bluuebunny/crossref_metadata_2025 huggingface dataset:
Some features of the spasmogenic actions of acetylcholine and histamine in guinea‐pig isolated trachealis
Authors: Ahmed F. , Foster R.W. , Small R.C. , Weston A.H.
Published: July 2012

Intracellular electrophysiological recording showed that acetylcholine (1 μmol l−1) and histamine (2 μmol l−1) depolarized trachealis cells and often increased the frequency of slow waves. Higher concentrations of these agents caused greater depolarization and abolition of slow waves. Marked depolarization was often associated with the appearance of electrical ‘noise’. These electrical phenomena were accompanied by tonic tension development in a contiguous segment of trachea.

Electrical ‘noise’ and tension evoked by high concentrations of acetylcholine or histamine could be dissipated by washing the agonist from the tissue. Acetylcholine‐induced ‘noise’ was resistant to tetrodotoxin (3 μmol l−1) and to hexamethonium (1 mmol l−1).

Neither acetylcholine (10–1,000 μmoll−1) nor histamine (2–200 μmol l−1) increased the lanthanum‐resistant calcium fraction of muscle‐containing strips of trachea.

It is concluded that, while developing tension under the influence of acetylcholine or histamine, trachealis cells depolarize markedly but there is relatively little cellular influx of Ca2+.
Pressure reversal of the action of octanol on postsynaptic membranes from Torpedo
Authors: Braswell L.M. , Miller K.W. , Sauter J.‐F.
Published: July 2012

Octanol increases the binding of [3H]‐acetylcholine to the desensitized state of the nicotinic receptor in postsynaptic membranes prepared from Torpedo californica.

This increase in binding results from an increase in the affinity of [3H]‐acetylcholine for its receptor without any change in the number of sites or the shape of the acetylcholine binding curve.

High pressures of helium (300 atm) decrease [3H]‐acetylcholine binding by a mechanism that changes only the affinity of acetylcholine binding.

Helium pressure reverses the effect of octanol on the affinity of [3H]‐acetylcholine for its receptor.

This pressure reversal of the action of octanol at a postsynaptic membrane is consistent either with pressure counteracting an octanol‐induced membrane expansion or with independent mechanisms for the actions of octanol and pressure.

The data do not conform with a mechanism in which pressure displaces octanol from a binding site on the receptor protein.
Effect of nicotine on the formation of prostacyclin‐like activity and thromboxane in rabbit aorta and platelets
Authors: Alster Pawel , Wennmalm Åke
Published: July 2012

The effect of nicotine on the bioformation of prostacyclin (PGI2) and of thromboxane (Tx)B2 in rabbit aorta and platelets, respectively, was investigated.

Rabbit aortic rings were incubated with [14C]‐arachidonic acid ([14C]‐AA) and the incubation products were separated with thin layer chromatography (t.l.c). Alternatively, the aortic rings were incubated without substrate and their spontaneous formation of platelet anti‐aggregatory activity was measured. Rabbit platelet microsomes were incubated with [14C]‐AA and the products formed were separated with t.l.c.

Rings of aorta were found to be incapable of converting added [14C]‐AA to labelled 6‐keto‐PGF1α (the stable hydrolysis product of PGI2). Rings of aorta incubated in saline medium spontaneously formed PGI2‐like activity. This formation was dose‐dependently inhibited by nicotine, with an I50 of about 10−4 m.

Platelet microsomes converted [14C]‐AA to labelled TxB2. This formation was unaffected by nicotine.

It is concluded that a true difference in sensitivity to nicotine exists between cyclo‐oxygenase in rabbit aorta and platelets. The data also demonstrate a tissue difference between rabbit aorta and platelets concerning their utilization of exogenous AA as substrate in the formation of platelet active compounds.
Mammalian platelet adrenoceptors
Authors: Kerry R. , Scrutton M.C. , Wallis R.B.
Published: July 2012

Mammalian platelets vary widely in their responses to catecholamines in part because these agonists can act via excitatory α‐ and inhibitory β‐adrenoceptors. In the absence of antagonists, adrenaline enhances the response of rabbit platelets to an excitatory agonist, e.g. adenosine‐5′‐O‐(1‐thiodiphosphate) (ADP‐α‐s) acting at another receptor, but has no effect on the response of rat or guinea pig platelets to such an agonist. In the presence of a β‐adrenoceptor antagonist, adrenaline enhances the response of rat, but not guinea‐pig platelets to ADP‐α‐S and the extent of the enhanced effect on rabbit platelets is increased. In the presence of an α‐adrenoceptor antagonist, adrenaline inhibits the response of rabbit and rat platelets to ADP‐α‐S but has no such effect on the response of guinea‐pig platelets.

Studies using selective agonists and antagonists demonstrate that the excitatory response of rat platelets to adrenaline is mediated by an α2‐adrenoceptor, and the inhibitory response of rabbit platelets to adrenaline by a β2‐adrenoceptor as is the case in other species which have been examined.

The mean α2‐adrenoceptor density on human, rabbit, rat and guinea‐pig platelets as assessed using [3H]‐yohimbine as radioligand is obtained as 258, 270, 42 and < 10 receptors per platelet.

The mean β2‐adrenoceptor density on human, rabbit, rat and guinea‐pig platelets as assessed using (‐)‐[125I]‐iodocyanopindolol is obtained as 66, 14, 41 and < 5 receptors per platelet.

The nature of the effect of adrenaline on the response of mammalian platelets to other excitatory agonists, e.g. ADP‐α‐S, appears therefore to be largely determined by the absolute number of α2‐adrenoceptors and by the relative content of α2‐ and β2‐adrenoceptors on these cells for the species which have been examined in this analysis.
Capsaicin inhalation in man and the effects of sodium cromoglycate
Authors: Collier J.G. , Fuller R.W.
Published: July 2012

The inhalation of capsaicin for 1 min, delivered as an aerosol by nebulising solutions of capsaicin at concentrations of 2–65 μmol l−1, caused dose‐dependent coughing in normal volunteers and subjects with mild asthma. Capsaicin did not cause a feeling of breathlessness, and had no effect on forced expiratory volume in 1 s (FEV1) measured at the 1st, 5th and 9th min after the challenge was completed.

Coughing started within seconds of applying the face mask, continued throughout the minute of capsaicin inhalation, and stopped within seconds of the mask being removed. In any one subject the number of coughs was reproducible when repeated on the same day or after an interval of several days.

Experiments using local anaesthesia applied to the buccal mucosa or larynx indicated that the cough was caused by the stimulation of capsaicin‐sensitive nerve terminals situated in the larynx.

Cough response was not altered by the prior inhalation of sodium cromoglycate.
Forskolin, cyclic nucleotides and positive inotropism in isolated papillary muscles of the rabbit
Authors: Rodger I.W. , Shahid M.
Published: July 2012

The effects of forskolin, isoprenaline, sodium nitroprusside and the frequency of stimulation were examined on cyclic nucleotide levels and tension responses in rabbit isolated right ventricular papillary muscles.

Increasing the frequency of stimulation from 0.01 Hz to 1.6 Hz induced positive inotropic responses that were not obviously related to alterations in the level of either cyclic AMP or cyclic GMP.

Isoprenaline induced rapid, concentration‐related positive inotropic responses that were associated with increases in the levels of both cyclic AMP and cyclic GMP. There existed good correlations between the increases in tension and the concentrations of both cyclic nucleotides measured in the tissues.

Forskolin induced concentration‐related positive inotropic responses that were slow to develop. These responses were accompanied by concentration‐related increases in the levels of cyclic AMP but not cyclic GMP. The tension responses correlated well with the levels of cyclic AMP measured. The cyclic AMP levels produced by forskolin were some 8 fold higher than those induced by isoprenaline for similar increases in tension.

Sodium nitroprusside was without inotropic effect either positive or negative; it nevertheless elevated cyclic GMP levels whilst slightly reducing cyclic AMP levels.

These data show that the ratio of cyclic AMP to cyclic GMP does not correlate well with changes in mammalian cardiac contractility. The data further suggest that whilst the intracellular concentration of cyclic AMP in rabbit ventricular myocardium may be an important determinant of positive inotropism, the relationship between the two parameters is more complex than simple proportionality between the tension generated and the amount of cyclic AMP measured within the cells.
Excitant activity of methyl derivatives of quinolinic acid on rat cortical neurones
Authors: Stone Trevor W.
Published: July 2012

Various synthetic analogues of quinolinic acid have been tested for agonist and antagonist properties when applied by microiontophoresis to neurones in the rat cerebral cortex.

Quinolinic acid 2‐methylester was a weak antagonist of N‐methyl‐d‐aspartate (NMDA) and quinolinic acid, but also showed agonist activity, being about half as active as quinolinic acid. The excitant effects of the compound could be antagonized by the NMDA receptor blocker, 2‐amino‐7‐phosphonoheptanoic acid (2APH). N‐methyl‐quinolinic acid 2,3‐dimethylester showed very weak agonist and antagonist activity.

Homoquinolinic acid was a potent excitant of cortical neurones, being about five times more active than quinolinic acid and approximately equipotent with NMDA. The excitations were blocked by 2APH or its pentanoate analogue (2APV). Homoquinolinic acid 2‐methylester was also active as an agonist.

N‐methyl‐dl‐glutamic acid was also tested, since homoquinolinic acid is a rigid analogue of this compound. Although it did cause excitation of 5 of the 16 units tested, N‐methyl‐glutamate was a weaker agonist than NMDA or homoquinolinate.

Phthallic acid, ejected as an anion caused excitation of 14 out of 16 units. It is therefore concluded that the ring nitrogen of quinolinic acid is not essential for excitant activity.

Since homoquinolinic acid is a rigid analogue of glutamic acid, but causes excitation by acting apparently on the NMDA receptor, the results are consistent with the suggestion that activation of the NMDA receptor may require the carboxyl groups to be held in a relatively extended configuration.
The effects of 3,5,5‐trimethylcyclohexanol on hepatic cholesterol synthesis, bile flow and biliary lipid secretion in the rat
Authors: Bell G.D. , Clegg R.J. , Ellis W.R. , Middleton B. , White D.A.
Published: July 2012

The chemical trimethylcyclohexanol (TMC) is closely related to menthol, the major component of a terpene preparation with known choleretic and cholelitholytic activity. Its effects on hepatic cholesterol synthesis and bile secretion were examined in the rat.

In both acute and long‐term dosing experiments TMC significantly inhibited hepatic S‐3‐hydroxy‐3‐methylglutaryl coenzyme A (HMGCoA) reductase. TMC was a potent choleretic, with detectable effects on bile flow at low doses, which also reduced coupling of cholesterol secretion to bile salt secretion. Single large doses tended to lower biliary cholesterol output and caused significant reduction in cholesterol saturation index after biliary diversion for 1h.

TMC and its widely prescribed ester cyclandelate, which is rapidly degraded to TMC after ingestion, should be investigated further as potential cholelitholytic treatments in man.
The platelet‐independent release of thromboxane A2 by Paf‐acether from guinea‐pig lungs involves mechanisms distinct from those for leukotriene
Authors: Lefort J. , Rotilio D. , Vargaftig B.B.
Published: July 2012

Intra‐arterial injections of platelet‐activating factor (Paf‐acether, 10–300 ng) to the perfused guinea‐pig lung induced a dose‐related bronchoconstriction, followed by contraction of the rat aorta superfused with the lung effluent, indicating the release of thromboxane A2 (TXA2) activity. These effects were matched with injections of bradykinin (Bk) at 100–1000 ng, leukotriene C4 (LTC4) at 10–300 ng or arachidonic acid (AA) at 30–300 μg.

Repeated doses of Paf‐acether led to a specific desensitization of the release of TXA2, under conditions where Bk, LTC4 and arachidonic acid retained their ability to release TXA2.

Bronchoconstriction and the release of TXA2 induced by Paf‐acether were suppressed when the lungs were perfused with acetylsalicylic acid, but not with salicylic acid.

The phospholipase A2 inhibitor, p‐bromophenacyl bromide suppressed the release of TXA2 by Bk, but did not interfere with its formation from AA, nor with its release with Paf‐acether and LTC4. The lipoxygenase inhibitor, nordihydroguaiaretic acid, inhibited to a similar extent the release of TXA2 by Bk, LTC4 and Paf‐acether but also reduced directly the formation of TXA2 from arachidonic acid, invalidating its use as a specific antilipoxygenase agent.

The leukotriene C4/D4 antagonist, FPL 55712, suppressed the TXA2 releasing effects of LTC4, and was completely inactive against Paf‐acether, Bk or arachidonic acid.

The aerosol of Paf‐acether was tested in the anaesthetized guinea‐pig and resulted in bronchoconstriction, unaccompanied by thrombocytopenia. Unlike bronchoconstriction induced by intravenous Paf‐acether, which is refractory to cyclo‐oxygenase inhibitors, the effects of the aerosol were suppressed by aspirin. Platelet depletion, which blocks the intravenous effects of Paf‐acether, failed to interfere with those of the aerosol.

Paf‐acether induced a marked contraction of the superfused guinea‐pig isolated parenchyma lung strip, which was followed by total and irreversible desensitization to itself. The contractile effect was not inhibited by aspirin or indomethacin, atropine, mepyramine, methysergide, phenoxybenzamine or propranolol, indicating that cyclo‐oxygenase products, cholinergic stimuli, histamine, 5‐hydroxytryptamine and catecholamine mechanisms are not involved.

Our results indicate that Paf‐acether interacts with pulmonary sites distinct from those for Bk, LTC4 or AA, since no cross‐desensitization between Paf‐acether and the other agonists was noted, p‐bromophenacyl bromide inhibited Bk only and FPL 55712 inhibited only LTC4. The phospholipase A2 involved with the release of the arachidonate needed for the formation of TXA2 by Paf‐acether or LTC4‐stimulated lungs may differ from the enzyme accounting for its formation by Bk. The cellular sites with which Paf‐acether interacts may also be distinct and less readily accessible to p‐bromophenacyl bromide.
Role of calcium ions in kinin‐induced chloride secretion
Authors: Cuthbert A. W. , Halushka P.V. , Margolius H.S. , Spayne J. A.
Published: July 2012

Electrogenic ion transport across the epithelium lining the descending colon of male Sprague‐Dawley rats has been measured under short‐circuit conditions.

Responses to kallidin (lysylbradykinin) were inhibited by 70% if calcium was removed from the solution bathing the basolateral aspect of the tissue. Under identical conditions responses to prostaglandin E1 and dibutyryl cyclic adenosine monophosphate were not changed. Forskolin, which directly activates the catalytic subunit of adenylate cyclase, was inhibited by 35% by calcium removal, whereas responses to the phosphodiesterase inhibitor isobutylmethylxanthine were inhibited by 45 % by the same procedure.

In the absence of calcium, strontium could substitute in promoting the chloride secretory events triggered by kallidin. Magnesium ions antagonized the effects of the kinin in the presence of calcium ions in the bathing solution.

The effects of kallidin were partially antagonized by verapamil and trifluoperazine and were potentiated by isobutylmethylxanthine.

These results, together with earlier evidence, suggest that kinin elicits a chloride secretory response in this epithelium by stimulating the formation of prostaglandins which then activate adenylate cyclase. Extracellular calcium ions appear to have an important role in the proximal part of this cascade for prostaglandin generation. However, biochemical correlates of these biophysical responses presented in the following paper indicate a more complex role for calcium in the genesis of the kinin response.
The channel‐blocking action of methonium compounds on rat submandibular ganglion cells
Authors: Gurney A.M. , Rang H.P.
Published: July 2012

The effects of drugs of the polymethylene bis‐trimethylammonium (methonium) series on the characteristics of the synaptic currents (e.s.cs) recorded from voltage‐clamped rat submandibular ganglion cells have been studied. The drugs studied were from C4 to C10 (decamethonium).

All of the drugs except C4 shortened the initial decay phase of the e.s.c.; C9 and C10 produced an additional slowly decaying component. These effects were interpreted in terms of an open channel block mechanism, the calculated rate constants for association with the open channel at — 80 mV being fairly similar (5.9 × 106 to 18.1 × 106m−1 s−1) for all of the compounds except C4, which had no effect on the e.s.c. decay.

All of the compounds produced use‐dependent block when tested with short trains of stimuli at 10 Hz, or with trains of ionophoretic pulses of acetylcholine, consistent with their channel blocking property. Tubocurarine had a similar effect, but not trimetaphan or mecamylamine.

Recovery from use‐dependent block with short chain methonium compounds, up to C8, was very slow in the absence of agonist, being incomplete even after several minutes. With C9 or C10 or tubocurarine, recovery from use‐dependent block was complete within a few seconds. With C6 recovery in the absence of agonist was unaffected by membrane potential, but could be accelerated by applying acetylcholine with the cell depolarized to — 40 mV. This persistent block was ascribed to the ability of the blocking molecule to become trapped by closure of the channel. With C9 and C10 it is assumed that their presence inhibits channel closure, so they can escape without the help of agonist.

When use‐dependent block is avoided by leaving the ganglion unstimulated during equilibration with the blocking drug, the first e.s.c. elicited shows no appreciable reduction of amplitude, though with C6, C7 or C8 subsequent responses elicited at 0.1 Hz become progressively more blocked.

Even at 1 mm, C6 does not prevent acetylcholine from opening ionic channels.

It is concluded that all of the effects on e.s.c. amplitude can be interpreted in terms of channel block, there being no evidence of any receptor blocking action.
Classification of β‐adrenoceptors in human isolated bronchus
Authors: Goldie Roy G. , Paterson James W. , Spina Domenico , Wale Janet L.
Published: July 2012

(±)‐Isoprenaline (Iso), (−)−adrenaline (Ad), (−)−noradrenaline (NA), (±)‐phenylephrine (Phe) and the β2‐selective adrenoceptor agonist (±)‐fenoterol (Fen) caused a concentration‐dependent relaxation of human isolated bronchial preparations. Iso, Ad and NA caused complete relaxation of both spontaneous and carbachol‐induced bronchial tone. Fen, which was only tested in preparations where tone was induced with carbachol, also caused complete relaxation. However, Phe was a partial agonist in all preparations tested.

When relaxation responses to these amines were calculated as a % of their maximal effects, comparison of EC50 values showed that the order of potency was Iso > Ad = Fen > NA > Phe (92:27:25:1:0.2) in preparations with carbachol‐induced tone and Iso > Ad > NA > Phe (112:38:1:0.3) in preparations with spontaneous tone.

pA2 values determined for the β‐adrenoceptor antagonists propranolol (non‐selective), atenolol (β‐selective) and ICI‐118, 551 (β2‐selective), using Iso as an agonist were, 9.3, 5.3 and 9.1 respectively.

These results indicate that β2‐adrenoceptors mediate relaxation of human isolated bronchus to sympathomimetic amines in preparations obtained 4–14 h post‐mortem from non‐diseased lung. α‐Adrenoceptors were apparently sparse or absent in this tissue.
Modification by betamethasone of the effects of bronchodilator drugs on cholinergic bronchoconstriction in rats
Authors: Mattila M.J. , Salonen R.O.
Published: July 2012

Effects of betamethasone (BM), a long‐acting glucocorticoid, given alone and in combination with bronchodilator drugs, terbutaline (Ter), theophylline (Theo), or ipratropium bromide (Ipra), were studied on dose‐related methacholine (MeCh 2, 3, and 4.5 μg i.v.)‐induced bronchoconstriction in anaesthetized rats. BM (0.4 or 2 mg kg−1) was given intraperitoneally 24 h before the experiment followed by a similar dose intravenously, 12 min before MeCh challenge. The bronchodilator drugs were given i.v. as acute single doses.

BM 0.4 mg kg−1 counteracted significantly MeCh‐induced bronchoconstriction without modifying MeCh‐induced transient bradycardia and hypotension. BM 2 mg kg−1 failed to improve that response. A time interval of 24 h after pre treatment proved mandatory to produce these effects.

Combined treatment with BM 0.4 mg kg−1 + Ter 20 μg kg−1 antagonized the MeCh‐induced bronchoconstriction in an additive manner at 2 and 3 μg of MeCh, but a synergistic interaction was found at the largest MeCh dose. The effects of the other combinations (BM 0.4 mg kg−1 + Theo 20 mg kg−1 and BM 0.4 mg kg−1 + Ipra 0.5 μg kg−1) on airways failed to exceed the expected sum of the individual drugs.

The combination of BM + Ter was selective to the airways only, whereas BM + Theo also counteracted MeCh‐induced bradycardia and BM + Ipra counteracted both hypotension and bradycardia.

It is concluded that combined treatment with glucocorticoid and β2‐adrenoceptor agonist may result in a synergistic interaction on severe airway obstruction without significant influence on cardiovascular system.
The antidyskinetic action of dihomo‐γ‐linolenic acid in the rodent
Authors: Costall Brenda , Kelly M. Elizabeth , Naylor R.J.
Published: July 2012

The antidyskinetic action of dihomo‐γ‐linolenic acid (DHLA) was assessed against dyskinesias induced in the guinea‐pig by dopamine injected into the striatum (200 μg bilateral 2 h after nialamide, 75 mg kg−1, i.p.) and in the guinea‐pig and rat by 2‐di‐n‐propylamino‐5, 6‐dihydroxytetralin (tetraiin), 0.025 mg kg−1, s.c.

Dopamine and tetralin‐induced dyskinesias in the guinea‐pig were reduced or abolished by DHLA given i.p., 30−100 mg kg−1, given once daily for 5–10 days.

Tetralin‐induced dyskinesias were antagonized by DHLA given orally to the guinea‐pig (50−200 mg kg−1, 5 days) or in the diet to the rat (approximately 200 mg kg−1 daily for 10−14 days).

DHLA injected into the striatum (2.5−20 μg bilateral, 2–4 days) also antagonized tetralin‐induced dyskinesias in the rat.

The antidyskinetic action of DHLA given i.p. to the guinea‐pig could be antagonized by aspirin or eicosa‐5,8,11,14‐tetraynoic acid (100 mg kg−1 i.p. daily, starting 2 days before a 5 day treatment with DHLA). Aspirin (25−100 mg kg−1, i.p.) dose‐dependently antagonized the antidyskinetic activity of 5 and 20 μg DHLA given bilaterally into the striatum (2 days).

DHLA (100 mg kg−1 i.p.) given daily for 10 days or approximately 200 mg kg−1 DHLA (daily for 10–14 days given in the diet) administration to the rat failed to modify the stereotyped behaviour induced by apomorphine, 0.5 or 2 mg kg−1 s.c., to induce catalepsy, or to modify the cataleptic effects of haloperidol 0.25 or 1 mg kg−1 i.p.

It is suggested that the selective inhibition of dyskinesias in the rodent by DHLA may reflect a striatal effect with a dependency on conversion to prostaglandins.
The molal volumes of atropine and hyoscine in relation to their respective potencies
Authors: Cohen Sasson , Haberman Frank
Published: July 2012

The partial molal volumes, , at infinite dilution of atropine and hyoscine were determined in each of eight different solvents having cohesive energy densities in the range 64 to 144 cal cm−3.

for hyoscine in a given solvent was invariably and significantly smaller than that of atropine in the same solvent. The difference being 1.58 cm3 mol−1 in the least polar solvent (n‐propylbenzene) and 4.29 cm3 mol−1 in the most polar one (acetonitrile) in the series studied.

It is proposed that the lower affinity of atropine relative to that of hyoscine for the muscarinic cholinoceptor could be accounted for by the relative increase in enthalpy in the adsorption of atropine to the receptor with respect to the same process with hyoscine.
Presynaptic, muscarinic inhibition of non‐adrenergic, non‐cholinergic neuromuscular transmission in the chicken rectum
Authors: Komori S. , Ohashi H.
Published: July 2012

Cholinergic inhibition of the non‐adrenergic, non‐cholinergic (NANC) transmission was investigated in the chicken isolated rectum with Remak's nerve attached.

Stimulation of Remak's nerve (RT stimulation) at frequencies higher than 5 Hz elicited a late, slow contraction of the rectum in addition to an initial, fast NANC contraction. The late, slow contraction was blocked by atropine (0.25 μg ml−1), potentiated by physostigmine (50 ng ml−1) and accompanied by an overflow of acetylcholine into the vascular perfusate, indicating the existence of cholinergic innervation to the rectum via Remak's nerve.

RT stimulation (10 pulses at 0.5–1.0 Hz) elicited NANC‐mediated excitatory junction potentials (e.j.ps). The e.j.p. amplitude declined at the second stimulus and then increased to reach a plateau. Atropine, by abolishing this decrease in amplitude, increased the mean amplitude of the e.j.ps during trains of stimuli but atropine did not affect the amplitude of the first e.j.p. Physostigmine reduced the mean e.j.p. amplitude, and this action was readily antagonized by atropine.

A single intramural nerve stimulation delivered 2 s or less before RT stimulation with trains of stimuli, suppressed the amplitude of the first e.j.p. of the train. This effect was abolished by atropine.

Atropine in concentrations high enough to affect the e.j.p. amplitude had no effect on the resting membrane potential, the threshold for generating an action potential, or membrane resistance of the smooth muscle.

It is concluded that RT stimulation at low frequencies causes the release of acetylcholine simultaneously with the NANC transmitter. The released acetylcholine acts mainly on prejunctional muscarinic receptors and mediates an inhibitory effect on the release of the NANC transmitter.
Orthograde and retrograde axonal transport of calmodulin in a cat noradrenergic neurone
Authors: Ceña V. , Garcia A.G. , Gonzalez‐Garcia C. , Kirpekar S.M.
Published: July 2012

Subcellular distribution studies of calmodulin in cat sympathetic ganglia demonstrated that about 90% of the protein remained in the 27,000 g supernatant, suggesting that it is a cytosolic protein. Only 4.5% was recovered in the microsomal fraction pellet.

The inferior mesenteric ganglia contained 93.3 ± 3 ng calmodulin per ganglion, and segments of unligated cat hypogastric nerves had 6.53 ± 0.32 ng per 5 mm segment.

When the nerve was ligated in the middle and left in the cat for 1–6 days, substantial amounts of calmodulin accumulated in segments of nerve immediately proximal (P1) and distal (D1) to the ligature. The amounts found in P1 amounted to 15.3, 20, 30.4 and 39.4 ng calmodulin per 5 mm segment 1, 2, 3 and 6 days after ligation, respectively. The average rate of transport was 5.5 mm per day, which corresponds to a slow component b of axonal transport (SCb).

The accumulation of calmodulin in D1 was also increased with the time of ligation. After 1, 2, 3 and 6 days, the amounts of the protein found in D1 were 14.4,17.7,19 and 21 ng per 5 mm segment, respectively. The calculated mean rate for the retrograde transport was 3.9 mm per day.

Decentralization of the inferior mesenteric ganglia did not affect the rate of accumulation of calmodulin or the basal amounts found in ganglia and nerves. Local injection inhibited the orthograde, but not the retrograde axonal transport of the protein.

It is concluded that calmodulin undergoes a process of slow orthograde axonal transport probably incorporated into the axoplasmic matrix of a network of actin microfilaments. The protein is also transported in a retrograde manner.
The calcium dependency of mucus glycoconjugate secretion by canine tracheal explants
Authors: Barbieri Edward J. , Bobyock Emil , Chernick Warren S. , McMichael Robert F.
Published: July 2012

Canine tracheal explants, incubated overnight with [14C]‐glucosamine, elicited an enhanced secretion of ethanol‐precipitated 14C‐labelled glycoconjugate when challenged with methacholine, 10 μM.

Explants were rendered deficient in total calcium content and unresponsive to methacholine, 10 μM, by incubating them in calcium‐free medium for 18 to 22 h; however, the secretory response to the cholinergic agonist was restored with the addition of calcium to the medium.

A dose‐response relationship resulted when explants were challenged with methacholine in nutrient medium containing varied calcium concentrations (0.45 to 7.2 mM); alterations in the calcium concentration in the absence of methacholine had no significant effect on the basal secretion of 14C‐labelled glycoconjugate.

The calcium‐selective ionophore A23187, 10 μM, stimulated [14C]‐glycoconjugate secretion and induced the most significant effect in the presence of nutrient medium containing calcium.

Verapamil, 10 μM, a calcium‐entry blocker failed to inhibit basal or stimulated [14C]‐glycoconjugate secretion; however, the intracellular calcium antagonist TMB‐8, 10 to 100 μM, inhibited methacholine‐induced [14C]‐glycoconjugate secretion in a dose‐dependent manner.

These data suggest that respiratory mucus secretion is a calcium‐dependent process and that intracellular calcium is more vital than extracellular calcium in supporting this phenomenon.
Contractile effects of cysteamine on the guinea‐pig ileum
Authors: Bakich V. , Brown J. , Kwok Y.N. , McIntosh C. , Nishimura E.
Published: July 2012

Cysteamine (β‐mercaptoethylamine HCl) (1.0–40.0 mM) induced a concentration‐dependent increase in tonic and phasic contractions of segments of guinea‐pig ileum in vitro. Myenteric plexus‐longitudinal muscle (MPLM) preparations also responded with an increase in tonic contractions but phasic contractions were either greatly reduced or absent, indicating that these were a response of the circular muscle.

Atropine (5 μM) inhibited the cysteamine‐induced contractions, whereas hexamethonium and guanethidine had no effect, suggesting that cysteamine was acting at least partly via a cholinergic mechanism involving muscarinic receptors.

Tetrodotoxin increased the phasic contractions of ileal segments, but had no effect on the tonic component.

Treatment of MPLM preparations with morphine (1 μM) resulted in a small reduction in responsiveness to cysteamine, and blocked electrically‐induced contractions by at least 90%. Since morphine acts by inhibiting acetylcholine release via hyperpolarization of intrinsic neurones, a small but significant part of the cysteamine‐induced contractions probably resulted from stimulation of acetylcholine release from intrinsic neurones.

Following a response to high cysteamine concentrations (> 15 mM) tissues were refractory to subsequent cysteamine administration. Cross‐desensitization between cysteamine and acetylcholine also occurred, as short term (1–3 min) incubation of MPLM preparations with high concentrations of either compound (1–10 μM acetylcholine or 20 mM cysteamine) resulted in a reduced responsiveness to both.

A reduced sensitivity to acetylcholine or cysteamine was obtained following long‐term (45 min) incubation with acetylcholine (1 μM). Removal of Na+ from the incubation medium negated this effect. In contrast, the refractoriness to acetylcholine or cysteamine following long‐term (45 min) incubation with cysteamine (20 mM) was accentuated in low Na+ medium.

It is suggested that cysteamine induces a contraction of both the circular and longitudinal muscle of the guinea‐pig ileum by stimulating the release of acetylcholine from intrinsic neurones, by an action at the level of the smooth muscle muscarinic receptor, and possibly by a non‐cholinergic mechanism. However, the mechanisms by which acetylcholine and cysteamine induce tissue refractoriness probably differ.
α‐Adrenoceptor stimulated lymphocytes trigger the mechanical response of vas deferens: participation of arachidonic acid metabolites
Authors: Borda Enri S. , de Bracco Maria M. , Cangiani Silvia , Finiasz Marta , Sterin‐Borda Leonor
Published: July 2012

Normal human lymphocytes (L) (8 × 105 ml−1) incubated with methoxamine (Me) (1 × 10−7 M) (Me‐L) triggered the mchanical response of the isolated vas deferens of the rat. L or Me alone did not modify this contractile activity at the concentrations cited above.

Me alone (10−6 to 10−3 M) increased the tension of the vas. In the presence of L (8 × 105 ml−1) the dose‐response curve to Me shifted to the left and the efficacy of Me was enhanced.

Inhibitors of α1‐adrenoceptors completely blocked the reaction between Me and L while drugs that block α1 and α2‐adrenoceptors reduced the reaction between Me‐L and the vas deferens.

Direct contact of Me‐L with the assay organ was not necessary. Cell‐free supernatants of L exposed to Me (Me‐L supernatants) elicited the reaction in the same way as Me‐L. This effect required the continuous presence of Me since dialyzed Me‐L supernatants were inactive.

Inhibitors of lipoxygenase(s) completely blocked the positive inotropic effect of Me‐L or of Me‐L supernatants. Inhibitors of cyclo‐oxygenase potentiated this effect.

These results suggest that Me reacts with α1‐adrenoceptors of L. From this reaction, soluble factors are released that potentiate the α‐adrenoceptor stimulatory effect of Me on the vas deferens as a consequence of the release of oxidative products of the lipoxygenase/s pathway of arachidonic acid.
The effect of fasting on 5‐hydroxytryptamine metabolism in brain regions of the albino rat
Authors: Fuenmayor Luis D. , García Susana
Published: July 2012

The turnover of 5‐hydroxytryptamine (5‐HT) in the whole brain and different brain regions was studied in rats fasted for 24 h. These rats showed an increased tissue concentration of the amine in the whole brain and of its metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) in the whole brain, the striatum, the combined pons‐medulla and the cerebral cortex.

The accumulation of 5‐HIAA after probenecid was increased by fasting in the regions mentioned above except for the striatum. The effect of probenecid was also increased by fasting in the midbrain, the hypothalamus and the hippocampus.

In the striatum, the administration of probenecid produced a smaller increase in 5‐HIAA concentration in fasted than in fed rats.

The decay of 5‐HT following p‐chlorophenylalanine (PCPA) was increased in the hypothalamus of fasted rats at 16 h, but not at 4 h, after the intraperitoneal administration of the inhibitor. In the midbrain, the striatum and the combined pons‐medulla, food deprivation did not modify the decrease induced by PCPA. However, the inhibitor induced a reduction of food consumption in the fed group, which made this group rather similar to the fasted one and complicated the interpretation of the results in these last three cerebral areas.

Our results confirm that food deprivation increases the turnover of brain 5‐HT and point out that the increase probably occurs in all brain areas. This increased tunover appears to be accompanied, in the hypothalamus, by an increased neuronal release of the amine. In the striatum, fasting probably blocks the active transport system which removes acid metabolites from the brain.
Enhancement of tetrodotoxin‐induced axonal blockade by adenosine, adenosine analogues, dibutyryl cyclic AMP and methylxanthines in the frog sciatic nerve
Authors: Ribeiro J. A. , Sebastião A.M.
Published: July 2012

The effects of adenosine, adenosine analogues (N6‐cyclohexyladenosine (CHA), L‐N6‐phenylisopropyladenosine (L‐PIA), D‐N6‐phenylisopropyladenosine (D‐PIA), N6‐methyladenosine and 2‐chloroadenosine), adenine, inosine, hypoxanthine, cyclic AMP and its analogue the dibutyryl cyclic AMP (db cyclic AMP), and methylxanthines (theophylline, caffeine and isobutylmethylxanthine (Ibmx) on compound action potentials were investigated in de‐sheathed sciatic nerve preparations of the frog.

Adenosine and its analogues enhanced, in a concentration‐dependent manner, the inhibitory action of tetrodotoxin (TTX) on nerve conduction. The order of potencies was: CHA ⋝ D‐PIA ⋝ L‐PIA ≫ N6‐methyladenosine ⋝ 2‐chloroadenosine ≫ adenosine.

The adenosine metabolites, inosine and hypoxanthine, were inactive on TTX‐induced axonal blockade. Adenine enhanced the inhibitory action of TTX on nerve conduction, but was less effective than adenosine.

db Cyclic AMP, but not cyclic AMP, mimicked the inhibitory effect of adenosine on nerve conduction.

Methylxanthines did not antagonize the effect of adenosine on TTX‐induced axonal block and in high concentrations also mimicked the effect of adenosine on nerve conduction.

The possibility of adenosine acting on TTX‐induced axonal block through an adenosine receptor positively coupled to adenylate cyclase is discussed.
Effects of raubasine stereoisomers on pre‐ and postsynaptic α‐adrenoceptors in the rat vas deferens
Authors: Demichel Patricia , Roquebert Jacques
Published: July 2012

The actions of raubasine, tetrahydroalstonine and akuammigine were studied on pre‐ and postsynaptic α‐adrenoceptors of the rat vas deferens.

These three drugs competitively antagonized the effect of noradrenaline on postsynaptic α‐adrenoceptors, yielding pA2 values of 6.57, 4.56 and 4.68 respectively.

The presynaptic α‐adrenoceptor antagonist activity of the drugs was quantitatively determined by studying the effect of increasing concentrations on the clonidine dose‐response curve in the electrically stimulated vas deferens.

The inhibitory effect of clonidine could be competitively blocked by these three compounds and the pA2 values for raubasine, tetrahydroalstonine and akuammigine were 6.02, 7.71 and 5.64 respectively.

These results indicate that: akuammigine is a very weak antagonist at pre‐ and postsynaptic sites; raubasine acts preferentially at postsynaptic sites; tetrahydroalstonine is a highly selective presynaptic α‐adrenoceptor blocking agent. The ratio of the pre/postsynaptic potency declines in the order tetrahydroalstonine > akuammigine > raubasine.
Effects of serum albumin, indomethacin and histamine H1‐antagonists on Paf‐acether‐induced inflammatory responses in the skin of experimental animals and man
Authors: Archer C.B. , MacDonald D.M. , Morley J. , Page C.P. , Paul W. , Sanjar S.
Published: July 2012

Cutaneous responses to synthetic platelet activating factor (Paf‐acether) have been studied in guinea‐pig and human skin.

Intradermal injection of Paf‐acether elicited an acute inflammatory response in guinea‐pig skin (assessed by means of radioisotopic techniques) and acute oedema formation in human skin (assessed by means of weal volume and flare area).

Acute inflammatory responses in guinea‐pig and human skin are potentiated by the presence of serum albumin, a phospholipid carrier.

Acute inflammatory responses induced by Paf‐acether in guinea‐pig and human skin are not significantly affected by concomitant administration of the cyclo‐oxygenase inhibitor, indomethacin.

Acute inflammatory responses induced by Paf‐acether in guinea‐pig and human skin are slightly modified by the H1‐receptor antagonists, mepyramine and chlorpheniramine.

These results indicate that the acute inflammatory response induced by Paf‐acether is independent of cyclo‐oxygenase products of arachidonic acid and that histamine release has a minor contribution to the inflammatory response induced by Paf‐acether.
Inhibition of tolbutamide metabolism by substituted imidazole drugs in vivo: evidence for a structure‐activity relationship
Authors: Back D.J. , Tjia J.F.
Published: July 2012

Tolbutamide has been used as a model drug for an examination of the effects of eleven substituted imidazole compounds on hepatic metabolism in vivo.

The 1‐substituted compounds 1‐methylimidazole, miconazole, clotrimazole and ketoconazole produced marked alterations in tolbutamide kinetics (increased half‐life, decreased clearance). However, if there was substitution in the 2‐ position, irrespective of a substituent on N‐1, then the compound did not appear to inhibit metabolism (e.g. 2‐methylimidazole, 1,2‐dimethylimidazole, methimazole, metronidazole). The 4‐ substituted compounds, 4‐methylimidazole and cimetidine were inhibitors.

A structure‐activity relationship for the inhibitory actions of the substituted imidazoles is thus evident in vivo.
Ketamine‐inhibition of calcium‐induced contractions in depolarized rat uterus: a comparison with other calcium antagonists
Authors: Calixto João B. , Loch Sirley
Published: July 2012

The inhibitory effect of the intravenous anaesthetic ketamine on CaCl2‐induced contractions in the isolated K+‐depolarized uterus of the rat in Ca2+‐free medium was compared with that produced by papaverine, theophylline and the calcium entry blocker verapamil.

Pre‐incubation for 20 min with either ketamine (0.3 to 3 mM), papaverine (3 to 30 μM), theophylline (0.1 to 1 mM) or verapamil (3 to 30 nM) induced parallel, concentration‐dependent rightward displacements of the dose‐response curves to Ca2+ (0.04 to 22 mM). The antagonism was competitive, except that due to verapamil, the Schild plot for which yielded a slope which differed significantly from unity. The calculated pA2 values (± s.e.mean) were: ketamine 3.90 ± 0.07; papaverine 5.55 ± 0.05; theophylline 3.99 ± 0.1 and verapamil 9.54 ± 0.24

These drugs differed in their ability to relax the sustained contraction induced by Ca2+ (1 mM) in K+‐depolarizing solution. Ketamine and verapamil relaxed the preparation in a concentration‐dependent manner whereas theophylline and especially papaverine were less potent and induced only partial maximal relaxation. The t1/2 of the relaxant effect was significantly less for ketamine than for verapamil (5 and 22 min, respectively). Only ketamine produced a relaxation comparable to that obtained by washing the preparation with Ca2+‐free solution (t1/2 = approx. 5 min).

Prior exposure of the depolarized uterine strip to a low concentration of Ca2+ (0.22 mM) increased the potency of ketamine, but decreased that of papaverine and theophylline, in antagonizing Ca2+‐induced contractions. In contrast, this procedure did not affect the potency of verapamil.

The inhibitory effects of these drugs, excluding those of verapamil, were completely reversed after washing the preparations with a high‐potassium Ca2+‐free solution, 3–5 times for about 30–60 min.

These experiments provide further evidence that the relaxant effect produced by ketamine on the rat isolated uterus is due to its ability to antagonize Ca2+ movements competitively and also show that there are marked differences between the nature of the relaxant effects of ketamine and those of papaverine, theophylline and verapamil.
Pharmacological characterization of the histamine receptor in the isolated muscularis mucosae of the guinea‐pig oesophagus
Authors: Fujinuma Sachie , Kamikawa Yuichiro , Shimo Yasuo
Published: July 2012

To characterize the histamine receptors in the muscularis mucosae, the isotonic responsiveness of the isolated muscularis mucosae of the guinea‐pig oesophagus to histamine receptor agonists and antagonists was examined in vitro.

Histamine (0.1–100 μM) produced a concentration‐dependent contraction of the muscularis mucosae (EC50 = 1.6 ± 0.2 μM). The contractions were rapid in onset, sustained, reversible by washing and the preparation did not show tachyphylaxis.

2‐Methylhistamine (2‐MH), 2‐pyridylethylamine (PEA) and 4‐methylhistamine (4‐MH) produced similar sustained contractions of the muscularis mucosae. The order of sensitivity was histamine > 2‐MH > PEA > 4‐MH. Impromidine (10–300 μM) and dimaprit (10–300 μM) caused no response in this tissue.

The contractile responses to histamine, 2‐MH, and PEA were competitively antagonized by diphenhydramine, and the pA2 values were almost the same (approximately 8.1). Cimetidine (100 μM) could not modify the contractile response to these agonists.

The contractile response to histamine was slightly inhibited by tetrodotoxin (0.3 μM), atropine (1 μM), indomethacin (0.1–3 μM) or aspirin (30–300 μM), and the EC50 value was increased about 2–6 times by these drugs.

When the preparation was incubated in Tyrode solution containing various calcium concentrations (0, 0.45, 0.9 and 1.8 mM), the concentration‐response curve to histamine was shifted to the right and downward; the effect was inversely dependent on the calcium concentration, and in a calcium‐free medium the response to histamine was abolished. Verapamil (1–10 μM) partially inhibited the contractile response to histamine.

The present results indicate that the contraction of the guinea‐pig oesophageal muscularis mucosae to histamine is mediated mainly by a direct action on the smooth muscle and partly by indirect actions via the stimulation of either endogenous prostaglandin biosynthesis or intramural cholinergic nerves. The histamine receptors responsible for contractions of this tissue are probably mainly of the H1‐subtype with H2‐receptors having a negligible role.
Modulation by endothelium of contractile responses in rat aorta in absence and presence of flunarizine
Authors: Miller R.C. , Stoclet J.‐C.
Published: July 2012

The possible modulation by endothelium of phenylephreine‐ and prostaglandin F2α‐induced mobilization of calcium for contraction in the rat aorta has been investigated. Contractions elicited by these and other agonists are inhibited in the presence of endothelium.

For any single concentration of phenylephrine in the presence of endothelium, the initial phasic components of contractions were significantly greater, the maximal contractions were achieved sooner and were less well maintained as compared to contractions elicited in the absence of endothelium.

The kinetic characteristics of contractions stimulated by single concentrations of PGF2α were similar in the presence and absence of endothelium and did not exhibit initial phasic components of contraction.

Sub‐maximal contractions elicited by both PGF2α and phenylephrine in the absence of endothelium were inhibited to a greater extent by flunarizine 3 μM than equieffective contractions elicited in the presence of endothelium.

Maximal contractions elicited by phenylephrine (1 μM) were inhibited to a similar extent by flunarizine in the presence and absence of endothelium, but maximal contractions elicited by PGF2α (30 μM) were inhibited by flunarizine to a greater extent in the presence than in the absence of endothelium.

It is concluded that an endothelium‐derived factor, perhaps distinct from endothelium‐derived relaxing factor, can modulate the ability of both phenylephrine and PGF2α to mobilize calcium for contraction. This modulatory effect is associated with an enhanced mobilization of intracellular calcium. Thus, submaximal concentrations of both agonists were less dependent on extracellular calcium than on intracellular calcium to elicit contractions in the presence of endothelium, as compared to contractions elicited in the absence of endothelium.
Potentiation by cholinoceptor agonists of contractions to field stimulation of rat vas deferens
Authors: Lee Chi‐Ming
Published: July 2012

Cholinoceptor agonists (arecoline > carbachol > acetylcholine > pilocarpine) potentiated contractions to field stimulation of rat vas deferens via the activation of an atropine‐sensitive muscarinic receptor.

The potentiating effect of carbachol was dependent on the level of calcium in the medium, being more potent at higher calcium concentrations.

The potentiating effect of carbachol was more pronounced in the epididymal than in the prostatic segment but was not attenuated by prazosin, an α1‐adrenoceptor antagonist.

Carbachol did not significantly modify the direct contractile effects of noradrenaline nor alter the field‐stimulation‐evoked release of noradrenaline from the epididymal vas deferens.

It is concluded that the potentiating effect of cholinoceptor agonists on the contractions to field stimulation in the rat vas deferens was not a result of an enhancement of adrenergic neurotransmission.