Sr‐EGTA Ringer. In the presence of high concentrations of Mn (3.6 or 5.4 mM with 0.9 mM Ca), the crotoxin‐induced initial fall and the onset of the secondary rise in m.e.p.p. and g.m.e.p.p. frequencies were slower. The timing of these phases was unaffected by Ca concentrations ranging from 6.3 to 0.9 mM.

High concentrations of Mn ions partially inhibited the phospholipase A2 activity of crotoxin on artificial phospholipid membranes. This also supports the involvement of the Ca‐dependent phospholipase A2 subunit in both phases of the physiological action of the toxin.

G.m.e.p.ps were associated with a moderate increase in m.e.p.p. frequency (2–3 s−1) and were of a time‐course similar to that of m.e.p.ps. They persisted after washing with medium lacking Ca ions and in the presence of Ca‐Mn Ringer that blocked evoked responses.

It is concluded that crotoxin, acting through its phospholipase A2 subunit, produces specific disturbances of synaptic exocytosis and vesicle formation in the axolemma of the motor nerve terminal which lead to biphasic changes in m.e.p.p. frequency and the onset of large spontaneous potentials.
Effects of clonidine and yohimbine on a C‐fibre‐evoked blood pressure reflex in the rat
Authors: Donnerer Josef , Yan Zhao , Lembeck Fred
Published: July 2012

The involvement of α2‐adrenoceptors in a capsaicin‐induced depressor reflex in the rat has been investigated.

The reflex fall in blood pressure following an intra‐arterial injection of capsaicin was partially blocked by an intrathecal infusion of clonidine (1 μg) at the spinal cord level L4‐L5, an effect which was abolished by the prior intrathecal infusion of yohimbine (5 μg).

Clonidine (1μg) given intracisternally blocked the depressor reflex almost completely; however, it also produced a gradual, prolonged fall in mean carotid pressure.

Yohimbine (20 μg) given intracisternally did not change mean blood pressure but had a dual effect on the depressor reflex in response to the capsaicin injection: a short period of enhanced reflex response was followed by a long lasting inhibition of the response.

It was concluded that α2‐adrenoceptors in the spinal cord inhibit the capsaicin‐evoked depressor reflex and that pre‐ and postsynaptic α2‐adrenoceptors in the brain stem modulate this reflex.
Perinatal lead exposure alters the development of δ‐but not μ‐opioid receptors in rat brain
Authors: McDowell Julia , Kitchen Ian
Published: July 2012

Low level lead exposure has been shown to impair the development of opioid peptide levels in the brain, and to impair antinociceptive responses to opioid drugs. We have now studied the effects of lead exposure on the development of opioid receptors using ligand binding studies.

The ontogenesis of μ‐ and δ‐opioid binding sites was studied using rat whole brain membranes and [3H]‐[D‐Ala2MePhe4‐Gly‐ol]enkephalin and [3H]‐[D‐Pen2,D‐Pen5]enkephalin as binding ligands. Rats were exposed to lead during development by addition of lead acetate (at 100–1000 p.p.m.) to the maternal drinking water from conception to postnatal day 14.

Perinatal lead exposure had no significant effects on the binding affinity (KD) or binding capacity (Bmax) for the μ‐opioid receptor measured at postnatal days 10, 21 and 30. Lead exposure (at 1000 p.p.m.) increased the KD for the δ‐opioid receptor at postnatal days 15, 21, 35 and 50 but had no effect on the binding capacity. No indications of overt toxicity were observed and blood lead levels were in the ranges considered to represent subclinical lead toxicity in man.

The lack of effect of lead on μ‐receptor binding contrasts with previously described impairment of antinociceptive effects of μ‐agonists suggesting that the toxicity is not manifested at the μ‐binding site. However, the δ‐opioid receptor appears to be more sensitive to lead exposure and the persistent changes in δ‐site affinity after cessation of lead exposure suggest irreversible damage in the production of the receptor protein.
Effect of soluble factors from nerve and muscle on α‐bungarotoxin binding sites in isolated sarcolemmal membranes of the rat
Authors: Harborne Alan J. , Smith Margaret E.
Published: July 2012

Sarcolemmal membranes were isolated from normal and from denervated muscles and the specific binding of [125I]‐α‐bungarotoxin to the membranes was determined.

Cytosol prepared from either slow (soleus) or fast (extensor digitorum longus) muscle increased the toxin binding. Similar effects were seen with cytosol from muscles which had been denervated 5 to 7 days previously and with cytosol from sciatic nerve. A purified preparation of a bacterial phospholipase C also produced this effect.

Bathing medium in which normal or denervated muscles had been incubated, increased the toxin binding to normal membranes, but the normal bathing medium decreased the binding to membranes prepared from denervated muscles.

The possibility that pre‐existing latent acetylcholine receptors can be activated by intracellular factors released from muscles is discussed.
A calcium‐dependent rather than a G‐protein mechanism is involved in the inward current evoked by muscarinic receptor stimulation in dialysed single smooth muscle cells of small intestine
Authors: Lim S.P. , Bolton T.B.
Published: July 2012

A role of internal calcium was found in the inward current response of single, dispersed, smooth muscle cells to muscarinic receptor activation but no obligatory role for guanine nucleotide binding proteins, in contrast to their obligatory role in muscarinic responses in heart and other tissues.
Bisoprolol improves perfusion of ischaemic myocardium in anaesthetized pigs
Authors: Sassen L.M.A. , den Boer M.O. , Rensen R.J. , Saxena P.R. , Verdouw P.D.
Published: July 2012

The ability of the cardioselective β‐adrenoceptor antagonist bisoprolol ((±)−1‐[4‐(2‐isopropoxyethoxymethyl)‐phenoxy]‐3‐isopropyl‐amino‐2‐propanol hemifumarate, EMD 33512) to suppress isoprenaline‐induced increases in heart rate and maximal rate of rise in left ventricular pressure (LVdP/dtmax) was studied in 6 anaesthetized pigs given 4 cumulative doses (16, 64, 256 and 1024 μg kg−1). Bisoprolol was about 2 times more effective in suppressing isoprenaline‐induced increases in LVdP/dtmax than those in heart rate.

In 8 animals which had a partial stenosis of the left anterior descending coronary artery (LADCA), the effects of 3 consecutive doses (50, 200 and 750 μg kg−1) of bisoprolol were studied on systemic haemodynamics, regional myocardial perfusion and function. The effects of the drug were compared with those obtained in a group of 9 animals with LADCA stenosis which did not receive any treatment.

The lowest dose of bisoprolol (50 μg kg−1) increased perfusion of the ischaemic myocardium (which had been reduced from 123 ± 20 ml min−1 100 g−1 to 42 ± 11 ml min−1 100 g−1) by 21 ± 10 ml min−1 100 g−1 (P < 0.05). In particular the subendocardial layers, which were most severely affected by the stenosis (a decrease from 128 ± 19 ml min−1 100 g−1 to 20 ± 6 ml min−1 100 g−1) benefited from the administration of the drug (an increase of 30 ± 10 ml min−1 100 g−1). Perfusion of the subepicardium was not significantly affected. With the higher dose only a minor additional improvement in perfusion of the ischaemic myocardium was observed.

The negative chronotropic response is the most likely factor leading to the improvement in perfusion.

Myocardial wall thickening, which decreased from 41 ± 2% to 9 ± 4% (P < 0.05) due to the hypoperfusion, did not improve after administration of the drug. This lack of improvement may possibly be due to the duration of ischaemia before and the magnitude of the flow deficit after bisoprolol administration.

Between 15 and 60 min of ischaemia, 5 of the 9 untreated animals had an episode of ventricular fibrillation compared with only 1 of the 8 animals treated with bisoprolol, in spite of an initially larger flow reduction in the treated animals. The more homogeneous flow distribution after bisoprolol might account for the lower incidence of arrhythmias in this group.

It was demonstrated that bisoprolol improves perfusion of ischaemic myocardium in anaesthetized pigs even at doses (50 μg kg−1) that only moderately antagonize isoprenaline‐induced cardiostimulatory effects.
Histamine‐induced inward currents in cultured endothelial cells from human umbilical vein
Authors: Bregestovski P. , Bakhramov A. , Danilov S. , Moldobaeva A. , Takeda K.
Published: July 2012

The membrane response to applied histamine of cultured endothelial cells from human umbilical vein was studied by use of whole cell and single channel patch clamp techniques. A value of −27 ± 1.4 mV was found for the resting potential under whole cell current clamp. No voltage‐gated currents were seen at either the macroscopic or single channel levels.

At holding potentials of −20 to −40 mV, histamine evoked slow rising, long lasting whole cell inward currents. The inward current was associated with depolarization and decreased input resistance. The calcium ionophore A23187 provoked similar whole cell inward currents.

Single channel currents were observed in cell‐attached and inside‐out patches for both histamine and A23187. The single channel conductance was about 20 pS with a mean open time of 5 ms and a reversal potential of 0 mV in symmetrical potassium solutions. Internal sodium blocked outward going currents.

For cell‐attached patches, histamine‐dependent channel activity required external calcium and was also seen when histamine was present in the bath but not the pipette. Recording from inside‐out patches revealed that decreases in ‘internal’ calcium resulted in the disappearance of channel activity.

The histamine‐dependent inward current appears to involve calcium‐dependent activation of cationic channels.
Prostaglandins involved in contractions by angiotensin II and bradykinin of isolated dog sphincter pupillae
Authors: Lu Wei , Okamura Tomio , Bian Ka , Inatomi Akihiro , Toda Noboru
Published: July 2012

The dog isolated sphincter pupillae contracted in response to acetylcholine, angiotensin II (AII), bradykinin, prostaglandins F2α, D2, E2 and I2, and thionate thromboxane A2 (sTXA2) in a concentration‐dependent manner.

AII‐induced contractions were suppressed by treatment with saralasin, indomethacin, aspirin and diphloretin phosphate (DPP), a prostaglandin receptor antagonist. Contractions induced by bradykinin were also attenuated by indomethacin, aspirin and DPP. The amount of prostaglandin F2α (PGF2α) in the bathing media was increased approximately 41% following stimulation of the preparations by bradykinin.

The potency of contractile responses was in the order of PGF2α > PGD2 = sTXA2 > PGE2 > arachidonic acid > PGI2. Contractions induced by PGF2α were not significantly affected by treatment with indomethacin and ONO3708, an antagonist of the vasoconstrictor effect of prostaglandins, but appreciably attenuated by DPP. Arachidonic acid‐induced contractions were inhibited by indomethacin.

Contractions of dog iris sphincter muscle in response to AII and bradykinin may be mediated via substances synthesized by cyclo‐oxygenase from arachidonic acid. The distribution and nature of the prostaglandin receptors appear to differ markedly in iris sphincter and vascular smooth muscles.
H1‐ and H2‐receptor characterization in the tracheal circulation of sheep
Authors: Webber S.E. , Salonen R.O. , Widdicombe J.G.
Published: July 2012

The effects of histamine, the specific H1‐agonist SKF 71481‐A2 and the H2‐agonist dimaprit were examined on tracheal vascular resistance in sheep anaesthetized with pentobarbitone. Tracheal vascular resistance was determined by perfusing the cranial tracheal arteries at constant flows and measuring inflow pressures. Changes in tracheal smooth muscle tone were also measured.

Histamine and SKF 71481‐A2 contracted the tracheal smooth muscle and this effect was blocked by the H1‐antagonist mepyramine. Stimulation of H2‐receptors with dimaprit had no effect on tracheal smooth muscle tone.

Histamine had a complex action on the tracheal vasculature producing either a triphasic change (early dilatation then constriction followed by late dilatation) or just a constriction. SKF 71481‐A2 always produced a biphasic change in vascular resistance (dilatation followed by constriction). Dimaprit dilated the tracheal vasculature.

The late dilatation produced by histamine in some sheep was blocked by bilateral cervical vagotomy but the mechanism for this effect is not known. No other responses to histamine, SKF 71481‐A2 or dimaprit were affected by vagotomy.

The vasoconstriction produced by histamine and SKF 71481‐A2 was antagonized by mepyramine indicating a H1‐receptor‐mediated effect. Cimetidine had no effect on the vasoconstriction to histamine suggesting a lack of involvement of H2‐receptors.

The vasodilatation produced by histamine and SKF 71481‐A2 was also antagonized by mepyramine, again suggesting a H1‐receptor‐mediated action. Cimetidine had no effect on the vasodilator response to histamine indicating no involvement of H2‐receptors in this response.

The dilator effect of dimaprit was antagonized by cimetidine suggesting this effect was mediated by H2‐receptors.

We conclude that H1‐receptors in the various parts of the sheep tracheal vasculature can cause increases and decreases in total tracheal vascular resistance; that H2‐receptors decrease resistance; and that the tracheal smooth muscle contracts on activation of H1‐receptors but has no response to H2‐agonists.
Quipazine reduces food intake in the rat by activation of 5‐HT2‐receptors
Authors: Hewson G. , Leighton G.E. , Hill R.G. , Hughes J.
Published: July 2012

To determine which subtype(s) of 5‐hydroxytryptamine (5‐HT) receptor are involved in the anorectic action of quipazine, the ability of selective antagonists at 5‐HT2‐ and 5‐HT3‐receptors, and an antagonist at 5‐HT1‐like receptors, to block this response were investigated in non‐deprived rats, trained to eat a palatable diet.

Quipazine (0.5–8 mg kg−1, i.p.) produced a dose‐related reduction in the intake of palatable diet.

The anorectic effect of 4 mg kg−1 quipazine was antagonized by the nonselective 5‐HT‐receptor antagonist methysergide (5 mg kg−1, i.p.) and by the selective 5‐HT2‐receptor antagonists ketanserin (1 mg kg−1 and 2.5 mg kg−1, i.p.) and ritanserin (0.5 mg kg−1 and 1 mg kg−1, i.p.). The selective 5‐HT3‐receptor antagonist GR38032F (1 mg kg−1, i.p.) and (−)‐pindolol (4 mg kg−1, i.p.), which blocks some of the effects mediated at 5‐HT1‐like receptors, did not block the reduction in food intake produced by this dose of quipazine.

None of the 5‐HT‐receptor antagonists had any effect on food intake when they were administered alone, suggesting that endogenous 5‐HT is not involved in the tonic control of food intake under the conditions of these experiments.

It is concluded that the anorectic action of quipazine is mediated, at least in part, by activation of 5‐HT2‐receptors.
The modulatory role of vascular endothelium in the interaction of agonists and antagonists with α‐adrenoceptors in the rat aorta
Authors: Alosachie Iyad , Godfraind Théophile
Published: July 2012

We have examined the effect of endothelium on the antagonistic action of prazosin, doxazosin, yohimbine and phentolamine against phenylephrine, clonidine and noradrenaline.

The action of prazosin against phenylephrine was similar to that earlier reported against noradrenaline, acting as a non‐competitive antagonist in the presence of endothelium and as a competitive antagonist in the absence of endothelium. Prazosin also acted as a non‐competitive antagonist against clonidine in the absence of endothelium.

Doxazosin behaved in a similar way to prazosin against noradrenaline, phenylephrine and clonidine acting as a non‐competitive antagonist in the presence of endothelium and as competitive antagonist after removal of endothelium. In contrast, yohimbine and phentolamine acted as competitive antagonists both in the presence and in the absence of endothelium.

Analysis of the concentration‐response curves for noradrenaline, phenylephrine and clonidine in the presence and in the absence of endothelium showed that the affinity for all three agonists was the same but not the efficacy and the receptor reserve, both of which were lower in the presence than in the absence of endothelium.

The rank order of agonist potency in the absence of endothelium was noradrenaline > phenylephrine > clonidine. The rank order of antagonist potency was prazosin ≥ doxazosin > phentolamine > yohimbine.

The results show that vascular endothelium modulates the contractile response to α‐adrenoceptor agonists and also modifies the action of the antagonists prazosin and doxazosin but not that of yohimbine and phentolamine. This effect of endothelium was related to a change in agonist efficacy and receptor reserve. These results also suggest that the α‐adrenoceptors of the isolated aorta of the rat are predominantly, if not exclusively of the α1‐subtype.
Pre‐and postjunctional actions of purine and xanthine compounds in the guinea‐pig caecum circular muscle
Authors: Hoyle Charles H.V. , Vladimirova Irina A. , Burnstock Geoffrey
Published: July 2012

The sucrose‐gap technique was used to study pre‐and postjunctional actions of P1‐purinoceptor and P2‐purinoceptor agonists and a range of xanthine derivatives in the guinea‐pig caecum circular muscle.

Adenosine, 2‐chloroadenosine (2‐ClAd), ATP and α,β‐methylene ATP all caused concentration‐dependent hyperpolarization of the smooth muscle membrane with a rank order of potency of 2‐ClAd > α,β‐methylene ATP > adenosine.

The xanthine derivatives caffeine, theophylline, 8‐phenyltheophylline and 1,3‐dipropyl‐8‐(2‐amino‐4‐chlorophenyl) xanthine (PACPX) at submicromolar concentrations evoked depolarization of the smooth muscle membrane. At higher concentrations, all these compounds and enprofylline caused concentration‐dependent hyperpolarization.

All the purine compounds tested caused a reduction in the amplitude of the non‐adrenergic, non‐cholinergic inhibitory junction potential (i.j.p.). For the P1‐purinoceptor agonists adenosine and 2‐ClAd this was almost entirely a prejunctional effect. For the P2‐purinoceptor agonists this was mostly a postjunctional effect because both ATP and α,β‐methylene ATP caused significantly greater increases in the conductance of the smooth muscle membrane than did adenosine or 2‐ClAd.

All the xanthine compounds tested (up to 100 μm), except enprofylline, were capable of increasing the amplitude of the i.j.p. At millimolar concentrations both caffeine and theophylline could reduce the i.j.p. amplitude.

. It is concluded that there are inhibitory prejunctional P1‐purinoceptors on the i.j.p.‐producing neurones in the guinea‐pig caecum circular muscle and that, of the xanthine derivatives tested, none of them would be suitable to use as a P1‐purinoceptor antagonist in this preparation because of their own direct effects.
The β1‐adrenoceptor antagonist, betaxolol, is not released from the heart of the anaesthetized dog during sympathetic nerve stimulation
Authors: Duval N. , Lee C.R. , Eon M.T. , Petruzzo P. , Langer S.Z.
Published: July 2012

We investigated the hypothesis that the β1‐adrenoceptor antagonist, betaxolol, can be accumulated by cardiac sympathetic nerve endings and then released together with noradrenaline during accelerans nerve stimulation.

Dogs were chronically treated with betaxolol (1 mg kg−1 daily, s.c.) for 7 days. Twenty four hours after the last dose, there was a significant retention of betaxolol in the heart of these dogs treated chronically with the β1‐adrenoceptor antagonist. However, during in vivo accelerans nerve stimulation, the concentration of betaxolol in the coronary sinus was not modified, whereas the noradrenaline concentration increased significantly.

Chronic betaxolol treatment antagonized the tachycardia induced by electrical stimulation of the cardiac accelerator nerves or by intravenous isoprenaline. However, the tachycardia induced by nerve stimulation was not antagonized to a greater extent than that induced by isoprenaline.

These findings are discussed in relation to a similar in vivo study in dogs treated with propranolol, in which the drug was found to be released into the coronary circulation during stimulation of the accelerans nerve.
Amino acid pharmacology in neocortical slices: evidence for bimolecular actions from an extension of the Hill and Gaddum‐Schild equations
Authors: Williams Thelma L. , Smith D.A.S. , Burton N.R. , Stone T.W.
Published: July 2012

The equivalent circuit of the cortical slice preparation has been analysed to show that the measured d.c. voltages can be used to estimate the Hill coefficient for ligands acting on the pyramidal cell bodies.

The Gaddum‐Schild equation for agonist‐antagonist interactions has been modified for applications in which the Hill coefficient is not equal to 1.

The equations obtained have been applied to recent data of Burton et al. (1988). The results provide evidence for a bimolecular action of the agonists N‐methyl‐D‐aspartate (NMDA) and quinolinic acid and the antagonists kynurenic acid and 2‐amino‐5‐phosphono‐pentanoic acid at NMDA receptors on mouse neocortical pyramidal cells.
Development before and after hatching of non‐cholinergic excitatory innervation to the rectum via Remak's nerve in the fowl
Authors: Komori Seiichi , Matsuo Konomi , Ohashi Hidenori
Published: July 2012

Development of the excitatory innervation to the rectal region of the intestine via Remak's nerve has been investigated in the rectum with Remak's nerve supply isolated from chicken embryos and young chicks aged less than two weeks.

Electrical stimulation of Remak's nerve produced a small contraction of the rectum isolated from chicken embryos on the 14th day of incubation (the earliest time examined). The contractile response was inhibited partially or totally by atropine (0.1 μg ml−1) but enhanced by physostigmine (0.01 to 0.05 μg ml−1), indicating its cholinergic nature.

During the embryonic stage, the proportion of the atropine‐resistant component in the contractile response increased, and the contractile response became almost entirely atropine‐resistant within the first week after hatching.

Later after hatching, the contractile response was increased in magnitude by atropine and reduced by physostigmine.

It is concluded that the excitatory innervation to the chicken rectum via Remak's nerve is cholinergic at the 14–16th day of incubation and is gradually replaced by a non‐cholinergic innervation during embryonic development.
Structural requirements of alloxan and ninhydrin for glucokinase inhibition and of glucose for protection against inhibition
Authors: Lenzen Sigurd , Brand Franz‐Hermann , Panten Uwe
Published: July 2012

In order to elucidate the mechanism underlying the interactions between glucose and alloxan when competing for the sugar binding site of glucokinase from pancreatic B‐cells or liver, the structural requirements of the enzyme for inhibition by alloxan and for protection by glucose were determined.

With a half‐maximal inhibitory concentration of 5 μm, alloxan was the most potent pyrimidine derivative inhibitor of glucokinase. Uramil was a less potent enzyme inhibitor. A variety of other pyrimidine derivatives and related substances were ineffective.

Ninhydrin also inhibited glucokinase with a half‐maximal inhibitory concentration of 5 μm. Isatin was a slightly less potent enzyme inhibitor. Several other indoline derivatives were ineffective.

Only glucose derivatives with a sufficiently bulky substituent in position C‐2, such as the glucokinase substrates glucose and mannose and the inhibitors mannoheptulose, glucosamine, and N‐acetylglucosamine, protected glucokinase against inhibition by alloxan by binding to the active site of the enzyme. Glucose epimers which differed in other positions did not protect the enzyme against alloxan inhibition.

DTT (dithiothreitol) protected glucokinase against inhibition by alloxan and reversed the inhibition of the enzyme induced by alloxan. Thus the mechanism of glucokinase inhibition by alloxan and other inhibitors, such as uramil and ninhydrin, is an oxidation of functionally essential SH groups of the enzyme, where the most reactive keto group of the inhibitor acts as the hydrogen acceptor. The protective action of glucose and several C‐2 epimers demonstrates that these functionally essential SH groups are situated in the sugar binding site of the glucokinase.

The present results support our contention, that the pancreatic B‐cell glucokinase is the major target mediating the inhibition of insulin secretion by alloxan.
Endothelin induces potent microvascular constriction
Authors: Brain S.D. , Tippins J.R. , Williams T.J.
Published: July 2012

Endothelin is a recently discovered peptide produced by endothelial cells. It has been shown to have potent constrictor effects on major arteries in vitro and to raise rat blood pressure in vivo. The present experiments show that endothelin has a potent constrictor action on the microvasculature. Blood flow changes were measured by a xenon clearance technique in rabbit skin. Endothelin, when injected intradermally into rabbit skin, decreased local blood flow in a dose‐dependent manner. Endothelin reduced basal skin blood flow and reversed the increased blood flow induced by a vasodilator. These results show that endothelin, administered extravascularly, has potent vasoconstrictor activity. This adds further support to the suggestion that endothelin may have an important role in the physiological control of blood flow and pressure.
Local anaesthetic actions of cocaine: effects on excitatory and inhibitory synaptic responses in the hippocampus in vitro
Authors: Dunwiddie Thomas V. , Proctor William R. , Tyma Jennifer
Published: July 2012

The basis for the proconvulsant action of cocaine was investigated in the CA1 region of the rat hippocampal slice in vitro.

Superfusion with 100 μm cocaine depressed inhibitory and excitatory postsynaptic potentials recorded intracellularly from CA1 pyramidal neurones; both types of potentials were inhibited to an equal extent. When inhibition was assessed using extracellular recording of population spike responses before and after conditioning impulses, there did not appear to be any selective effect upon either recurrent or feed‐forward γ‐aminobutyric acid (GABA)ergic inhibition.

Not all responses showed equivalent sensitivity to the local anaesthetic actions of cocaine. In particular, the antidromic population spike evoked by stimulation of the alveus was significantly more sensitive than the presynaptic fibre spike elicited by stimulation of stratum radiatum.

The rate of interictal spiking in hippocampus, induced by penicillin and increased potassium in the perfusion medium, was depressed by superfusion with cocaine in the range 5–100 μm.

These results suggest that cocaine does not have a selective depressant effect upon inhibitory pathways in the CA1 region of the hippocampus. Although the hippocampus shows epileptiform activity following systemic administration of local anaesthetics such as cocaine in the intact rat, this effect may not reflect a direct hippocampal site of drug action.
The dihydropyridine derivative 202–791: interpretation of the effects of the racemate considering inverse agonistic enantiomers
Authors: Damarowsky Marion , Lüllmann Heinz , Ravens Ursula
Published: July 2012

The influence of the enantiomers and the racemate of the dihydropyridine derivative 202–791 [isopropyl 4‐(2,1,3‐benzoxadiazol‐4‐yl)−1,4‐dihydro‐2,6‐dimethyl‐5‐nitro‐3‐pyridinecarboxylate] on force of contraction and action potential was studied in guinea‐pig isolated papillary muscles. The effects were investigated during regular stimulation (1 Hz) and after a period of rest (10 min).

The enantiomers of the dihydropyridine derivative 202–791 had opposite effects on the mechanical and bioelectrical parameters: the (+,S)‐enantiomer enhanced contractility and prolonged action potential duration whereas the (‐,R)‐enantiomer reduced force and shortened action potential duration. Analogous to the effects during regular stimulation, the post‐rest adaptation was modified adversely: in the presence of the (+,S)‐enantiomer the pattern of adaptation was intensified while the (‐,R)‐enantiomer caused an attenuation. The term ‘inverse agonism’ seems more suitable than the commonly used comparison of agonist and antagonist, because each enantiomer possesses intrinsic activity, albeit in opposite directions.

The racemate of 202–791 acted like the (+,S)‐enantiomer. In concentrations up to 1μm, the racemate increased the force of contraction to the same extent as if the cardiodepressant (‐,R)‐enantiomer was not present. Only at the highest concentration (3 μm) did the counteracting effect of the (‐,R)‐enantiomer become evident. The racemate prolonged the action potential duration like the (+,S)‐enantiomer although to a lesser extent. Moreover, the typical post‐rest adaptation of contractile force and action potential duration was accentuated by the racemate as with the (+,S)‐enantiomer.

The results demonstrate that in case of 202–791, the effects of the racemate do not reflect the opposite actions of the two enantiomers, but rather mimic that of the (+,S)‐enantiomer. A prediction concerning the effects of the enantiomers which is based on findings obtained with the racemate is not possible.
Prostacyclin releases endothelium‐derived relaxing factor and potentiates its action in coronary arteries of the pig
Authors: Shimokawa Hiroaki , Flavahan Nicholas A. , Lorenz Robert R. , Vanhoutte Paul M.
Published: July 2012

The possible interactions between prostacyclin and endothelium‐derived relaxing factor were examined, in isolated coronary arteries of the pig treated with indomethacin (10−5 m).

In organ chamber experiments, prostacyclin caused relaxations, which were potentiated in the presence of the endothelium; the potentiation was abolished by oxyhaemoglobin.

In bioassay experiments, prostacyclin caused minimal relaxations of bioassay rings without endothelium; these relaxations were potentiated when the bioassay ring was exposed to basally‐released endothelium‐derived relaxing factor (interaction between prostacyclin and basal endothelium‐derived relaxing factor) and further augmented when the endothelial cells were exposed to the prostanoid (stimulated release of endothelium‐derived relaxing factor). The endothelium‐dependent, but not the direct effects of prostacyclin were augmented by superoxide dismutase plus catalase and abolished by oxyhaemoglobin.

Forskolin, a direct activator of adenylate cyclase, caused relaxations of rings without endothelium, which were augmented by the presence of the endothelium.

The relaxations induced by prostacyclin or forskolin also had an endothelium‐dependent component in basilar and femoral arteries and in jugular veins of the pig.

The endothelium‐dependent actions of prostacyclin probably reflect activation of adenylate cyclase.
Agonists, antagonists and modulators of excitatory amino acid receptors in the guinea‐pig myenteric plexus
Authors: Luzzi S. , Zilletti L. , Franchi‐Micheli S. , Gori A.M. , Moroni F.
Published: July 2012

The receptors for glutamic acid (L‐Glu) present in the guinea‐pig myenteric plexus‐ileal longitudinal muscle preparation have been studied by measuring the muscle contraction induced by numerous putative endogenous agonists acting at these receptors. Furthermore, the actions of different concentrations of antagonists, glycine, Mg2+ and Ca2+ on the ileal contractions induced by l‐G1u have been evaluated.

The EC50 values of the most common putative endogenous agonists of these receptors were: L‐Glu 1.9 × 10−5 m; L‐aspartate 8 × 10−5 m; quinolinate 5 × 10−4M; L‐homocysteate 1.4 × 10−4M; the dipeptide aspartyl‐glutamate 8 × 10−5m, while N‐acetyl‐aspartyl‐glutamate was inactive. Among the molecules used to classify excitatory amino acid receptors, N‐methyl‐D‐aspartate (NMDA) was the most potent (EC50 5 × 10−4m). Kainic and quisqualic acids were almost completely inactive.

The responses to L‐Glu were competitively antagonized by 2‐amino‐5‐phosphonovaleric acid. They were, also, prevented by hyoscine (10−7m) and by tetrodotoxin (3 × 10−7 m), suggesting that the L‐Glu‐induced ileal contraction was in some way dependent upon an action on the myenteric cholinergic neurones. Kynurenic acid was a non‐competitive antagonist, γ‐D‐glutamyl‐taurine (10−4m) and aminophosphonobutyric acid (10−4m) did not modify the L‐Glu‐induced contractions.

Glycine (10−5 m) significantly potentiated the effects of glutamate especially when the ionic composition of the superfusion medium contained concentrations of Ca2+ in the range of 0.6–1.2 mM. Strychnine 3 × 10−5 m did not modify the actions of glycine.

The data presented here confirm the presence of NMDA receptors in the guinea‐pig myenteric plexus, and show that these receptors, similar to those present in primary neuronal cultures may be modulated by glycine.
Effects of charybdotoxin, a blocker of Ca2+ ‐activated K + channels, on motor nerve terminals
Authors: Anderson A.J. , Harvey A.L. , Rowan E.G. , Strong P.N.
Published: July 2012

The contribution of Ca2+‐activated K+ currents (IK,Ca)to the control of electrical excitability of motor nerve terminals and the control of acetylcholine release was assessed by studying the effects of the specific K(Ca) channel blocking toxins charybdotoxin and apamin. Electrical activity of the terminal regions of motor nerves was assessed by extracellular recording from an electrode placed in the perineural sheaths of nerves in the mouse triangularis sterni and frog cutaneous pectoris preparations. Acetylcholine release was monitored by intracellular recording of endplate potentials (e.p.ps).

Charybdotoxin (20–300 nm), but not apamin (10nM‐2.5 μm), selectively reduced the amplitude of an IK,Ca unmasked by prior blockade of the delayed rectifier K+ current with 3,4‐diaminopyridine (3,4‐DAP).

In the combined presence of 3,4‐DAP and charybdotoxin, large Ca2+‐dependent plateau responses developed, but only moderate and transient increases in acetylcholine release occurred.

In the absence of 3,4‐DAP, charybdotoxin did not alter the electrical activity of, or the transmitter release from motor nerve terminals.

A possible role of the charybdotoxin‐sensitive IK,Ca in the control of transmitter release is discussed.
Alfaxalone potentiates and mimics GABA‐induced contractile responses in the guinea‐pig isolated ileum
Authors: Ong Jennifer , Kerr David I.B. , Johnston Graham A.R.
Published: July 2012

Alfaxalone (1–100 nM) potentiated γ‐aminobutyric acidA (GABAA)‐receptor‐mediated contractile responses in the guinea‐pig isolated ileum, with a leftward shift of the GABA concentration‐response curve, and a significant potentiation of the GABA‐induced contractions over the lower concentration‐range for GABA (3–30 μM). Alfadalone on the other hand, did not affect contractile responses to GABA.

Picrotoxinin (10 μM) induced a non‐parallel rightward shift of the GABA concentration‐response curve, with a 50% depression of the maximum response to GABA. Alfaxalone (100 nM) potentiated the responses to GABA in the presence of picrotoxinin (10 μM) over the GABA concentration‐range of 10–100 μM, causing a leftward shift of the concentration‐response curve, but without affecting the depression of the maximum response by picrotoxinin.

Bicuculline methochloride (10 μM) caused a parallel rightward shift of the GABA concentration‐response curve; the ratio of this shift was unchanged in the presence of alfaxalone (100 μM), although the latter itself displaced the curve leftwards.

Alfaxalone (1–100 mM) also induced a similar potentiation of contractile responses to 3‐amino‐1‐propanesulphonic acid (3‐APS), a GABA agonist not subject to uptake. Such concentrations of alfaxalone were ineffective against contractile responses to exogenous acetylcholine.

Higher concentrations of alfaxalone (1 μM and above), however, elicited a GABA‐like ileal contraction, sensitive to both picrotoxinin (10 μM) and bicuculline (10 μM).

In conclusion, alfaxalone potentiated GABAA‐receptor‐mediated contractile responses in the guinea‐pig isolated ileum by acting at a modulatory site on GABAA‐receptor‐chloride‐ionophore complexes of GABA‐sensitive myenteric neurones, whilst high concentrations of alfaxalone exhibited a GABA‐mimetic action at GABAA‐receptors in the ileum. It is suggested that more than one site may exist where steroids interact with the GABAA‐receptor‐ionophore complexes.
Presence of a substance P‐like peptide in an acid extract of the intestinal bulb of the carp (Cyprinus carpio)
Authors: Kitazawa Takio , Kondo Hiroshi , Temma Kyosuke
Published: July 2012

The effect of an acid extract of the carp intestinal bulb (ECI) on guinea‐pig ileum longitudinal smooth muscle (GPLM) and carp intestinal bulb longitudinal smooth muscle (CIBLM) was examined.

ECI caused a concentration‐dependent contraction of GPLM and CIBLM. This ECI‐induced response was reduced by atropine to 30–40% of the control, indicating that part of the contracting activity of ECI is attributable to acetylcholine. The atropine‐resistant contracting activity of ECI was not mediated by histamine, 5‐hydroxytryptamine, ATP, ADP, angiotensin II, neurotensin, vasoactive intestinal peptide or an opioid peptide.

The active material mediating the atropine‐resistant contracting activity is probably a peptide, because the contraction in response to ECI was abolished on incubation with pepsin or α‐chymotrypsin.

[D‐Pro2, D‐Trp7,9]‐substance P, [D‐Pro4, D‐Trp7,9]‐substance P (4–11) decreased the atropine‐resistant contracting activity of ECI as did desensitization induced by substance P.

On a Sephadex G 25 column, the active material was eluted as one peak. The active fractions were pooled and then applied to another Sephadex G25 column to compare the Ve/Vo value for the active material with those for peptides of known molecular weights. The molecular weight of the active material was estimated to be 1200–1700 (1410 ±70, n = 6).

The results indicate the presence of a substance P‐like peptide in the carp intestinal bulb.
Contribution of β1‐ and β2‐adrenoceptors of human atrium and ventricle to the effects of noradrenaline and adrenaline as assessed with (−)‐atenolol
Authors: Lemoine H. , Schönell H. , Kaumann A.J.
Published: July 2012

(−)‐Atenolol was used as a tool to assess the function of β1 and β2‐adrenoceptors in human heart. Right atrial and left ventricular preparations from patients undergoing open heart surgery were set up to contract isometrically. Membrane particles were prepared for β‐adrenoceptor labelling with [3 H]‐(−)‐bupranolol and adenylate cyclase assays.

The positive inotropic effects of (−)‐noradrenaline were antagonized to a similar extent by (−)‐atenolol in atrial and ventricular preparations. (−)‐Atenolol consistently antagonized the effects of (−)‐adrenaline to a lesser extent than those of (−)‐noradrenaline in atrial preparations. In ventricular preparations (−)‐atenolol antagonized the effects of low concentrations of (−)‐adrenaline to a lesser extent than those of high concentrations.

pKB values (M) of (−)‐atenolol, estimated with non‐linear analysis from the blockade of the positive inotropic effects of the catecholamines, were 7.4 for β1‐adrenoceptors and 6.0 for β2‐adrenoceptors.

(−)−Atenolol inhibited the binding of [3 H]‐(−)‐bupranolol to ventricular β1‐adrenoceptors with a pKD (M) of 5.9 and to ventricular β2‐adrenoceptors with a pKD of 4.6.

(−)‐Atenolol inhibited the catecholamine‐induced adenylate cyclase stimulation in the atrium and ventricle with pKB values of 5.8‐6.4 for β1 and pKB values of 4.7‐5.7 for β2‐adrenoceptors. The binding and cyclase assays suggest a partial affinity loss for (−)‐atenolol inherent to membrane preparations.

β1 ‐Adrenoceptors mediate the maximum positive inotropic effects of (−)‐noradrenaline in both the atrium and ventricle of man. β2‐Adrenoceptors appear to be capable of mediating maximal positive inotropic effects of (−)‐adrenaline in atrium. In contrast, ventricular β2‐adrenoceptors mediate only submaximal effects of (−)‐adrenaline.
Effect of pertussis toxin on A1‐receptor‐mediated inhibition of insulin secretion
Authors: Hillaire‐Buys D. , Gross R. , Loubatières‐Mariani M.M. , Ribes G.
Published: July 2012

Previous studies have provided evidence for the presence on B cell membrane of adenosine receptors (P1‐purinoceptors) of the A1‐subtype which inhibit insulin secretion. In this work we have investigated the implication of a guanosine triphosphate (GTP) binding protein (G protein) in the A1 purinoceptor‐induced inhibition of insulin secretion from the isolated perfused pancreas of the rat. A group of rats was treated with pertussis toxin (10 μgkg−1, i.v.) 28 h prior to pancreas extirpation. This treatment totally abolished the 50% decrease in insulin secretion induced by (+)‐N6‐phenylisopropyl adenosine (1.65 μm), a P1‐purinoceptor agonist. These results indicate that the A1‐receptor‐mediated inhibition of insulin secretion involves a pertussis toxin‐sensitive G protein.
An anti‐inflammatory steroid inhibits tissue sensitization by IgE in vivo
Authors: Hellewell P.G. , Williams T.J.
Published: July 2012

An anti‐inflammatory corticosteroid, dexamethasone, was found to be a potent suppressor of cell sensitization induced by IgE antibody in a model of type I allergic inflammation in vivo. Low doses (≲ 10−10 mol) of dexamethasone, administered intradermally to rabbits 90min before injection of IgE into the same sites, suppressed local oedema induced by a local challenge with antigen 72 h later. The effect was not due to antiinflammatory activity persisting in the skin site for the 3 day period. This novel potent activity of the corticosteroid may be an important component of its antiallergic effect in diseases such as asthma.
Potent contractile activity of endothelin on the human isolated urinary bladder
Authors: Maggi Carlo Alberto , Giuliani Sandro , Patacchini Riccardo , Santicioli Paolo , Turini Damiano , Barbanti Gabriele , Meli Alberto
Published: July 2012

Endothelin (1 nm‐0.3μm) produced a concentration‐related contraction of mucosa‐free muscle strips excised from the dome of the human urinary bladder. The response to endothelin was unaffected by either atropine (1 μm) or nifedipine (1 μm) at concentrations that abolished the response to carbachol and KCl, respectively. These findings indicate that mechanisms other than activation of dihydropyridine‐ and voltage‐sensitive calcium channels may be involved in the action of endothelin on smooth muscles.
Elevation of intracellular cyclic AMP concentration fails to inhibit adrenaline‐induced hyperpolarization in amphibian sympathetic neurones
Authors: Zidichouski J.A. , Kehoe M.P. , Wong K. , Smith P.A.
Published: July 2012

The effect of drugs on the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) content of desmethylimipramine (DMI)‐treated bullfrog paravertebral sympathetic ganglia was studied by radioimmunoassay. The adrenaline‐induced hyperpolarization (Adh) in this tissue was recorded by means of the sucrose‐gap technique.

In the presence of propranolol (1 μm) and DMI (0.5 μm), adrenaline (1 μm) significantly reduced the concentration of cyclic AMP in forskolin‐treated ganglia. This effect was prevented by pertussis toxin (5 μg ml−1).

The relative potency for drugs which increased ganglionic cyclic AMP content was: 50 μm forskolin ≤ 5 mm fluoride > 2 mm fluoride > 2 mm isobutylmethylxanthine (IBMX) > 5 mm caffeine. In contrast, their relative potency for inhibition of the Adh was: 2 mm IBMX > 5 mm fluoride > 5 mm caffeine > 2 mm fluoride > 50 μm forskolin. The Adh was unaffected by pertussis toxin (5 μg ml−1).

Although the Adh was slightly reduced by the extracellular application of 8‐bromo (8‐Br) cyclic AMP, the majority of the data suggest that the transduction mechanism underlying the Adh is independent of the intracellular cyclic AMP concentration and provide an example of an α2‐adrenoceptor‐mediated response that occurs independently of inhibition of adenylate cyclase.
An evaluation of the structure‐activity relationships of a series of analogues of mephenesin and strychnine on the response to pressure in mice
Authors: Bowser‐Riley F. , Daniels S. , Hill W.A.G. , Smith E.B.
Published: July 2012

A range of compounds structurally related to the centrally acting muscle relaxant mephenesin and to the chemical convulsant strychnine were synthesized and tested for their ability to alter the threshold pressures for the onset of high pressure convulsions in mice.

The ability of both groups of compounds to alter the threshold pressures for convulsions was found to be dependent on the nature of a simple molecular skeleton. Thus, compounds that possessed a negatively polarized group located both in the same plane as and some 4.5 A from an aromatic nucleus increased the thresholds whereas compounds with a positively polarized group at the same location reduced the thresholds.

These findings support the suggestion that pressure elicits convulsions via a selective action on a receptor protein complex rather than via some general perturbation of the lipid regions of cellular membranes.
Evidence that the hypertrophic action of clenbuterol on denervated rat muscle is not propranolol‐sensitive
Authors: Maltin C.A. , Hay S.M. , Delday M.I. , Reeds P.J. , Palmer R.M.
Published: July 2012

The effect of propranolol on the clenbuterol‐induced protein anabolism in innervated and denervated soleus and plantaris muscles of the rat was studied.

The response to the β‐agonist, clenbuterol, in both innervated and denervated muscles, was not significantly inhibited by the β‐antagonist, propranolol.

The results provide further evidence to suggest that the action of clenbuterol on skeletal muscle protein accretion may not be directly mediated by β‐adrenoceptors.