bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of angiotensin II upon electrogenic ion transport in rat intestinal epithelia
Authors: Cox H.M. , Cuthbert A.W. , Munday K.A.
Published: July 2012

Epithelial sheets from rat jejunum and descending colon have been shown to respond to angiotensin II (AII) when studied under short‐circuit conditions and bathed on both sides with Krebs‐Henseleit solution.

The octapeptide AII elicited increases in short‐circuit current (SCC) in preparations of jejunum and decreases in SCC in the descending colon; both responses occurred when the peptide was applied to the basolateral surface, but not when applied to the apical solution.

Responses in both tissues were highly specific, being inhibited by a range of AII antagonists with the following order of potency: [Sar1. Thr8]‐AIi>[Sar1. Leu8]‐AIi>[Sar1. Ile8]‐AIi>[Sar1. Ala8]‐AIi>[Des, Asp1. Ile8]‐AII in rat jejunum. AII responses were not affected by α‐or β‐adrenoceptor antagonists, atropine or tetrodotoxin.

AII responses were totally inhibited by the chloride channel blocker, diphenylamine‐2‐carboxylate (DPC) while cotransport inhibitors e.g. piretanide and frusemide significantly reduced the size of AII responses in colon and jejunum. These patterns of activity suggest that in the jejunum the responses result from electrogenic chloride secretion. Although AII responses in colon were sensitive to DPC the transporting ions have not yet been identified.

Both piroxicam and indomethacin inhibited the increase in SCC elicited by AII in the jejunum, and the reduction in SCC caused by AII in the colon. Taken together these results indicate that eicosanoids are involved in AII responses in both tissues.

This is the first study to demonstrate a direct, electrogenic effect for AII on transporting epithelia from the gastrointestinal tract. The responses are most probably initiated by AII interacting with previously identified specific AII receptors within the epithelial membranes.
The adenosine receptor‐mediated inhibition of noradrenaline release possibly involves a N‐protein and is increased by α2‐autoreceptor blockade
Authors: Allgaier Clemens , Hertting Georg , Kügelgen Oda V.
Published: July 2012

The stimulation‐evoked overflow of [3H]‐noradrenaline from slices of the rabbit hippocampus is inhibited by α2‐autoreceptors as well as by adenosine (A1)‐receptors. Slices of rabbit hippocampus were labelled with [3H]‐noradrenaline, superfused continuously and stimulated twice electrically (rectangular pulses; 2 ms, 3 Hz, 24 mA, 5 V cm−1).

Treatment of hippocampal slices with N‐ethylmaleimide (NEM, 30 μm; 30 min), which functionally disturbs certain N‐proteins, decreased the inhibitory action of adenosine receptor agonists like (‐)‐N6‐(R‐phenylisopropyl)‐adenosine ((‐)‐PIA) and adenosine on noradrenaline release. Release inhibition caused by (‐)‐PIA (0.03‐1 μm) was antagonized by NEM in a non‐competitive manner in the absence and in the presence of the α2‐adrenoceptor antagonist yohimbine.

The adenosine receptor antagonist 8‐phenyltheophylline significantly increased the evoked noradrenaline release by about 15% in control slices by diminishing the inhibitory action of endogenous adenosine. In NEM‐treated slices this effect of 8‐phenytheophylline was not seen. In the presence of (‐)‐PIA (0.1 μm), i.e. under conditions of an increased inhibitory tone, release facilitation by 8‐phenyltheophylline was decreased by NEM compared to that in the respective controls.

Occupation of the A1‐receptor with (‐)‐PIA prior to and during the NEM treatment did not protect the A1‐receptor‐coupled signal transduction system from being affected by NEM.

In the presence of the α2‐adrenoceptor antagonist yohimbine, the inhibitory action of (‐)‐PIA was strongly increased.

The above results suggest the involvement of a regulatory N‐protein in the A1‐receptor‐mediated inhibition of noradrenaline release and an interaction between the α2‐autoreceptor and the A1‐receptor‐coupled signal transduction system, possibly at the level of a N‐protein.
Inhibition of the sodium pump by cardioactive DPI 201‐106
Authors: Kaumann Alberto J. , Richards Donald E. , Russell Deborah A.
Published: July 2012

The effects of DPI 201‐106 were examined on contractions of papillary muscles from the right ventricle of feline heart, on [3H]‐ouabain binding and Na+, K+‐ATPase activity in feline ventricular membrane particles and on ouabain‐sensitive 86Rb uptake in human erythrocytes. DPI 201‐106 partially inhibited the Na+ pump at concentrations that caused pronounced positive inotropic effects.
The obligatory role of calcium in the development of antigen‐induced airway hyperreactivity to cold provocation in the rat isolated trachea
Authors: Chand N. , Diamantis W. , Sofia R.D.
Published: July 2012

The effect of antigen challenge on cold provocation (30‐10°C) in isolated tracheal segments from control (normal) and ovalbumin‐sensitized rats was studied.

Sensitization alone or acute cold provocation (10°C) alone was not sufficient to cause contraction of tracheal smooth muscle preparation.

Following recovery from antigen‐induced responses (Schultz‐Dale phenomenon) in sensitized rat segments, cold provocation induced strong contractile responses.

Both the antigen‐induced contractions and the subsequent development of airway hyperreactivity to cold were dependent on extracellular Ca2+ and inhibited by verapamil.

The data in this study indicate that extracellular Ca2+ plays an obligatory role in the mediation of antigen‐induced contractile responses as well as the subsequent development of hyperreactivity to cold provocation in rat tracheal smooth muscle.
Calcitonin gene‐related peptide is localised to human airway nerves and potently constricts human airway smooth muscle
Authors: Palmer James B.D. , Cuss Francis M.C. , Mulderry Peter K. , Ghatei Mohamed A. , Springall David R. , Cadieux Alain , Bloom Stephen R. , Polak Julia M. , Barnes Peter J.
Published: July 2012

In human airways synthetic human sequence calcitonin gene‐related peptide (hCGRP), a novel peptide produced by alternative processing of mRNA from the calcitonin gene, caused concentration‐dependent contraction of human bronchi (EC50 4.9 × 10−9 m) and was significantly more potent than substance P or carbachol.

The contractile response was unaffected by atropine (2 × 10−6 m), propranolol (10−6 m), indomethacin (10−5 m), tetrodotoxin (3 × 10−6 m), chlorpheniramine (10−4 m), cimetidine (10−5 m), or FPL55712 (10−4 m) suggesting a direct effect of CGRP on airways smooth muscle.

CGRP was detected in human airways by radioimmunoassay with highest concentrations in cartilaginous airways.

CGRP was localised by immunocytochemistry to both nerves and ganglia in human airways.

CGRP, is a potent constrictor of human airways and may have important effects on airway function and be implicated in the pathogenesis of bronchial hyper‐responsiveness and asthma.
Absence of effect of calcium antagonists on endothelium‐dependent relaxation in rabbit aorta
Authors: Jayakody R.L. , Kappagoda C.T. , Senaratne M.P.J. , Sreeharan N.
Published: July 2012

The effect of chronic feeding of New Zealand White rabbits with nicardipine (60 mg kg−1 daily for 5 weeks) on the endothelium‐dependent relaxation (EDR) to acetylcholine (ACh) was examined in vitro. The effect of acute exposure to nicardipine and diltiazem (10 μmol l−1) in the tissue bath was also examined.

A bioassay system for endothelium‐dependent relaxation factor (EDRF) in which a rabbit aortic ring with endothelium removed was used as recipient and a segment of rabbit aorta with endothelium as donor (producing EDRF in response to ACh) was developed. This system enabled the effect of nicardipine on the synthesis/release and on the relaxation to EDRF to be studied separately.

The maximum relaxations to ACh in control and nicardipine‐fed animals were 43.6 ± 5.5 and 53.8 ± 6.7% (mean ± s.e.mean) of the contractile response to noradrenaline (NA, 1 μmol l−1) (n = 6, P > 0.05). Similarly the EDR to ACh was not significantly altered by acute exposure (30 min) to nicardipine or diltiazem. The maximum relaxations without and with nicardipine were 32.4 ± 4.2% and 28.0 ± 3.1% of the contraction to NA (1 μmol l−1) (n = 11, P > 0.05). The corresponding data for diltiazem were 42.1 ± 5.7 and 36.4 ± 7.3% respectively (n = 11, P > 0.05).

Both calcium antagonists inhibited the contraction induced by potassium (100 mmol l−1). Nicardipine and diltiazem in concentrations of 100 μmol l−1 reduced the potassium‐induced contraction to 33.0 ± 9.0% and 53.8 ± 6.7% of control respectively (n = 6, P < 0.05).

In the bioassay experiments the infusion of nicardipine on (a) the recipient tissue only and (b) the donor and the recipient tissue had no significant effect on the relaxant response observed in the recipient tissue when superfused with Krebs‐bicarbonate buffer containing ACh via the donor tissue (n = 6, P > 0.05).

These results indicate that nicardipine and diltiazem had no significant effect on synthesis/release and the relaxant response to EDRF in the rabbit aorta. Thus the translocation of Ca2+ accompanying the EDR to ACh in the rabbit aorta is likely to utilize Ca2+ channels not blocked by these calcium antagonists.
The involvement of platelet activating factor in endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig
Authors: Beijer L. , Botting J. , Crook P. , Oyekan A.O. , Page C.P. , Rylander R.
Published: July 2012

Exposure of conscious guinea‐pigs to an aerosol of endotoxin (25–100 μg ml−1) resulted in a dose‐related, progressive accumulation of platelets in the thoracic region. Accumulation of 111indium oxine labelled erythrocytes was not observed following exposure to an aerosol of endotoxin (50 μg ml−1).

Pretreatment of guinea‐pigs with the selective platelet activating factor (Paf)‐antagonists. CV‐3988 or brotizolam resulted in a dose‐related inhibition of endotoxin‐induced pulmonary platelet recruitment. Pretreatment of guinea‐pigs with the selective Paf‐antagonist BN 52021 resulted in significant inhibition of endotoxin‐induced pulmonary platelet recruitment, although the effects of BN 52021 were not dose‐related.

Pretreatment of guinea‐pigs with indomethacin at doses known to inhibit cyclo‐oxygenase did not inhibit endotoxin‐induced pulmonary platelet recruitment, whereas higher doses of indomethacin produced a reduction in platelet recruitment in the lung.

Pretreatment of guinea‐pigs with the anticoagulant heparin and the prostacyclin analogue ZK 36374 inhibited endotoxin‐induced platelet recruitment.

These observations suggest that endotoxin‐induced pulmonary platelet recruitment in the guinea‐pig is secondary to the release of platelet activating factor, but not to cyclo‐oxygenase products of arachidonic acid and may also involve activation of the coagulation cascade.
Decreased responsiveness of the aortae of hypertensive rats to acetylcholine, histamine and noradrenaline
Authors: Sim M.K. , Singh M.
Published: July 2012

The responses to noradrenaline (NA) of the aortae of various hypertensive rats, namely the spontaneously hypertensive rat (SHR), the low blood pressure SHR (LBP‐SHR), and the left renal artery stenosed LBP‐SHR (LRAS‐LBR‐SHR), were compared to those of the normotensive Wistar‐Kyoto rats (WKY).

The aortae of the hypertensive rats were significantly more responsive (P <0.05) to 10−8 m NA. However, the reverse was true for higher doses of NA. The ED50 values for the aortae of WKY, LBP‐SHR, SHR and LRAS‐LBP‐SHR were 20, 8.5, 7.8 and 8 nM respectively.

The NA‐contracted aortae of the LRAS‐LBP‐SHR were significantly less responsive (P < 0.05) to the relaxant action of histamine and acetylcholine (ACh) compared to those of the WKY. This observation was not made in the aortae of the LBP‐SHR. The maximal relaxation (% of the maximal contraction induced by 10−8 m NA) observed in the aortae of WKY, LBP‐SHR and LRAS‐LBP‐SHR were, respectively, 72 ± 2, 66 ± 6, 39 ± 7 for ACh and 50 ± 3, 36 ± 4, 27 ± 3 for histamine.

In aortae where the endothelium had been removed by collagenase treatment, histamine induced a dose‐related contraction. The rank order of this dose‐related contraction was WKY > LBP‐SHR > SHR> LRAS‐LBP‐SHR with the corresponding maximal tension (g) 0.89 ± 0.04, 0.59 ± 0.04, 0.36 ± 0.04, 0.19 ± 0.05.

The results suggested that elevation of blood pressure above the normal (due either to intrinsic or extrinsic factors), as seen in SHR and LRAS‐LBP‐SHR, results in a decreased response of the aortae to ACh and histamine. This effect was seen in both the endothelium mediated relaxation and the non‐endothelium mediated contraction.
Influence of 5‐hydroxytryptamine uptake on the apparent 5‐hydroxytryptamine antagonist potency of metoclopramide in the rat isolated superior cervical ganglion
Authors: Ireland S.J. , Straughan D.W. , Tyers M.B.
Published: July 2012

Metoclopramide, 1 × 10−6−1 × 10−4 m, was found to behave as a reversible, competitive antagonist of 5‐hydroxytryptamine (5‐HT)‐induced depolarization of the rat isolated vagus nerve (VN) and superior cervical ganglion (SCG). The pKB values were 6.60 (± 0.04) and 5.74 (± 0.07), respectively. The possibility that this apparent difference in potency was due to saturable 5‐HT uptake was investigated.

The SCG, but not the VN, accumulated tritium‐labelled 5‐HT via a saturable, sodium‐ and temperature‐dependent mechanism. Ganglionic 5‐HT uptake was blocked by desmethylimipramine (IC50 1.4 × 10−6 m), chlorimipramine (8.7 × 10−9 m), zimelidine (1.5 × 10−7 m), paroxetine (4.3 × 10−8 m) and citalopram (6.2 × 10−8 m).

The 5‐HT uptake inhibitor paroxetine, 1 × 10−6 m, did not modify the apparent 5‐HT antagonist potency of metoclopramide on the VN, but raised the pKB obtained against 5‐HT on the SCG from 5.74 (± 0.07) to 6.25 (± 0.03).

It is suggested that the observed difference in the potency of metoclopramide as a 5‐HT antagonist on the rat VN and SCG was due to saturable 5‐HT uptake in the latter preparation. The results do not support a difference in the 5‐HT receptors mediating depolarization on the VN and SCG.
Pharmacological characterization of 5‐hydroxytryptamine‐induced depolarization of the rat isolated vagus nerve
Authors: Ireland S.J. , Tyers M.B.
Published: July 2012

A study has been made of the pharmacology of the 5‐hydroxytryptamine (5‐HT)‐induced depolarization responses that can be recorded extracellularly from the rat isolated cervical vagus nerve.

Phenylbiguanide (PBG) and 2‐methyl‐5‐hydroxytryptamine (2‐methyl‐5‐HT) were found to mimic the effects of 5‐HT on the vagus nerve. Their EC50 values were respectively 2.0 fold and 3.9 fold greater than that of 5‐HT.

Metoclopramide behaved as a reversible competitive antagonist of depolarization induced by PBG and 2‐methyl‐5‐HT, with pKB values of 6.48 ± 0.04 and 6.64 ± 0.04, respectively. These agreed well with the pKB value of 6.60 ± 0.04 obtained previously for metoclopramide against 5‐HT on the rat vagus nerve. 5‐HT, PBG and 2‐methyl‐5‐HT had no demonstrable agonist effects at non‐5‐HT receptors on the rat vagus nerve.

Tropacaine and m‐chlorophenylpiperazine were found to behave as reversible competitive antagonists of 5‐HT‐induced depolarization of the vagus nerve. The pKB values were 6.29 ± 0.03 and 6.90 ± 0.03, respectively.

Quipazine, MDL 72222 and ICS 205–930 were also shown to be effective antagonists of 5‐HT on the vagus nerve. However, although these compounds were highly potent, they all caused a marked concentration‐dependent reduction in the amplitude of the maximum response to 5‐HT. This behaviour was not consistent with a simple reversible competitive mechanism.

The results are discussed with reference to the current classification of mammalian peripheral neuronal 5‐HT receptors.
Effects of morphine on catecholamine release and arrhythmias evoked by myocardial ischaemia in rats
Authors: Addicks Klaus , Hirche Hansjürgen , McDonald Fiona M. , Polwin Wolfgang
Published: July 2012

The effects of morphine (10 mg kg01 i.p.) on haemodynamics, arrhythmias and plasma and myocardial catecholamines (CA) were studied after coronary artery occlusion in anaesthetized rats. Myocardial intraneuronal CA were assessed histofluorimetrically and CA concentrations measured by high performance liquid chromatography.

Morphine increased blood pressure, presumably due to higher plasma noradrenaline (NA) concentrations found in morphine‐treated rats.

Morphine increased the area of catecholamine‐containing fluorescing neurones in the myocardium (as a percentage of total field area) 60 min after sham‐operation (0.87 ± 0.07%) or occlusion (0.57 ± 0.05%) compared to untreated animals (0.67 ± 0.06 and 0.38 ± 0.03% respectively). Tissue NA content was not significantly affected by coronary occlusion and/or morphine within the first 60 min.

Morphine had no effect on ischaemia‐induced arrhythmias.

Whether the higher intraneuronal NA content following morphine resulted from reduced central sympathetic outflow to the heart, presynaptic inhibition of NA release, or increased uptake due to higher plasma concentrations is unclear. Ischaemia‐induced local NA release appears independent of these mechanisms, as it was unaffected by morphine.
(5Z)‐carbacyclin discriminates between prostacyclin‐receptors coupled to adenylate cyclase in vascular smooth muscle and platelets
Authors: Corsini A. , Folco G.C. , Fumagalli R. , Nicosia S. , Noe M.A. , Oliva D.
Published: July 2012

(5E)‐ and (5Z)‐carbacyclin are prostacyclin (PGI2) analogues endowed with antiaggregating and vasodilator properties, which stimulate adenylate cyclase activity in membranes from human platelets and cultured myocytes from rabbit mesenteric artery.

In platelets they display the same efficacy as prostaglandin E1 (PGE1), and hence PGI2, both as activators of adenylate cyclase and as inhibitors of aggregation.

In contrast, in vascular smooth muscle cells (5Z)‐carbacyclin fails to produce the same degree of stimulation of the enzyme as PGI2, (5E)‐carbacyclin and PGE, nor does it induce the maximal relaxation of the mesenteric artery as do the other prostaglandins.

(5Z)‐carbacyclin is also able to antagonize the activation of adenylate cyclase and the relaxation elicited by PGE1 or PGI2 in the mesenteric artery, and therefore it displays partial agonist properties in these cells.

We conclude that the receptors for PGI2 coupled to adenylate cyclase in platelets and vascular smooth muscle cells are different from each other, because (5Z)‐carbacyclin can discriminate between them, being a partial agonist at myocyte but not at platelet level.
Control of alveolar surfactant in rats at rest and during prolonged hyperpnoea: pharmacological evidence for two tissue pools of surfactant
Authors: Barr Heather A. , Nicholas Terence E. , Power John H.T.
Published: July 2012

Propranolol, atropine and indomethacin (i.p.) affect neither the amount (PLalv), nor the specific activity (PLalvsp.act.) of alveolar surfactant‐type phospholipids lavaged from the lungs of unanaesthetized rats, either at rest or made hyperpnoeic for 24 h with 5%CO2/13%O2/82%N2.

Whereas salbutamol (280 μg kg−1 body weight, i.p.) consistently increased PLalv and PLalvsp.act., pilocarpine (1.5, 3, 10 and 50 mg kg−1, i.p.) and labetalol (1 and 5 mg kg−1, i.p.) had no effect. The dose of pilocarpine reported by others to release surfactant (150 mg kg−1) induced marked salivation, diarrhoea, chromodacryorrhoea and a three‐fold increase in tidal volume.

In the isolated perfused lung of the rat, salbutamol (1.5 μm) consistently increased PLalvsp.act, whereas pilocarpine (0.1 and 1 μM) had no effect on these variables.

In the isolated perfused lung, the maximum amount of surfactant that could be released by salbutamol (0.5 mM) was smaller than that which could be released in response to an increase in tidal volume (peak inflation pressure 28 cmH2O).

When the concentration of salbutamol in the isolated perfused lung was adjusted to produce the same increase in PLalv as did a single simulated deep breath, the PLalvsp.act was significantly increased by salbutamol, but not by the simulated deep breath.

We conclude, that neither the autonomic nervous system nor the prostaglandin system is essential for the release of surfactant at rest or during hyperpnoea. Furthermore, we suggest that two pools of surfactant, with different release mechanisms, exist in lung tissue.
Studies on the anti‐vasoconstrictor activity of BRL 34915 in spontaneously hypertensive rats; a comparison with nifedipine
Authors: Buckingham Robin E.
Published: July 2012

The blood pressure lowering and anti‐vasoconstrictor effects of BRL 34915 and nifedipine were compared in female spontaneously hypertensive rats (SHR).

In conscious SHR, intravenous injection of BRL 34915 (0.1, 0.3 mg kg−1) produced rapid, dose‐related falls in mean arterial pressure of greater than 3 h duration. Nifedipine, at the same intravenous dose levels, also evoked rapid anti‐hypertensive effects, though these responses were of lesser magnitude and duration than those observed for BRL 34915.

In anaesthetized, ganglion‐blocked SHR, BRL 34915 (0.1, 0.3 mg kg−1 i.v.) dose‐dependently antagonized the pressor responses to incremental intravenous influsions of noradrenaline (3.8–28.5 ng min−1) or phenylephrine (120–907 ng min−1) but did not inhibit pressor responses to incremental infusions of methoxamine (0.47‐3.63 μh min−1), angiotensin II (7.0–52.9 ng min−1) or vasopressin (0.27‐2.0 mu min−1).

In anaesthetized, ganglion‐blocked SHR, nifedipine (0.1, 0.3 mg kg−1 i.v.) antagonized the pressor responses to each of the infused vasoconstrictor agents, being most effective against responses to noradrenaline or angiotensin II.

In pithed SHR, both BRL 34915 and nifedipine (each at 0.3 mg kg−1 i.v.) reduced the basal blood pressure level and produced marked inhibition of frequency‐dependent pressor responses evoked by electrical stimulation of the spinal cord sympathetic outflow (0.25‐4.0 Hz). Restoration of the basal diastolic blood pressure to within the control range, using a continuous intravenous infusion of vasopressin (0.98 mu min−1), prevented the inhibitory effect of BRL 34915. In the case of nifedipine, however, even raising the basal blood pressure to a level exceeding that recorded in control rats (with vasopressin, 2.0 mu min−1), did not reverse the inhibitory effect of the drug on frequency‐dependent pressor responses.

It is concluded that the anti‐hypertensive properties of BRL 34915 in SHR are probably unrelated to an anti‐vasoconstrictor action. In contrast, it is suggested that the broadly‐based anti‐vasoconstrictor properties of nifedipine may contribute substantially to the anti‐hypertensive properties of this drug.
A study of the action of amlodipine on adrenergically regulated sodium handling by the kidney in normotensive and hypertensive rats
Authors: Johns Edward J.
Published: July 2012

An investigation was undertaken to examine the effect of calcium channel blockade, induced by amlodipine, on the ability of the renal sympathetic nerves to cause an antidiuresis and anti‐natriuresis in normotensive Sprague Dawley and spontaneously hypertensive rats anaesthetized with pentobarbitone.

Low frequency renal nerve stimulation in normotensive rats, which did not change renal blood flow, caused a 15% reduction in glomerular filtration rate and was associated with falls in urine flow of 37%, absolute sodium excretion of 47%, and fractional sodium excretion of 38%. The magnitude of these renal excretory changes was unaffected by prior administration of amlodipine at either 200 μg kg−1 plus 50 μg kg−1 h−1 or 400 μg kg−1 plus 100 μg kg−1 h−1. Amlodipine given in the higher dose, decreased basal levels of blood pressure and increased basal urine flow and sodium excretion.

In spontaneously hypertensive rats, renal nerve stimulation minimally affected renal haemodynamics but decreased urine flow, absolute and fractional sodium excretion by 29%, 31% and 24%, respectively.

Similar renal nerve stimulation in spontaneously hypertensive rats given amlodipine at 200 μg kg−1 plus 50 μg kg−1 h−1 or 400 μg kg−1 plus 100 μg kg−1 h−1 caused minimal changes in renal haemodynamics and in the excretion of water and sodium. The higher dose of drug resulted in decreased blood pressure and increased basal rates of urine flow and sodium excretion.

These data show that in spontaneously hypertensive rats but not normotensive rats, calcium channel blockade inhibited the ability of the renal nerves to stimulate the reabsorptive processes for sodium at the renal tubule. This indicated that in spontaneous hypertension the post‐receptor mechanisms had changed and become more dependent on the inward movement of calcium.
The effect of nedocromil sodium, sodium cromoglycate and codeine phosphate on citric acid‐induced cough in dogs
Authors: Jackson D.M.
Published: July 2012

The effects of nedocromil sodium, sodium cromoglycate and codeine phosphate on citric acid‐induced cough have been studied in conscious tracheostomised dogs.

Nedocromil sodium (approximately 15 mg given as an aerosol) and codeine phosphate (5 mg kg−1, i.v.) significantly increased the time to the first cough when dogs were challenged with citric acid aerosol. The mean number of coughs in the initial period of coughing fell after treatment of dogs with nedocromil sodium or with codeine phosphate, but this reduction in mean cough number was not statistically significant.

Neither sodium cromoglycate (approximately 15 mg given as an aerosol) nor saline had significant effect on a citric acid challenge.

It is concluded that nedocromil sodium, but not sodium cromoglycate, possesses an anti‐tussive action that may result from inhibition of sensory nerve activity in the lung. Nedocromil sodium may prove useful in the treatment of unproductive cough in situations where the use of a centrally‐acting antitussive is undesirable.
5‐Hydroxytryptamine‐induced tachycardia in the pig: possible involvement of a new type of 5‐hydroxytryptamine receptor
Authors: Bom A.H. , Duncker D.J. , Saxena P.R. , Verdouw P.D.
Published: July 2012

The mechanism of 5‐hydroxytryptamine (5‐HT)‐induced tachycardia is species‐dependent and is mediated directly or indirectly either by ‘5‐HT1‐like’ (cat), 5‐HT2 (rat, dog) or 5‐HT3 (rabbit) receptors, or by an action similar to tyramine (guinea‐pig). The present investigation is devoted to the analysis of the positive chronotropic effect of 5‐HT in the pentobarbitone‐anaesthetized pig.

Intravenous bolus injections of 5‐HT (3, 10 and 30 μg kg−1) in pigs resulted in dose‐dependent increases in heart rate of 24 ± 2, 38 ± 3 and 51 ± 3 beats min−1, respectively (n = 39). Topical application of a high concentration of 5‐HT (150 μg kg−1 in 5 ml) on the right atrium was also followed by tachycardia (38 ± 6 beats min−1, n = 4).

A number of drugs which antagonize responses mediated by different 5‐HT receptors ‐ phenoxybenzamine, methiothepin, metergoline, methysergide and mesulergine (‘5‐HT1‐like’ and 5‐HT2 receptors), ketanserin, cyproheptadine, pizotifen and mianserin (5‐HT2 receptors), and MDL 72222 and ICS 205–930 (5‐HT3 receptors) — did not attenuate the chronotropic responses to 5‐HT.

The 5‐HT‐induced tachycardia was also not affected by antagonists at α‐ and β‐adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, and calcium channels.

Selective inhibitors of 5‐HT‐uptake, indalpine and fluvoxamine, themselves increased porcine heart rate and facilitated 5‐HT‐induced tachycardia both in magnitude and in duration.

A number of putative selective agonists at ‘5‐HT1‐like’ receptors or their possible subtypes (5‐carboxamidotryptamine (5‐CT), 8‐hydroxy‐2‐(di‐N,N‐n‐propylamino) tetralin (8‐OH‐DPAT), BEA 1654 and RU 24969), or at 5‐HT3 receptors (2‐methyl‐5‐HT), elicited no or only a weak tachycardiac response in the pig. RU 24969, but not 8‐OH‐DPAT, seemed to potentiate the responses to 5‐HT, whereas 5‐CT slightly inhibited these responses.

It was concluded that the tachycardia induced by 5‐HT in the pig does not involve the receptors for some common neurotransmitter substances but may be mediated by a new 5‐HT receptor type that is clearly different from ‘5‐HT1 ‐like’, 5‐HT2 or 5‐HT3 receptors.
The effects of the novel anti‐anginal compound RS 43285 on myocardial conduction in the anaesthetized dog
Authors: Allely Maxine C. , Alps B.J.
Published: July 2012

A pentobarbitone‐anaesthetized canine model of myocardial conduction was developed to evaluate drug effects on intra‐atrial (I‐A), intra‐ventricular (I‐V) and atrioventricular (A‐V) conduction parameters, both at rest and during electrical pacing of the right atrium or ventricle. Drug effects on the ability of the sino‐atrial (SA) node to re‐establish sinus rhythm on switching off electrical pacing were also considered. The effects of the novel anti‐anginal compound RS 43285‐193 ((±)‐N‐(2,6‐dimethylphenyl)‐4[2‐hydroxy‐3‐(2‐methoxyphenoxy)propyl]‐1‐piperazine acetamide dihydrochloride) were compared to those of the standard anti‐anginal compounds nicardipine, nifedipine and verapamil.

In the dose range 15–7000 μg kg−1, RS 43285 had no significant effects on I‐A, I‐V or A‐V conduction either at rest or during electrical pacing and did not affect the re‐establishment of sinus rhythm.

Nicardipine had no effects on conduction parameters at resting heart rate. There were no effects on I‐A or I‐V conduction on electrical pacing but A‐V conduction was increased at 200–500 μg kg−1 (with a 2:1 A‐V conduction block in two out of six dogs); this was accompanied by a prolongation of the interval to reversion of sinus rhythm.

Nifedipine had no significant effects on I‐A or I‐V conduction but significantly prolonged A‐V conduction at 1000 μg kg−1 and this dose also increased the interval to SA node recovery.

Verapamil did not effect I‐A or I‐V conduction. However, A‐V conduction was affected with a significant prolongation occurring at resting heart rate at 100–400 μg kg−1 and a 2:1 A‐V block in one dog at rest. During right atrial pacing verapamil significantly increased A‐V conduction at 50–400 μg kg−1. All dogs exhibited a 2:1 A‐V conduction block at the highest frequency at 400 μg kg−1.
Inhibitory regulation by co‐released peptides of catecholamine secretion by the canine adrenal medulla
Authors: Critchley J.A.J.H. , MacLean Margaret R. , Ungar A.
Published: July 2012

We have stimulated the peripheral end of the cut left splanchnic nerve in anaesthetized dogs while collecting the venous effluent of the left adrenal gland for catecholamine estimation.

With low frequency stimulation the resting output of catecholamines was inhibited but at high frequencies it was augmented.

The inhibition of catecholamine output by low frequency stimulation was reversed by opiate antagonists (naloxone and nalmefene) but enhanced by angiotensin converting enzyme inhibitors (captopril and enalapril).
Inhibition by nedocromil sodium of early and late phase bronchoconstriction and airway cellular infiltration provoked by ovalbumin inhalation in conscious sensitized guinea‐pigs
Authors: Hutson Penny A. , Holgate Stephen T. , Church Martin K.
Published: July 2012

Bronchial challenge of ovalbumin‐sensitized conscious guinea‐pigs induced a triphasic reduction in specific airways conductance (sGaw) with maximal reductions being observed at 2, 17 and 72 h. accompanied by infiltration of the airways with neutrophils at 17 h and eosinophils at 17 and 72 h. Nedocromil sodium (10 mg ml−1) inhaled before challenge blocked the 2 and 17 h sGaw responses and the neutrophil influx. When inhaled 6 h after challenge, nedocromil inhibited the 17 h sGaw response but not neutrophil influx, suggesting that these are unrelated. The sGaw response and eosinophil accumulation at 72 h was also inhibited by nedocromil given at this time. Our findings correlate with the clinical effects of nedocromil, suggesting the guinea‐pig model may be useful for investigating the mechanism of action of anti‐asthmatic drugs.
Comparison of the haemodynamic effects of the selective bradycardic agent UL‐FS 49, with those of propranolol during treadmill exercise in dogs
Authors: Krumpl G. , Winkler M. , Schneider W. , Raberger G.
Published: July 2012

To clarify whether the bradycardic agent UL‐FS 49 exhibits a positive inotropic effect even in the absence of improvement in regional myocardial function of an underperfused myocardial area, this study was undertaken in dogs with unimpaired coronary flow.

We also investigated the haemodynamic and functional effects of the negative chronotropic and inotropic β‐adrenoceptor blocker propranolol.

UL‐FS 49 did not depress total or regional myocardial performance. Moreover, an increase in positive left ventricular dp/dt max at rest suggests a positive inotropic effect of UL‐FS 49.

Propranolol, in contrast to UL‐FS 49, led to a marked reduction in positive dp/dt max, stroke volume and systolic wall thickening at rest and during exercise. Additionally, propranolol decreased the exercise values of cardiac output, left ventricular work and left ventricular power to a far greater extent than UL‐FS 49.

In contrast to propranolol, the selective bradycardic agent UL‐FS 49 did not decrease total or regional ventricular performance and caused less reduction in cardiodynamic parameters during exercise.

These results suggest that patients with moderate coronary insufficiency or patients with coronary vessel disease and mild left ventricular failure may attain a higher exercise limit under selective bradycardia with UL‐FS 49 in comparison to that possible with a β‐adrenoceptor antagonist, such as propranolol.
The effect of anti‐inflammatory drugs on eicosanoid formation in a chronic model of inflammatory bowel disease in the rat
Authors: Boughton‐Smith N.K. , Wallace J.L. , Morris G.P. , Whittle B.J.R.
Published: July 2012

The effects of anti‐inflammatory drugs on eicosanoid formation and colonic damage in a chronic model of inflammatory bowel disease (IBD) in the rat were investigated.

A single colonic instillation of the hapten, trinitrobenzene sulphonic acid (TNB) resulted in ulceration and inflammation which persisted for 3 weeks.

The macroscopic colonic damage, present 3 weeks after TNB, was correlated with an increase in immunoreactive 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) and leukotriene B4 (LTB4) synthesis by the rat colon.

Anti‐inflammatory drugs were administered 2 weeks after TNB, when there was substantial colonic damage, and continued for a week. The experimental drug BW755C inhibited the increased formation of 6‐keto‐PGF1α and LTB4 by the inflamed colon. Indomethacin and aspirin markedly inhibited prostanoid formation in both inflamed and control colon. Sulphasalazine or prednisolone also inhibited the formation of 6‐keto‐PGF1α but the effects were less marked.

None of the anti‐inflammatory drugs significantly reduced the colonic damage induced by TNB.

The results suggest that eicosanoids, including LTB4, have only a minor role in maintaining the chronic macroscopic damage induced in the rat colon by TNB. The role of such eicosanoids in the underlying infiltration and activity of inflammatory cells in this model of IBD, however, is not known.
Mustard oil excites but does not inhibit nociceptive dorsal horn neurones in the rat: a presumed effect on A‐delta fibres
Authors: Harris N.C. , Ryall R.W.
Published: July 2012

Mustard oil was applied topically in concentrations of 10–20% to the excitatory and inhibitory nociceptive receptive fields in glabrous and hairy skin of the anaesthetized rat while recording the activity of nociceptive dorsal horn neurones. The noxious stimulus was radiant heat which is known to activate C‐fibres in glabrous and hairy skin.

Mustard oil had little effect when applied to glabrous skin and this was attributed to poor penetration of the skin.

Mustard oil excited cells in the dorsal horn which were excited by noxious heat in the receptive field on hairy skin.

Mustard oil excited cells in the dorsal horn which were inhibited by noxious heat in the receptive field on hairy skin.

Inhibitory effects of mustard oil were never seen, even when applied to receptive fields in which noxious heating caused inhibition.

The excitatory effects of mustard oil on cells inhibited by noxious heating of the skin are attributed to the reported activation of A‐delta fibres which probably masked any C‐fibre activation.
Vasodilator response to dopamine in the ferret pulmonary circulation
Authors: Gorman P.
Published: July 2012

The isolated perfused lung of the ferret was used to study the effects of dopamine receptor agonists and antagonists. Under constant flow, a fall in pulmonary artery pressure reflects a vasodilator response. Since tone is normally low, agonists were given during hypoxic pulmonary vasoconstriction to enable detection of dilator responses.

Vasodilator responses were produced by bolus doses of dopamine over the range 0.1 to 5.0 μg kg−1, and by the selective DA1 agonist SK&F 38393 (1‐phenyl‐7,8‐dihydroxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine hydrochloride).

The dopamine response was blocked by low doses of the selective DA1‐antagonist SCH23390 (R‐(+)‐8‐chloro‐2,3,4,5‐tetrahydro‐3‐methyl‐5‐phenyl‐1H‐3‐benzazepine‐7‐ol maleate), and by sulpiride.

The vasodilator response to the relatively selective DA2‐agonist N,N‐di‐n‐propyl dopamine occurred only at high dose and was incompletely blocked by the selective DA2 antagonist domperidone at a cumulative dose of 10 mg kg−1.

Thus dopamine receptors of the DA1 type may mediate vasodilatation in the ferret pulmonary circulation, but no evidence was obtained for the existence of DA2‐receptors.
Actions of baclofen on components of the Ca‐current in rat and mouse DRG neurones in culture
Authors: Green K.A. , Cottrell G.A.
Published: July 2012

Ca currents in rat and mouse sensory dorsal root ganglion (DRG) neurones were inhibited by concentrations of (—)‐baclofen as low as 1 μm. The proportion of neurones responding to baclofen was low (<20%), except in young cultures of neonate rat DRG neurones (3 days in culture), where 86% of the neurones were responsive.

Three types of unitary Ca currents were observed in the rat DRG neurones, corresponding to the T‐, N‐ and L‐type currents of chick DRG neurones.

Baclofen produced two types of response on whole‐cell currents of DRG neurones from both species. The first was on an early inactivating component of the Ca current. This early current was partially inactivated at a holding potential of −40 mV. It was also reduced during the second of a pair of depolarizing command pulses. The results suggest that this action of baclofen is due to an action on an N‐type component of the current. The second response to baclofen persisted throughout the command step and was not reduced during the second of a pair of command pulses, indicating that this effect is due to an action on the L‐type current.

Unitary or ensemble Ca currents recorded in cell‐attached patches, on neurones previously shown to respond to baclofen in whole‐cell clamp mode, were generally not inhibited by baclofen application external to the patch electrode. This indicates that a readily diffusible internal second messenger substance is probably not involved in coupling the GABAB receptor to the ion channels.
Effects of cholecystokinin and related peptides on neuronal activity in the ventromedial nucleus of the rat hypothalamus
Authors: Boden P. , Hill R.G.
Published: July 2012

An investigation into the effects of cholecystokinin octapeptide (CCK‐8S) and its pentapeptide analogue, pentagastrin, on neurones located in ventromedial nuclei of rat hypothalamic slices maintained in vitro has been undertaken.

CCK‐8S (0.01‐1.0 μm) applied in the perfusion medium produced a concentration‐dependent increase in firing rate. This effect could be mimicked by pentagastrin and was selectively blocked by L‐364,718, a potent peripheral CCK receptor antagonist that has been shown to possess micro‐molar affinity for central CCK receptors.

Intracellular recordings from ventromedial nucleus neurones revealed two distinct populations with comparable resting membrane parameters but differing neuronal activity. One group fired tetrodotoxin (TTX)‐sensitive action potentials spontaneously at resting membrane potential whilst the second group fired action potentials only on injection of depolarizing current and were otherwise silent.

Application of CCK‐8S or pentagastrin to spontaneously active neurones produced a small depolarization concomitant with an increase in action potential firing rate but the peptides had no effect on membrane properties of ‘silent’ neurones.

These data suggest the existence of at least two populations of neurones in the ventromedial hypothalamus, only one of which is excited by CCK‐8S and pentagastrin.
The Ca2+‐antagonist and binding properties of the phenylalkylamine, anipamil
Authors: Dillon J.S. , Nayler W.G.
Published: July 2012

Isolated, Langendorff‐perfused rat hearts, isolated membranes, and pharmacological and receptor binding techniques were used to study the properties of the newly developed verapamil derivative, anipamil.

When added acutely to isolated, spontaneously beating or electrically paced hearts, anipamil (0.01‐0.15 μm) exerted a dose‐dependent negative inotropic effect which developed slowly and persisted after 60 min washout.

When added acutely (0.05‐0.1 μm) to isolated hearts, or when given intravenously (2 mg kg−1 body weight 1 h before the animals were killed), anipamil displaced the dose‐response curves for the positive inotropic effect of (0.10‐3.mm) Ca2+ and (10–50 nm) Bay K 8644 to the right.

When added to freshly isolated cardiac membranes, 0.1 μm anipamil increased the dissociation constant (KD) of the phenylalkylamine (—)‐[3H]‐desmethoxyverapamil ((—)‐[3H]‐D888) from 1.22 ± 0.2 to 2.91 ± 0.46 nm, without any significant change in density (Bmax; control: 163 ± 17; anipamil: 117 ± 20fmol mg−1 protein). Bound (—)‐[3H]‐D888 was displaceable by (—)‐D888 (Ki, 1.7 ± 0.4 nm) > (—)‐D600 (Ki 12 ± 0.5 nm) > verapamil (Ki 55 ± 11 nm) > (+)‐D600 (Ki 108 ± 12.2) > anipamil (Ki 471 ± 52 nm).

In cardiac membranes isolated from rats pretreated with anipamil (2 mg kg−1 i.v.) 1 h before they were killed, the KD of (—)‐[3H]‐D888 binding was increased (P < 0.05) from 1.59 ± 0.18 to 3.28 ± 0.65 nm with no significant change in density, compared to the placebo‐treated (control) rats.

These results establish that anipamil interacts in a competitive manner with the phenylalkylamine binding sites in cardiac membranes, and that it resembles other Ca2+ antagonists in displacing the dose‐reponse curve for the positive inotropic effect of Ca2+ to the right. The results also show that although anipamil binds tightly to the cardiac membranes, it binds to the (—)‐[3H]‐D888 recognition sites less potently than (—)‐D888, (—)‐D600 or verapamil.
Electrophysiological effects of melperone on isolated rabbit heart muscles
Authors: Ikeguchi Shigeru , Hashimoto Satoshi , Horie Minoru , Kadoya Makoto , Konishi Tomotsugu , Kawai Chuichi
Published: July 2012

Electrophysiological effects of melperone on isolated atrial and ventricular muscle preparations of the rabbit were studied by a conventional microelectrode technique.

Melperone (3.3 μm) prolonged the action potential duration and effective refractory period of the atrial preparations without affecting the maximum rate of depolarization (). These effects of melperone on action potential duration and effective refractory period were inhibited by a low potassium perfusate (2.7 mm).

A high concentration of melperone (16.6 μm) decreased of atrial preparations. In ventricular muscles, melperone at either concentration decreased , although the increase in action potential duration was greater than in the atrium.

Depression of of ventricular muscles by melperone was found to be augmented by an increase of stimulation frequency and drug concentration.

The rate of onset of rate‐dependent block of in ventricle was increased with drug concentration and frequency of stimulation. However, the time constant of recovery from rate‐dependent block was almost constant. The kinetics of rate‐dependent block of by melperone were approximately similar to those of quinidine and disopyramide. Consequently it is concluded that melperone possesses class la antiarrhythmic activity as well as class 3 activity.
Investigations into the origin of the high pressure neurological syndrome: the interaction between pressure, strychnine and 1,2‐propandiols in the mouse
Authors: Bowser‐Riley F. , Daniels S. , Smith E.B.
Published: July 2012

The effects of a variety of structural isomers of the centrally acting muscle relaxant mephenesin on the high pressure neurological syndrome have been investigated. Threshold pressures for the onset of the behavioural signs, tremors and convulsions, were established. The effects of these compounds on the response to pressure were also compared with their ability to antagonize the convulsive action of strychnine.

The dose‐response relationships for strychnine and picrotoxin were investigated at fixed pressures. Additionally, the dose‐response relationship of strychnine, in the presence of mephenesin, at pressure was investigated.

All the isomers of mephenesin protected against the effects of both pressure and strychnine. The relative potency was found to be identical with respect to both. Mephenesin was clearly the most effective; it raised the threshold pressure for tremors by 2.5 times, that for convulsions elicited by pressure by 1.5 and the ED50 for strychnine convulsions by 1.6 times. Strychnine was found to be strictly additive with pressure whereas picrotoxin exhibited gross deviations from additivity. Mephenesin ameliorated the combined effects of pressure and strychnine equally.

The marked dependence on structure of the anticonvulsant activity of the mephenesin isomers can be interpreted as evidence that pressure acts not by some general perturbation of the membranes of excitable cells but rather via some specific interaction. The finding that strychnine and pressure are strictly additive supports the idea of specificity and also indicates that they may share a common mechanism in the production of convulsions. By analogy with the established mechanism of action of strychnine, it is suggested that the hyperexcitability associated with pressure might arise from an action on glycine‐mediated inhibitory processes.
Evidence that the population of postjunctional‐adrenoceptors mediating contraction of smooth muscle in the rabbit isolated ear vein is predominantly α2
Authors: Daly C.J. , McGrath J.C. , Wilson V.G.
Published: July 2012

Noradrenaline (NA), phenylephrine and UK‐14304 elicited concentration‐dependent contractions of the rabbit isolated ear vein of similar maximal magnitude. The rank order of potency, UK‐14304 > noradrenaline > phenylephrine, is consistent with that of an effect mediated through an α2‐subtype.

The potent and highly selective α1‐adrenoceptor antagonists prazosin and YM‐12617, at concentrations as high as 1 μm, produced less than a 4 fold rightward displacement of the NA concentration‐response curve.

The selective α2‐adrenoceptor antagonists rauwolscine, Wy‐26703 and CH‐38083 antagonized responses to noradrenaline in a competitive manner. For all three antagonists, the pA2 values were consistent with an effect at α2‐adrenoceptors. However, 0.1 μm YM‐12617 increased the potency of rauwolscine 2 fold indicating the presence of a small population of postjunctional α1‐adrenoceptors.

The relative antagonist potency of the yohimbine diastereoisomers rauwolscine and corynanthine against noradrenaline (rauwolscine 30 fold > corynanthine) is also consistent with an effect at α2‐adrenoceptors.

Contractions elicited by noradrenaline in the rabbit isolated ear vein appear to be mediated predominantly by postjunctional α2‐adrenoceptors.