bluuebunny/crossref_metadata_2025 huggingface dataset:
PHARMACOLOGICAL EVIDENCE FOR THE SUBCLASSIFICATION OF CENTRAL DOPAMINE RECEPTORS IN THE RAT
Authors: GOWER ALMA J. , MARRIOTT A.S.
Published: July 2012

The relative potencies of dopamine receptor agonists in causing stereotypy in rats when injected into the olfactory tubercles, and contralateral rotation when injected unilaterally into the caudate nucleus of rats with lesions of the nigro‐striatal dopamine pathway, were determined. The actions of some agonists in eliciting these responses following peripheral injection, and the relative potencies of dopamine receptor antagonists in inhibiting them were also determined.

Dopamine, apomorphine and 2‐amino‐5, 6 and 2‐amino‐6, 7‐dihydroxy‐1,2,3,4‐tetrahydronaphthalene (A‐5, 6 DTN, A‐6, 7 DTN) and N,N dipropyl A‐5, 6DTN induced both responses. In contrast, 2,3,4,5‐tetrahydro‐7,8‐dihydroxy‐1‐phenyl‐1H‐3‐benzazepine HCl (SK & F 38393) whether injected intracerebrally or peripherally, induced contralateral rotation but not stereotypy.

Contralateral rotation and stereotypy induced by apomorphine or N,N dipropyl A‐5, 6 DTN were inhibited by haloperidol, pimozide and fluphenazine but these drugs failed to inhibit rotation induced by SK & F 38393. Clozapine inhibited rotation induced by SK & F 38393, apomorphine or N,N dipropyl A‐5, 6 DTN but failed to inhibit stereotypy. Loxapine was more potent in inhibiting stereotypy than rotation, whereas clothiapine inhibited rotation and stereotypy at similar doses irrespective of the agonist used to elicit the response.

Contralateral rotation induced by SK & F 38393 was not inhibited by yohimbine, prazosin, atropine, methysergide, mepyramine or propranolol.

The results provide evidence that contralateral rotation induced by dopamine receptor agonists is mediated by two different classes of dopamine receptors and that these receptors differ from those mediating the stereotypy response.

The receptors mediating these responses appear classifiable in terms of their sensitivity to the agonist actions of SK & F 38393 or apomorphine respectively. SK & F 38393‐sensitive receptors are susceptible to blockade by clozapine but are not blocked by haloperidol, pimozide or fluphenazine. Apomorphine‐sensitive receptors are susceptible to blockade by haloperidol, pimozide and fluphenazine but appear divisible into two sub‐classes depending on whether or not they are blocked by clozapine and on their sensitivity to blockade by loxapine.
Antinociceptive actions of morphine and buprenorphine given intrathecally in the conscious rat
Authors: Bryant Rosamunde M. , Olley Jean E. , Tyers M.B.
Published: July 2012

The antinociceptive effects of morphine and buprenorphine given intrathecally and subcutaneously have been compared in the conscious rat.

In the paw pressure test, when given subcutaneously buprenorphine 0.001–0.1 mg/kg s.c., was approximately 100 times more potent than morphine 0.1–3 mg/kg s.c., but in the hot plate test, buprenorphine 0.03–3.0 mg/kg s.c., produced a bell‐shaped dose‐response curve of low maximum effect and was about equipotent with morphine 0.03–3 mg/kg s.c.

When given intrathecally buprenorphine 10 μg and morphine, 10–60 μg, were approximately equipotent in both paw pressure and hot plate tests. Furthermore, morphine produced these effects at 1/25th of the minimum effective parenteral dose while the dose of buprenorphine exceeded the parenteral dose.

It is concluded that the predominant site of the analgesic action of buprenorphine is supraspinal. The significance of these findings in relation to the role of spinal opiate receptors is discussed.
Inhibition of cardiac sympathetic neurotransmission by histamine in the dog is mediated by H1‐receptors
Authors: Kimura T. , Satoh S.
Published: July 2012

The role of histamine H1‐ and H2‐receptors in mediating prejunctional inhibition of cardiac sympathetic neurotransmission and histamine‐induced coronary vasodilatation were investigated in perfused dog hearts in situ.

Intra‐arterial injections of histamine into the right coronary artery during the resting state caused slightly positive chronotropic responses in doses larger than 1 μg.

Histamine in doses of 0.1 to 10 μg into the right coronary artery reduced the tachycardia resulting from electrical stimulation of the cardiac sympathetic nerves.

Intra‐coronary infusions of chlorpheniramine (300 μg/min) significantly reduced the histamine‐induced depression of cardiac nerve stimulation. The effects of cimetidine (300 μg/min) and metiamide (300 μg/min) were less pronounced.

Histamine (1 to 10 μg) further increased heart rate resulting from the continuous intra‐coronary infusion of noradrenaline (1 or 3 μg/min).

Intra‐arterial injections of histamine (0.1 to 10 μg) caused an increase in coronary blood flow in a dose‐dependent manner. This was partially inhibited by intra‐coronary infusion of chlorpheniramine (10 to 300 μg/min) and by cimetidine (10 to 300 μg/min). The combination of both drugs (10 to 100 μg/min of each) caused a larger inhibition.

The present results suggest that the histamine‐induced depression of heart rate during cardiac sympathetic nerve stimulation is due to a prejunctional effect mediated mainly by H1‐receptors. Histamine‐induced coronary vasodilatation in the dog is mediated both by H1‐ and H2‐receptors.
Studies on the interaction between cerebral 5‐hydroxytryptamine and γ‐aminobutyric acid in the mode of action of diazepam in the rat
Authors: Collinge J. , Pycock C.J. , Taberner P.V.
Published: July 2012

The effect of the benzodiazepine, diazepam, administered for 7 days in doses between 1.25 and 5 mg kg−1 was studied on the turnover of 5‐hydroxytryptamine (5‐HT) in rat cerebral cortex. 5‐HT turnover was assessed by calculating the ratio of the concentration of the major metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) to that of 5‐HT (i.e., 5‐HIAA:5‐HT). Diazepam (2.5 and 5 mg kg−1 i.p. daily for 7 days) significantly reduced cerebral cortical 5‐HT turnover.

The effect of manipulating cerebral γ‐aminobutyric acid (GABA) mechanisms on this action of diazepam was studied. Treatment of animals with a subconvulsive dose of Picrotoxin (3 mg kg−1 i.p.) reversed the fall in cortical 5‐HT turnover seen following diazepam. In contrast, however, treatment with the GABA transaminase inhibitors, amino‐oxyacetic acid (25 mg kg−1) or ethanolamine‐O‐sulphate (250 mg kg−1, 7 days) which elevated cerebral GABA concentrations, enhanced the reduction in cortical 5‐HT turnover following diazepam.

Focal injection of picrotoxin (0.1 μg) into the region of the dorsal raphé nucleus reversed the decrease in cortical 5‐HT turnover caused by diazepam.

The hypothesis that doses of diazepam which result in total plasma concentrations comparable to those observed in man produce a reduction in 5‐HT turnover mediated via GABA neurones is discussed.
Interactions of γ‐aminobutyric acid and noradrenaline in the high pressure neurological syndrome
Authors: Angel A. , Halsey M.J. , Wardley‐Smith Bridget
Published: July 2012

The effects on the high pressure neurological syndrome (HPNS) of reducing brain noradrenaline (NA) levels were studied in adult rats. The onset of tremors and convulsions, which occur as pressure is increased, were used as endpoints for assessing the onset and severity of the HPNS.

Neonatal treatment with 6‐hydroxydopamine (6‐OHDA; 100 mg kg−1 i.p. alternate days from birth for 2 weeks) which depleted brain NA, produced no change in the HPNS as assessed by the appearance of tremors and convulsions.

A second series of NA‐depleted rats and equivalent controls were treated with a GABA agonist, muscimol, 0.1 μg intracerebroventricularly. Subsequently the rats were exposed to pressure and the onset and severity of the HPNS was assessed by observation of tremors and convulsions. A combination of NA depletion and intracerebroventricular injection of muscimol significantly raised the onset pressures for tremors and convulsions, i.e. delayed the appearance of the HPNS.

These results are consistent with the HPNS being associated with a disturbance in the balance of two or more neurotransmitter systems, rather than simply an increase or reduction in levels of a single transmitter.
Conversion of sodium channels to a form sensitive to cyclic AMP by component(s) from red cells
Authors: Cuthbert A.W. , Spayne J. A.
Published: July 2012

Sodium transport has been measured in the isolated epithelium from colons of male Sprague‐Dawley rats.

Sodium transport in colons was induced by pretreating the animals with dexamethasone (6 mg kg−1) which caused the appearance of an amiloride‐sensitive short circuit current within a few hours.

Forskolin, a diterpene, which activates adenylate cyclase, was found to increase the cyclic adenosine monophosphate (cyclic AMP) content of rat colons and also to increase short circuit current at the same time. However, measurements of chloride and sodium fluxes across the epithelium indicated that forskolin activates chloride secretion but has no effect on sodium transport.

In confirmation of (3) it was found that the amiloride‐sensitive short circuit current was unchanged after the short circuit current had been increased by forskolin under a variety of conditions.

The behaviour of the mammalian colon as indicated in (3) and (4) is unlike that of amphibian sodium transporting epithelia. It is shown that in toad urinary bladder forskolin increases amiloride‐sensitive short circuit current.

Procedures were investigated which might make sodium transport in the mammalian colon sensitive to cyclic AMP. Exposing the apical surface to sonicated suspensions of nucleated red cells (frog, toad and duck), followed by washing, gave preparations with amiloride‐sensitive short circuit currents which were increased by forskolin or dibutyryl cyclic AMP.

It would appear that the sodium channel in the mammalian colon, unlike that of amphibian tissues, has lost the ability to have its properties modified by cyclic AMP. Incubation of colons with sonicated suspensions of nucleated red cells apparently modifies the tissues such that sodium transport across the tissue becomes sensitive to the nucleotide.
The effect of felodipine on ventricular fibrillation after coronary artery ligation in the anaesthetized pig
Authors: Verdouw P.D. , Wolffenbuttel B.H.R.
Published: July 2012

A 10 min ligation of the left anterior descending coronary artery in anaesthetized pigs resulted in ventricular fibrillation (VF) in 70% of control and propranololtreated animals. Felodipine (10 nmol kg−1) not only reduced ventricular ectopic activity by 90%, but also completely abolished VF. When a second occlusion was applied after 20 min of reperfusion, felodipine was less effective against VF, possibly due to decreasing felodipine concentrations or only a transient increase in VF threshold.
Copper metabolism during acute inflammation: studies on liver and serum copper concentrations in normal and inflamed rats
Authors: Conforti A. , Franco L. , Milanino R. , Totorizzo A. , Velo G.P.
Published: July 2012

The concentration of copper in serum and liver was determined by atomic absorption spectrophotometry in a study performed on normal rats of either sex and in female rats with carrageenan‐induced pleurisy.

In the normal animal, total serum copper concentration is significantly higher in female rats, and appears to be higher in mature animals in females.

In normal rats of either sex, liver copper concentration undergoes daily variations which are inversely related to the weight of the organ and which leave constant the total amount of metal in the liver. Moreover a day to day non‐cyclic variability of liver copper concentration and liver weight was observed.

This first set of data showed that comparison with time control was essential.

In the inflamed rat, a significant rise of total serum copper at 22, 48 and 72 h after the induction of inflammation was observed. From 96 h up to 240 h post‐injection no significant differences were evident.

Total liver copper content did not change in the inflamed rats.

During acute inflammation in the rat, the copper needed for the increased synthesis of caeruloplasmin is supplied without depletion of liver copper stores.
The binding of [125I]‐angiotensin to rat renal epithelial cell membranes
Authors: Cox Helen M. , Munday Kenneth A. , Poat Judith A.
Published: July 2012

Specific high affinity binding sites for [125I]‐angiotensin II have been identified in crude basolateral and brush border membranes from rat renal cortex.

A central high affinity site, KD 0.62 nM; Bmax 299 fmol/mg was identified as part of a complex multicomponent binding system.

This high affinity site was saturable and exhibited specificity for angiotensin II analogues and closely related peptides but not for bradykinin, substance P or peptide fragments of angiotensin II.

Specific [125I]‐angiotensin II binding was partially dependent on NaCl. Absence of NaCl resulted in a decrease in Bmax, had no effect on the rate of association but increased the rate of dissociation of [125I]‐angiotensin from its binding site.
An investigation of the importance of the adrenal gland to the action of dopamine in the rat kidney
Authors: Akpaffiong M.J. , Redfern P.H. , Woodward B.
Published: July 2012

In the rat, administration of dopamine is associated with diuresis, natriuresis and a decreased excretion of K+. The site of action of dopamine in mediating these responses has been investigated.

Urine volume, and urinary Na+, K+, Cl− and dopamine concentrations have been measured in adrenalectomized and sham‐operated male Wistar rats.

As expected, adrenalectomy decreased urine volume and increased Na+ and Cl− excretion; at the same time the amount of dopamine excreted fell, and K+ excretion did not change.

Administration of either 3% NaCl (20 ml/kg orally) or frusemide (100 mg/kg s.c.) significantly elevated dopamine excretion after adrenalectomy.

When dopamine, 1, 10 and 30 mg/kg (s.c.) was given to adrenalectomized rats, the diuresis and fall in K+ excretion seen in control animals was still present. No further natriuresis, over and above the already high urinary Na+ levels, was observed.

The results show that the three actions of dopamine in inducing diuresis and natriuresis, and decreasing K+ excretion, are clearly separable.

It is further argued that in mediating these effects the main site of action of dopamine is the kidney rather than the adrenal gland.
Influence of extracellular calcium and calcium antagonists on contractions induced by potassium and prostaglandin F2α in isolated cerebral and mesenteric arteries of the cat
Authors: Andersson K.‐E. , Edvinsson L. , MacKenzie E.T. , Skärby T. , Young A.R.
Published: July 2012

The effects of a number of calcium antagonists (diltiazem, nifedipine, nimodipine and verapamil) have been studied on feline isolated pial arteries contracted by potassium (127 mM) or prostaglandin F2α (PGF2α, 2.5 μM) and mesenteric arteries contracted by potassium (127 mM).

Withdrawal of Ca2+ from the extracellular medium for 30 min reduced the contractile response to potassium in cerebral vessels by 92% and in mesenteric vessels by 96%. Subsequent addition of Ca2+ caused reproducible contractions which were inhibited by both nifedipine and nimodipine.

The four calcium antagonists relaxed the isolated middle cerebral artery contracted either by potassium or PGF2α, and mesenteric arteries contracted by potassium, in the following order of potency: nimodipine > nifedipine > verapamil > diltiazem.

Nimodipine was more potent than nifedipine in cerebral arteries, and more potent in cerebral than in mesenteric arteries. Otherwise, the potassium‐contracted cerebral and mesenteric vessels showed no major differences in sensitivity to calcium antagonists.
A comparison of the effects of morphine, enkephalin, kyotorphin and D‐phenylalanine on rat central neurones
Authors: Stone T.W.
Published: July 2012

Morphine, Met‐enkephalin, kyotorphin and D‐phenylalanine have been applied by microion‐tophoresis to neurones in the globus pallidus and cerebral cortex of rats anaesthetized with urethane.

In the pallidum, most cells were inhibited by all the agonists, with a high correspondence between cells inhibited by Met‐enkephalin and D‐phenylalanine and by Met‐enkephalin and kyotorphin. Whereas responses to Met‐enkephalin were readily antagonized by naloxone, responses to kyotorphin and D‐phenylalanine were not.

In the cerebral cortex a high proportion of cells was excited by all four agonists and antagonism by naloxone was less consistent than in pallidum.

It is concluded that the naloxone‐reversible analgesic effects of kyotorphin and D‐phenylalanine may be mediated indirectly, rather than through an activation of opiate receptors.
Characterization and partial purification of ‘renocortins’: two polypeptides formed in renal cells causing the anti‐phospholipase‐like action of glucocorticoids
Authors: Cloix Jean François , Colard Odile , Rothhut Bernard , Russo‐Marie Françoise
Published: July 2012

Anti‐inflammatory steroids reduce prostaglandin E2 (PGE2) synthesis in rat renomedullary interstitial cells in culture by inhibiting the release of arachidonic acid from membranous phospholipid stores, exhibiting antiphospholipase‐like properties.

After treatment of the cells with dexamethasone 10−6M, these cells release a protein in the supernatant.

This supernatant is able to inhibit PGE2 secretion in untreated cells and to inhibit phospholipase A2 activity in an in vitro system.

Using chromatofocusing separation, we showed that two distinct proteins exist with isoelectric points of 5.8 and 8.3.

Using gel permeation separation, we showed that two proteins exist with apparent molecular weights of 15,000 and 30,000 daltons.

We conclude that, in renal cells in culture, anti‐inflammatory steroids induce the synthesis and the release of two polypeptides which we have named ‘Renocortins’ (induced by corticoids in renal cells) causing the antiphospholipase‐like action of glucocorticoids.

Our results are in good agreement with others, but as renal cells are not directly involved in the inflammatory process, we suggest that this steroid‐induced phenomenon is not solely involved in the inflammatory reaction but is of more general physiological relevance.
Comparison of the excitatory actions of substance P, carbachol, histamine and prostaglandin F2α on the smooth muscle of the taenia of the guinea‐pig caecum
Authors: Benham C.D. , Bolton T.B.
Published: July 2012

A comparison was made of the actions of substance P, prostaglandin F2α (PGF2α), histamine and carbachol on the membrane potential and conductance of the longitudinal smooth muscle of the taenia of the guinea‐pig caecum using the double sucrose gap apparatus.

The increases in conductance produced by the four drugs during matched depolarizations in the sucrose gap were not significantly different and they were substantially larger than the increase in conductance brought about during the same depolarization produced by passing outward current.

In sucrose‐substituted, Na‐ and Cl‐deficient solution the increases in conductance and depolarization due to carbachol, substance P, and PGF2α were attenuated to a similar extent. The depolarization due to histamine under these conditions was reduced to a significantly greater extent than that due to carbachol. In Tris‐benzene‐sulphonate substituted Na‐ and Cl‐deficient solution the responses due to carbachol and histamine were attenuated to a similar extent. This suggests that sucrose addition may have a specific effect on the histamine response.

In Tris‐substituted Na‐deficient solution the increases in conductance and depolarization produced by substance P, histamine and carbachol were attenuated to a similar extent. The depolarization due to PGF2α was reduced by a significantly greater amount which may be due to unmasking an inhibitory effect that was sometimes apparent in normal solution.

In benzenesulphonate‐substituted, Cl‐deficient solution the increases in conductance and depolarizations produced by moderate concentrations of PGF2α, histamine and carbachol were attenuated to a similar extent. The response to substance P was little affected. In glucuronate‐substituted, Cl‐deficient solution the increases in conductance and depolarizations due to substance P and carbachol were attenuated to a similar extent. This result, and the observation that the depolarization to large concentrations of carbachol was not reduced in benzenesulphonate‐substituted, Cl‐deficient solution, suggest that benzenesulphonate interferes with the reactions of the non‐peptide stimulants with their respective receptors.

The similarities in the effects of activating the four types of receptor under some conditions could be explained if they all acted on the same population of receptor‐operated channels. In addition it seems that PGF2α acts also on a population of inhibitory receptors, sucrose interferes with histamine's action, and benzenesulphonate interferes with the reactions of non‐peptide stimulants with their respective receptors.
The effect of bilateral adrenal demedullation on vascular reactivity and blood pressure in spontaneously hypertensive rats
Authors: Borkowski K.R. , Quinn P.
Published: July 2012

Bilateral adrenal demedullation of juvenile spontaneously hypertensive rats attenuated, but did not prevent, the development of hypertension. Neither did it affect the subsequent vascular reactivity to phenylephrine though it significantly reduced the vascular effects of sympathetic nerve stimulation.

Demedullation of adult spontaneously hypertensive rats did not alter blood pressure, but did attenuate the pressor responses to both α‐adrenoceptor agonists and sympathetic nerve stimulation.

In acutely demedullated adult rats, vascular reactivity to sympathetic nerve stimulation, but not to exogenous amines, could be restored by slow i.v. infusion of adrenaline in a dose‐dependent manner.

The results support a possible facilitatory role for adrenaline in sympathetic neurotransmitter release, both during the development of genetic hypertension and in vascular responses to sympathetic nerve stimulation.
Functional interactions of calcium‐antagonists in K+‐depolarized smooth muscle
Authors: Spedding Michael
Published: July 2012

The functional significance of the interaction of certain calcium‐antagonists with nimodipine was examined so that this might be related to binding studies. To this end, the relaxant effects of nimodipine (1–100 nm) on Ca2+ (10 mm) ‐induced contractions of K+‐depolarized taenia preparations from the guinea‐pig caecum were compared in the presence of nifedipine and cinnarizine (which competitively displace [3H]‐nimodipine with high and low affinities respectively), diltiazem (which increases binding), verapamil (which allosterically reduces binding) and W‐7, a calmodulin antagonist.

The relaxant effects of nimodipine were similar in the presence of nifedipine, diltiazem and cinnarizine, but were slightly attenuated in the presence of verapamil and W‐7.

These findings can be reconciled with the differentiation of calcium antagonists evident from [3H]‐nimodipine binding studies, but indicate that the functional consequences of allosteric interactions disclosed in such studies are small. Drugs which bind to calcium channels and drugs which bind to calmodulin did not potentiate each other.
Responses of human skin to intradermal injection of leukotrienes C4, D4 and B4
Authors: Camp R.D.R. , Coutts A.A. , GreavesM M.W. , Kay A.B. , Walport M.J.
Published: July 2012

The ability of intradermally injected leukotrienes C4 (LTC4), LTD4 and LTB4 to produce inflammatory changes in human skin alone and in combination with prostaglandin E2 (PGE2) has been investigated.

LTC4 and D4 (0.012–0.38 nmol) caused dose‐related erythema and wealing. No evidence of synergism between PGE2 and LTC4 or LTD4 was detected, although only single dose combinations were studied.

LTB4 (0.15–1.5 nmol) caused areas of induration which persisted for more than 4 h and which showed perivascular neutrophil infiltrates on histological examination. Only slight synergism between PGE2 and LTB4 was found.

It was concluded that these pro‐inflammatory properties of LTC4, LTD4 and LTB4 are consistent with their proposed roles as mediators of inflammation in the skin and other tissues.
The inhibitory effects of N2‐dansyl‐l‐arginine‐4‐t‐butylpiperidine amide (TI 233) on contraction of vascular and intestinal smooth muscle
Authors: Karaki H. , Murakami K. , Nakagawa H. , Urakawa N.
Published: July 2012

Effects of N2‐dansyl‐l‐arginine‐4‐t‐butylpiperidine amide (TI 233) on the contractions in vascular and intestinal smooth muscles were examined.

High K‐induced sustained contractions in the smooth muscles were inhibited by TI 233 with an IC50 of 2.1 × 10−5m for rabbit aorta and 3.6 × 10−6m for guinea‐pig taenia coli in a solution containing 1.5 mm Ca. Initial transient contraction induced by K in taenia coli was less sensitive to the inhibitory effect of TI 233. When the Ca concentration in the medium was decreased to 0.3 mm, the concentration‐inhibition curves for TI 233 shifted to the left in both aorta and taenia coli. Increasing the Ca concentration to 7.5 mm shifted the curve to the right in the aorta. TI 233 also inhibited the noradrenaline‐induced contraction in the aorta (IC50 = 2.1 × 10−5 m).

In a hypoxic solution without added glucose, the inhibitory effect of TI 233 on the K‐induced contraction in aorta was augmented. In the presence of high concentrations (40 mm) of glucose in hypoxia, TI 233 did not inhibit the noradrenaline‐induced contraction of the aorta. Hypoxia and a high concentration of glucose also decreased the inhibitory effect of TI 233 on the K‐induced contraction in taenia coli.

TI 233 inhibited the K‐induced increase in cellular Ca content measured by a modified lanthanum method.

TI 233 decreased oxygen consumption and ATP content of resting and K‐stimulated aorta and taenia coli.

It was concluded that TI 233 inhibits the vascular and intestinal smooth muscle contraction by a Ca antagonistic action and also by inhibition of aerobic metabolism.
Separation of adrenergic and non‐adrenergic contractions to field stimulation in the rat vas deferens
Authors: Brown D. A. , Docherty J.R. , French A.M. , MacDonald A. , McGrath J.C. , Scott N.C.
Published: July 2012

Adrenergic and ‘non‐adrenergic’ nerve‐induced contractions in rat vas deferens were separated pharmacologically.

Responses to single stimuli comprised two components, an α‐noradrenergic component (IIs), dominant in the epididymal portion, and a ‘non‐adrenergic’ component (Is), dominant in the prostatic portion. Is but not IIs was blocked by nifedipine. A combination of adrenergic blockade and nifedipine virtually abolished all components. After cocaine, a third component (IIIs) emerged which was abolished by either adrenergic blockade or nifedipine.

The response to trains of stimuli consisted of ‘twitch’ and ‘secondary’ components. This biphasic time course was modified by adrenergic blockade or nifedipine to reveal the time course of the ‘non‐adrenergic’ and adrenergic components, respectively: these did not correspond to the ‘twitch’ and ‘secondary’ components. A combination of adrenergic blockade and nifedipine virtually abolished the whole response.

Prejunctional α2‐adrenoceptor‐mediated inhibition of the contractile responses could be blocked by selective α2‐adrenoceptor antagonists. The adrenergic contractile response demonstrated this ‘feed‐back’ even on the second pulse at 0.5 Hz. Endogenous inhibition of the ‘non‐adrenergic’ contraction required higher frequencies or enhancement of the extracellular concentration of noradrenaline by blockade of its neuronal uptake.

Contractile responses to exogenous noradrenaline were abolished by nifedipine, at a concentration that did not affect the adrenergic (IIs) neurotransmission.

These results reinforce the view that part of the motor transmission in rat vas deferens is non‐adrenergic and allow the disentanglement of the various postjunctional and prejunctional elements contributing to the complex response to a train of stimuli.
Plasma acid phosphatase levels in endotoxaemia: modification by drugs and chemically detoxified endotoxins
Authors: Godin David V. , Tuchek John M.
Published: July 2012

The ability of chemically detoxified E. coli endotoxins and membrane‐active agents to modify the toxicity of native E. coli endotoxin in vivo was examined.

The time‐ and dose‐dependent increase in plasma acid phosphatase activity following toxin administration to rats provided a convenient quantitative measure of in vivo toxicity under various experimental conditions.

Treatment of endotoxin with either sodium hydroxide or sodium periodate produced substances which, when injected alone, failed to cause an increase in plasma acid phosphatase activity. When given before native endotoxin, periodate‐detoxified toxin produced a dose‐dependent reduction in the elevation of plasma enzyme activity caused by unmodified toxin. Pretreatment with pranolium, hydrocortisone or (+)‐propranolol also reduced the in vivo toxicity of endotoxin.

Mortality studies in mice provided further independent support for the effectiveness of periodate‐detoxified endotoxin and membrane‐active drugs as endotoxin antagonists.

Evidence has been found that under certain conditions gentamicin may act synergistically with bacterial endotoxins in vivo.
Depolarization of rat isolated superior cervical ganglia mediated by β2‐adrenoceptors
Authors: Brown D.A. , Dunn P.M.
Published: July 2012

Depolarizations of freshly‐dissected isolated superior cervical ganglia of the rat were recorded extracellularly. The following sympathomimetic amines (in order of decreasing potency) produced depolarizations of up to 0.4 mV: isoprenaline, salbutamol, adrenaline, noradrenaline. Depolarizations were lost after overnight storage, leaving only hyperpolarizing responses.

Depolarizations by isoprenaline were antagonized by (‐)‐propranolol (pA2 8.94 ± 0.15), (±)‐butoxamine (pA2 7.36 ± 0.12) and (±)‐practolol (pA2 5.14 ± 0.13). They were not blocked by phentolamine (1 μm) or phenoxybenzamine (1 μm). Isoprenaline and salbutamol were antagonized with equal facility by practolol or butoxamine.

In concentrations producing ganglionic depolarization, these compounds also produced a smaller depolarization of presynaptic elements in the ganglion, but not preganglionic trunk fibres. Presynapic depolarization was blocked by 100 nM propranolol but not by 1 μm phentolamine.

Isoprenaline and salbutamol increased the amplitude of the compound ganglionic action potential recorded following single preganglionic nerve stimuli when transmission had been rendered submaximal by adjusting the Ca/Mg ratio, but not in normal solution.

Isoprenaline (0.1 μm) also increased the amount of [3H]‐acetylcholine released by preganglionic stimulation in low Ca/high Mg solution.

It is concluded that facilitatory adrenoceptors are present on pre‐ and postsynaptic elements in rat superior cervical ganglia, which resembles the ‘β2’ subclass of β‐receptors.
The effect of choline mustard on the rat superior cervical ganglia
Authors: Allen M.C.
Published: July 2012

The effect of choline mustard aziridinium ion (ChM) on the isolated superior cervical ganglion of the rat was investigated.

In the presence of ChM (22.5 μM), stimulation at 1 Hz resulted in a slowly developing blockade of transmission, which did not occur at a stimulus frequency of 0.1 Hz.

Choline (0.1 mm) slowed the onset of the blockade produced by stimulation at 1 Hz in the presence of ChM.

The presence of excess thiosulphate ions prevented the action of ChM on the transmission in the superior cervical ganglion.

Treatment of the ganglion with ChM (22.5 μm) only slightly inhibited the depolarization produced by carbachol (dose ratio 1.3), suggesting the drug produced a small degree of receptor blockade.

[3H]‐choline accumulation in the rat superior cervical ganglia displays several components: (a) sodium‐dependent high affinity uptake (SDHAU) that can be activated further by preincubation in a high concentration of K+ ions; (b) sodium‐dependent low affinity uptake (SILAU); (c) linear diffusional accumulation which does not saturate.

Hemicholinium‐3 selectively inhibits the activated sodium‐dependent high affinity uptake, but is a weak inhibitor of resting sodium‐dependent high affinity uptake and sodium‐independent low affinity uptake.

ChM inhibits both activated and resting sodium‐dependent high affinity uptake, but is a very weak inhibitor of sodium‐independent low affinity uptake. Homocholine shows similar selectivity.

ChM inhibition of activated sodium‐dependent high affinity uptake is very much more persistent than that of hemicholinium‐3.

Hemicholinium‐3 and ChM both inhibit [3H]‐acetylcholine synthesis.
Age‐dependent differences in the positive inotropic effect of phenylephrine on rat isolated atria
Authors: Hashimoto Hisakuni , Nakashima Mitsuyoshi , Sugino Naoko
Published: July 2012

The age‐dependent differences in the involvement of α‐adrenoceptors in the positive inotropic effect of phenylephrine (Phe) were examined in isolated atria of male Wistar rats 6 weeks (6W), 10 weeks and 7 months (7M) of age.

The maximal increase in tension development induced by Phe increased with age, whereas the EC50 values for the positive inotropic effect of Phe did not change with age. The inhibitory effect of phentolamine on the response to Phe increased with age. Propranolol caused only slight inhibition of the effect of Phe in both 6W and 7M rats, and the EC50 values for Phe in the presence of propranolol did not change significantly with age.

The EC50 values for isoprenaline and 5‐hydroxytryptamine in 7M rats were higher than those in 6 W rats.

In 7M rats, the duration of the tension development was only slightly affected by Phe in the presence or absence of propranolol, but it was markedly decreased by Phe in the presence of phentolamine.

The dose‐response curve for Phe was markedly shifted to the left by papaverine in 6W rats, but slightly in 7M rats. The dose‐response curve for isoprenaline was markedly shifted to the left by papaverine in both groups.

These results are consistent with effects of Phe being mediated by both α‐ and β‐adrenoceptors in both 6W and 7M rats, but there is a shift in the balance from rather more β‐receptors in the young animals to more α‐receptors in the adults.
The effects of atropine and secoverine on gastric secretion and motility in the mouse isolated stomach
Authors: Davison J.S. , Greenwood Beverley , Najafi‐Farashah A. , Read N.W.
Published: July 2012

The isolated perfused stomach of the mouse was used to study the effect of atropine and secoverine on bethanechol‐induced gastric acid secretion and gastric motility.

Both atropine and secoverine inhibited cholinergically induced gastric acid secretion and gastric motility.

Inhibition of gastric acid secretion by atropine and secoverine occurred at a similar dose‐range (10−9 and 2 × 10−9m).

Secoverine inhibited bethanechol‐induced hypermotility at doses (10−11 m and above) that were lower than those of atropine (2 × 10−9 m and above) required to produce this effect.

Secoverine, unlike atropine markedly inhibited gastric motility at lower doses than those which affected secretion.
Parallel secretion of endogenous 5‐hydroxytryptamine and histamine from mast cells stimulated by vasoactive peptides and compound 48/80
Authors: Carraway R.E. , Cochrane D.E. , Granier C. , Kitabgi P. , Leeman Eve , Singer E.A.
Published: July 2012

The peptides, neurotensin, substance P, somatostatin, and bombesin, several analogues and fragments of neurotensin and compound 48/80, all caused the secretion of both endogenous 5‐hydroxytryptamine (5‐HT) and histamine. There was no differential effect of any of the secretagogues tested on the secretion of 5‐HT and histamine. Amitriptyline prevented the secretion of histamine in response to stimulation by neurotensin, substance P, somatostatin or compound 48/80 but was without effect on the secretion of endogenous 5‐HT.
Dynorphin‐related peptides cause motor dysfunction in the rat through a non‐opiate action
Authors: Faden Alan I. , Jacobs Thomas P.
Published: July 2012

We compared effects on motor function of four peptides belonging to the dynorphin family ‐dynorphin‐(1–17) (DYN‐(1–17)), dynorphin‐(1–13) (DYN‐(1–13)), dynorphin‐(1–8) (DYN‐(1–8)) and α‐neo‐endorphin (αNE).

After intrathecal administration, each of these peptides produced dose‐related, flaccid, hindlimb paralysis, with the order of potency being DYN‐(1–17) > DYN‐(1–13) > αNE ≏DYN‐(1–8).

This motor dysfunction was not reversed or blocked by the opiate receptor antagonist naloxone and was not produced by a variety of other κ‐selective agonists.

However, paralysis was produced by des‐Tyr‐dynorphin (DYN‐(2–17)), which does not act at the opioid receptor.

Taken together, the present studies show that dynorphin‐related peptides, uniquely amongst opioids, produce motor dysfunction, an action which does not appear to be mediated by opioid receptors.
A 1H n.m.r. study of the role of the glutamate moiety in the binding of methotrexate to Lactobacillus casei dihydrofolate reductase
Authors: Antonjuk David J. , Birdsall Berry , Cheung H.T. Andrew , Clore G. Marius , Feeney James , Gronenborn Angela , Roberts Gordon C.K. , Tran Trung Q.
Published: July 2012

The binding of a series of amide derivatives of methotrexate to Lactobacillus casei dihydrofolate reductase has been studied by inhibition constant measurements and by 1H n.m.r. spectroscopy.

Amide modification of the α‐carboxylate of methotrexate was found to prevent interaction of the γ‐carboxylate with the imidazole of His 28.

Estimates of the contributions to the binding energy from the α‐carboxylate‐Arg 57 and γ‐carboxylate‐His 28 interactions have been made from a combination of inhibition and n.m.r. data.
Actions of picrotoxinin and related compounds on the frog spinal cord: the role of a hydroxyl‐group at the 6‐position in antagonizing the actions of amino acids and presynaptic inhibition
Authors: Kudo Yoshihisa , Niwa Haruki , Tanaka Atsuko , Yamada Kiyoyuki
Published: July 2012

The frog spinal cord has been used to test the effects of naturally occurring picrotoxane compounds (picrotoxinin, picrotin, tutin and coriamyrtin) and semisynthetic ones (6‐acetylpicrotoxinin and anhydropicrotin) on the electrical activities of dorsal and ventral roots and on amino acid‐induced depolarizations of primary afferent terminals.

Picrotoxinin, tutin and coriamyrtin (10−5‐3 × 10−5m), which have a free hydroxyl group at the 6‐position, caused a gradual depolarization in both ventral and dorsal roots. The depolarizations were accompanied by a reduction in the size of the dorsal root potential (DR‐DRP), dorsal root reflex (DR‐DRR) and ventral root potential (DR‐VRP) and by an augmentation of the first spike potential and polysynaptic components in the ventral root reflex (DR‐VRR).

6‐Acetylpicrotoxinin (10−5‐3 × 10−5m) caused a slight hyperpolarization in both roots, and this hyperpolarization was accompanied by the augmentation of DR‐DRP, DR‐VRP and DR‐VRR. The DR‐DRR was reduced or abolished by the compound.

Picrotoxinin, tutin and coriamyrtin reduced γ‐aminobutyric acid (GABA)‐, β‐alanine‐ and taurine‐induced depolarizations of primary afferent terminals. 6‐Acetylpicrotoxinin showed almost the same degree of inhibition of β‐alanine and taurine as did picrotoxinin, but the GABA‐antagonizing action of the compound was significantly weaker than was that of picrotoxinin.

Picrotoxinin, tutin, coriamyrtin and 6‐acetylpicrotoxinin all blocked presynaptic inhibition of the first spike potential caused by antidromic conditioning stimulation.

The present results suggest that the hydroxyl group at the 6‐position of picrotoxane compounds are important for antagonism of the effects of GABA, but not of β‐alanine and taurine and for the blocking action of the presynaptic inhibition in the frog spinal cord.
Presynaptic α‐adrenoceptors: do exogenous and neuronally released noradrenaline act at different sites?
Authors: Baker D.J. , Drew G.M. , Hilditch A.
Published: July 2012

The effects of dopamine receptor and α‐adrenoceptor agonists and antagonists on the stimulation‐evoked overflow of radioactivity from strips of dog saphenous vein previously loaded with [3H]‐noradrenaline have been examined alone and in combination.

In the presence of neuronal and extraneuronal catecholamine uptake inhibitors, noradrenaline (0.1–1 × 10−6 m) and dopamine (0.01–1 × 10−6 m) both inhibited the stimulation‐evoked overflow of radioactivity. Sulpiride (1 × 10−6 m) was without effect and prazosin (1 × 10−7 m) had little effect on stimulation‐evoked overflow but yohimbine enhanced it approximately 2 fold; the effect of yohimbine was similar at concentrations of 1 × 10−7 and 1 × 10−6 m.

Sulpiride abolished the inhibitory effect of dopamine on stimulation‐evoked overflow, but was without effect against noradrenaline. When allowance was made for the effects of yohimbine, alone, on overflow, yohimbine (1 × 10−7 m) had no effect against dopamine and minimal effects against noradrenaline. A similar result was obtained when the concentration of yohimbine was increased to 1 × 10−6 m. Prazosin did not antagonize the effect of noradrenaline.

In the absence of the uptake inhibitors, clonidine (0.01–1 × 10−5 m) inhibited stimulation‐evoked overflow of radioactivity. Yohimbine (1 × 10−6 m) was without effect on its own and antagonized the effects of clonidine at a concentration of 0.1 × 10−5 m, but not at 0.01 or 1.0 × 10−5 m.

These findings suggest that dopamine inhibits overflow by stimulating presynaptic dopamine receptors on the terminals of the noradrenergic nerves supplying the dog saphenous vein. The interaction between yohimbine and noradrenaline is discussed in terms of the current concepts of control of transmitter release mediated via presynaptic α2‐adrenoceptors.
Effects of α‐ and β‐adrenoceptor blockade on the neurally evoked overflow of endogenous noradrenaline from the rat isolated heart
Authors: Dart A.M. , Dietz R. , Hieronymus K. , Kübler W. , Mayer E. , Schömig A. , Strasser R.
Published: July 2012

β‐Adrenoceptor blockade by propranol (4 × 10−6 m) was without effect on the overflow of endogenous noradrenaline from the isolated heart of the rat induced by stimulation of sympathetic nerves for 1 min at 1 and at 4Hz. The increase in heart rate in response to such stimulation was abolished by propranolol treatment.

α2‐Adrenoceptor blockade by yohimbine (10−6m) induced approximately a two fold increase in the overflow of endogenous noradrenaline induced by stimulation of sympathetic nerves for 1 min at 1 and at 4 Hz.

A combination of yohimbine (10−6m) and desipramine (10−7 m) induced a more than 3 fold increase in the overflow of endogenous noradrenaline produced by sympathetic nerve stimulation at 1 and at 4 Hz. Heart rate increases produced by such stimulation were intensified.

These results provide no evidence for the feedback stimulation of presynaptic β‐adrenoceptors in this preparation. The action of α2‐blockade was equipotent at stimulation frequencies of 1 and 4 Hz.
Release of noradrenaline and dopamine by nerve stimulation in the guinea‐pig and rat vas deferens
Authors: Bell C. , Gillespie J.S. , Macrae I.M.
Published: July 2012

Spontaneous and nerve stimulated release of noradrenaline and dopamine from rat and guinea‐pig vas deferens have been measured electrochemically after separation by high performance liquid chromatography (h.p.l.c).

In the absence of nerve stimulation both noradrenaline (NA) and dopamine were released into the bathing fluid in the rat but in the guinea‐pig only noradrenaline could be detected. Drugs which block neuronal and extraneuronal uptake of catecholamines had little effect on spontaneous overflow but both tetraethylammonium and phenoxybenzamine increased overflow.

Transmural nerve stimulation (5–10 Hz) increased catecholamine overflow in both species and dopamine release was now measurable from the guinea‐pig vas. In the rat, the proportion of dopamine to NA was unchanged from that released spontaneously. The release of both amines was little affected by drugs that block neuronal and extraneuronal uptake and a monoamine oxidase inhibitor, but was inhibited by tetrodotoxin 0.2 μg ml−1.

In the guinea‐pig tetraethylammonium 10 mm doubled overflow and phenoxybenzamine 10−5 m increased it by five times but the dopamine percentage remained constant and equal to the control.

Following nerve stimulation the amount of dopamine released expressed as a percentage of total catecholamine release was 6% for the rat and 1.3% for the guinea‐pig. These values were considerably higher than the comparable figures for dopamine: NA content of the two tissues (2% and 0.5% respectively). Repeated periods of stimulation depleted these tissue stores and the depletion of dopamine was significantly greater than that of NA.

Our interpretation of these results is that both dopamine and NA are released from a common store during normal noradrenergic transmission. While all or most of the axonal dopamine is contained in this releasable pool, most of the axonal NA lies in a second, less readily released pool.
Interactions of Cholinesterase inhibitors and glucocorticoids with ketamine and pentobarbitone‐induced general anaesthesia in the rat: possible effects on central cholinergic activity
Authors: Leeuwin Remy S. , van der Wal Jan K. , Spanjer Willem
Published: July 2012

Doses of 100, 150 and 200 μg kg−1 of the Cholinesterase inhibitor neostigmine reverse the anaesthetic action of ketamine. The antagonistic effect is increased as the dose is increased. The duration of anaesthesia induced by pentobarbitone is reversed by the Cholinesterase inhibitor in doses of 150, 200 and 250 μg kg−1.

Choline, in a dose of 50 mg kg−1, significantly antagonizes the action of the two anaesthetics, whereas hemicholinium‐3, an inhibitor of the uptake of choline and the synthesis of acetylcholine, markedly potentiates their action.

Dexamethasone induces a significant reduction of the duration of anaesthesia produced by ketamine and pentobarbitone. The potentiation of the anaesthetic effect caused by hemicholinium‐3 is also reversed by dexamethasone.

The acetylcholine content in rat cerebral cortex is increased after treatment with ketamine and pentobarbitone.

Measurements of the course of the plasma level of pentobarbitone do not reveal alterations in the pharmacokinetic profile by either neostigmine or dexamethasone.

These results indicate that central cholinergic systems may somehow be involved in the anaesthesia induced by ketamine and pentobarbitone and that the interactions described in this paper may be the result of modification by neostigmine and dexamethasone of the alterations in cholinergic activity caused by the two anaesthetics.
Frusemide releases renin in the rat kidney when prostacyclin synthesis is suppressed
Authors: Barden Anne E. , Mahoney Denis P. , Tunney Anne M. , Vandongen Robert
Published: July 2012

The effect of inhibiting prostaglandin (PG) synthesis on basal and frusemide‐stimulated renin secretion was examined in the rat isolated perfused kidney. The stable PGI2 derivative, 6‐keto PGF1α, was measured by radioimmunoassay in urine collected from the kidney.

Treatment of rats with indomethacin (3.0 mg kg−1) reduced 6‐keto PGF1α excretion from 121.3 ± 39.1(n = 9) to 15.5 ± 6.6 (n = 9) pg min−1 (P < 0.02) but had no effect on basal renin secretion. Renal perfusion pressure, flow rate and vascular resistance were similar in treated and control rats. Mean urine flow was lower after treatment.

Infusion of frusemide (250 μg min−1) did not alter 6‐keto PGF1α excretion in control or indomethacin‐treated (P > 0.05) rats. Although renin secretion was increased during frusemide infusion, there was no significant difference between control (1,806 ± 384 ng angiotensin I (AI) min−1) and treated (2,310 ± 554 ng AI min−1) rats (P > 0.05). Propranolol, at a dose (8 pig min−1) which suppressed renin secretion after isoprenaline stimulation, had no effect on the response to frusemide in indomethacin‐treated rats.

These results demonstrate that frusemide‐stimulated renin secretion in the rat kidney does not require intact renal PGI2 synthesis and is independent of β‐adrenergic mechanisms.