bluuebunny/crossref_metadata_2025_split huggingface dataset:
Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea‐pig
Authors: Subissi Alessandro , Guelfi Marco , Criscuoli Marco 
Published: July 2012

The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea‐pig.
Captopril and enalaprilic acid (1.6–200 μg kg−1) enhanced dose‐dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 μg kg−1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea‐pigs. This drug produced a dose‐dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 μg kg−1, respectively: this inhibitory activity was positively correlated to substance P potentiation.
Captopril (8–1000 μg kg−1) enhanced dose‐dependently the BC induced by capsaicin. The threshold effective dose was 40 μg kg−1 and maximal potentiation about 90%.
Captopril (200–1000 μg kg−1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 μg kg−1 in propranolol‐pretreated animals.
Captopril and enalaprilic acid (200–1000 μg kg−1) slightly (20–40%) but significantly enhanced the BC induced by 5‐hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors.
In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea‐pig. Potentiation of substance P is well correlated with ACE inhibition in guinea‐pig serum and lungs. These experimental results may offer a mechanistic interpretation of cough and bronchial hyperreactivity observed in patients receiving treatment with ACE inhibitors.
Sympathetic neurotransmission in the rabbit isolated central ear artery is affected as early as one week following a single dose of X‐irradiation
Authors: Stewart‐Lee A.L. , Maynard K.I. , Lincoln J. , Burnstock G. 
Published: July 2012

The short‐term effect of a single dose of 4500 rad X‐irradiation on sympathetic neurotransmission (involving both noradrenergic and purinergic components) was assessed in the rabbit central ear artery, 1, 4 and 6 weeks post‐irradiation.
Neurally mediated contractions were reduced as early as 1 week post‐irradiation, with responses to lower frequency stimulation being initially most affected. This suggests that the purinergic component of the contractile response is affected earlier than the adrenergic component.
There was no change in the amplitude or sensitivity of treated preparations to the cumulative application of noradrenaline when compared with untreated preparations. In contrast, contractions to α,β‐methylene ATP (1 μm), a P2‐purinoceptor agonist, were significantly increased at 4 and 6 weeks post‐irradiation, although not at 1 week post‐irradiation.
There were no apparent changes in the pattern of catecholamine fluorescence as a result of irradiation. However, the tissue content of noradrenaline was significantly reduced 6 weeks post‐irradiation when compared with control preparations.
It is concluded that damage to sympathetic cotransmission is one of the early effects of irradiation, with initial impairment predominantly of the purinergic component.
Modes of hexamethonium action on acetylcholine receptor channels in frog skeletal muscle
Authors: Adams D.J. , Bevan S. , Terrar D.A. 
Published: July 2012

The antagonism between hexamethonium and cholinoceptor agonists was investigated in frog skeletal muscle fibres with voltage‐clamp techniques. Hexamethonium caused a voltage‐dependent reduction in the amplitude of endplate currents. For neurally evoked endplate currents, the reduction increased e‐fold with a 38 mV membrane hyperpolarization.
The effect of hexamethonium on the time course of endplate currents was small, and was most apparent as a slight prolongation of the decay phase at hyperpolarized potentials (more negative than—100 mV). A similar small prolongation of single channel lifetime was detected with fluctuation analysis techniques. Hexamethonium produced a voltage‐dependent reduction in apparent single channel conductance as the membrane was hyperpolarized.
Log (concentration‐response) curves for acetylcholine (ACh)‐induced currents, determined either from currents accompanying ramp changes in membrane potential or from steady state currents in voltage‐jump experiments, were less steep for responses in the presence of hexamethonium. This reduction in slope became more pronounced at more negative membrane potentials. Observations at +50 mV suggested that the equilibrium constant for competitive antagonism was approximately 200 μm.
In voltage‐jump experiments with a two‐microelectrode voltage clamp, the current evoked by ACh in the presence of hexamethonium differed from that recorded with ACh alone. In the presence of hexamethonium, the expected ‘instantaneous' ohmic increase in membrane current in response to a hyperpolarizing step was not detected; instead a decrease in current was observed. This problem was further investigated with a vaseline‐gap voltage‐clamp technique which provides improved temporal resolution. With this method a rapid decrease in the ACh‐induced inward current was observed with step hyperpolarizations in the presence of hexamethonium.
When the membrane potential was stepped back to its resting level from a more hyperpolarized potential in the presence of hexamethonium, there was a surge of ACh‐induced inward current that decayed with a time constant of less than 100 μs.
The slow relaxation in the ACh‐induced current that followed a voltage step recorded in the presence of hexamethonium was slower than that recorded with ACh alone. In the presence of hexamethonium the time constant of this relaxation increased e‐fold for a 67 mV hyperpolarization.
The results are consistent with a rapid voltage‐dependent block of ACh‐activated channels by hexamethonium with hyperpolarization, and voltage‐dependent unblock with depolarization. The voltage‐dependent block is combined with competitive antagonism at the ACh receptors. However, not all observations appear to be compatible with a simple sequential block of open ion channels, but rather suggest that occupation of the channel by hexamethonium may not prevent channel closure.
Inhibition of inositol 1,4,5‐trisphosphate formation by cyclic GMP in cultured aortic endothelial cells of the pig
Authors: Lang Derek , Lewis Malcolm J. 
Published: July 2012

In cultured endothelial cells of the pig the endothelium‐derived relaxing factor (EDRF) releasing agent thrombin (2 u ml−1) caused a significant increase in basal levels of both guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) and inositol 1,4,5‐trisphosphate (IP3). This increase was time dependent, with peak levels occurring at 2 min and returning towards basal values after 5 min.
Pretreatment of the cells with the EDRF inhibitors haemoglobin (1 μm) or l‐NG‐nitro arginine (50 μm) significantly reduced the cyclic GMP response to thrombin. Both agents also resulted in significant elevations in basal levels of IP3. The IP3 response to thrombin was significantly enhanced at all time points by haemoglobin and at 5 min for l‐NG‐nitro arginine, when compared with the response to thrombin alone.
Pretreatment of the cells with either sodium nitroprusside (10 μm) or atrial natriuretic peptide (1 μm) caused a significant elevation of basal cyclic GMP levels. Although subsequent exposure to thrombin caused a further increase in cyclic GMP, which together with the rise induced by the previous two agents was significantly greater than the increase caused by thrombin alone, the incremental increase induced by thrombin was markedly less in the presence of nitroprusside or atrial natriuretic peptide. Both these agents, as well as 8‐bromo cyclic GMP, resulted in a significant suppression of the IP3 response to thrombin.
These findings show that one mechanism for the inhibitory effect of cyclic GMP on EDRF release from endothelium may be through the inhibition of IP3 formation in response to EDRF releasing agents.
Muscarinic receptor subtypes coupled to generation of different second messengers in isolated tracheal smooth muscle cells
Authors: Yang Chuen Mao , Chou Sheng‐Ping , Sung Tsung‐Chang 
Published: July 2012

Activation of muscarinic receptor subtypes leads to contraction, an increase in the accumulation of inositol phosphates (IPs) and a decrease in adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) synthesis in tracheal smooth muscle. The concentrations of carbachol that produced a half‐maximal effect (EC50) in inhibition of cyclic AMP generation, stimulation of IPs formation and contraction were 15 nm, 2.0 μm and 0.17 μm, respectively.
Pirenzepine, a selective M1 antagonist, displayed a low affinity for antagonizing cyclic AMP inhibition, IPs formation and contraction induced by carbachol (pKB = 6.8, 7.0, and 7.1, respectively).
Methoctramine, a cardioselective M2 antagonist, blocked cyclic AMP inhibition with a high affinity (pKB = 7.5), while it antagonized IPs formation and contraction with a low affinity (pKB = 6.2 and 6.1, respectively).
4‐Diphenylacetoxy‐n‐methylpiperidine (4‐DAMP), a selective smooth muscle M3 antagonist, possessed a high affinity in blocking IPs formation (pKB = 8.8) and contraction (pKB = 9.2) as well as a low affinity for antagonism of cyclic AMP inhibition (pKB = 8.1).
In conclusion, we have demonstrated that M2 and M3 receptor subtypes are coupled to different effector systems in tracheal smooth muscle. An M1 receptor subtype is not involved in the generation of the second messengers examined. Inhibition of cyclic AMP formation may be coupled to the M2 receptor subtype. The accumulation of IPs and presumably IP‐induced Ca2+ release may function as the transducing mechanism for cholinergic contraction of tracheal smooth muscle through the activation of M3 receptors.
Action of heptaminol hydrochloride on contractile properties in frog isolated twitch muscle fibre
Authors: Allard Bruno , Jacquemond Vincent , Lemtiri‐Chlieh Fouad , Pourrias Bernard , Rougier Oger 
Published: July 2012

Heptaminol stopped or delayed the progressive decline in tension which characterizes the phenomenon of fatigue in frog isolated twitch muscle fibre.
Heptaminol had no action on the sodium, potassium and calcium voltage‐dependent ionic conductances.
The hypothesis of an action via an internal alkalinization was tested by comparison with the action of NH4Cl. Both substances increased the tension.
The action of heptaminol was suppressed in sodium‐free (TRIS) solution or in the presence of amiloride while the action of NH4Cl was always observed.
These results could be explained by a stimulation of the Na/H antiport by heptaminol.
Differential effects of phosphoramidon on neurokinin A‐ and substance P‐induced airflow obstruction and airway microvascular leakage in guinea‐pig
Authors: Lötvall Jan O. , Elwood Wayne , Tokuyama Kenichi , Barnes Peter J. , Chung K. Fan 
Published: July 2012

The effects of the inhaled neuropeptides, neurokinin A (NKA) and substance P (SP) on lung resistance (RL) and airway microvascular permeability were studied in anaesthetized guinea‐pigs.
Single doses of inhaled NKA (3 × 10−5, 1 × 10−4, 3 × 10−4 m; 45 breaths) and SP (1 × 10−4, 3 × 10−4, 1 × 10−3; 45 breaths) caused a dose‐dependent increase in both RL and airway microvascular leakage, assessed as extravasation of the albumin marker, Evans blue dye.
NKA at 1 × 10−4 and 3 × 10−4 m resulted in a significantly higher increase in RL than SP at the same doses.
Inhaled SP (3 × 10−4 m; 45 breaths) caused significantly higher Evans blue dye extravasation in main bronchi and proximal intrapulmonary airways compared to the same dose of NKA.
Pretreatment with the specific inhibitor of neural endopeptidase (NEP24.11), phosphoramidon, caused an approximately 100 fold leftward shift of the RL responses to inhaled NKA and SP.
Phosphoramidon significantly potentiated both NKA‐ and SP‐induced airway microvascular leakage at proximal intrapulmonary airways, but not at any other airway level.
Inhibition of NEP24.11 potentiate both the SP‐ or NKA‐induced airflow obstruction to a larger extent than the induced airway microvascular leakage, suggesting that NEP24.11 is more important in the modulation of the airflow obstruction observed after these mediators.
Selective antagonism of capsaicin by capsazepine: evidence for a spinal receptor site in capsaicin‐induced antinociception
Authors: Dickenson A.H. , Dray A. 
Published: July 2012

Capsazepine has recently been described as a competitive capsaicin antagonist. We have used this compound to test the hypotheses that the in vitro and in vivo effects of capsaicin are due to interactions with a specific receptor.
In an in vitro preparation of the neonatal rat spinal cord with functionally connected tail, the activation of nociceptive afferent fibres by the application of capsaicin, bradykinin or noxious heat (48°C) to the tail could be measured by recording a depolarizing response from a spinal ventral root. Application of capsaicin or substance P to the spinal cord also evoked a depolarizing response which was recorded in a ventral root.
When capsazepine (50 nm‐20 μm) was administered to the tail or spinal cord it did not evoke any measurable response. However on the tail, capsazepine reversibly antagonized (IC50 = 254 ± 28 nm) the responses to capsaicin but not to heat or bradykinin administered to the same site. Similarly capsazepine administration to the spinal cord antagonized the responses evoked by capsaicin (IC50 = 230 ± 20 nm) applied to the cord but not responses evoked by substance P on the cord or by noxious heat and capsaicin on the tail.
In halothane anaesthetized rats, C‐fibre responses evoked by transcutaneous electrical stimulation of the receptive field were recorded from single wide dynamic range neurones located in the spinal dorsal horn. C‐fibre evoked discharges were consistently reduced by the systemic administration of capsaicin (20 μmol kg−1, s.c.) and this action of capsaicin was antagonized by capsazepine (100 μmol kg−1) administered by the same route. In addition the systemic effect of capsaicin was antagonized by a spinal intrathecal administration of capsazepine (5–50 nmol).
Intradermal injections of capsaicin, localized to the peripheral receptive field, usually one toe of the ipsilateral hind‐paw, produced a transient increase in C‐fibre‐evoked activity followed by a prolonged period of localized insensitivity to transcutaneous C‐fibre stimulation. These effects of capsaicin were significantly reduced by the concommitant administration of capsazepine to the same site.
These data demonstrate that capsazepine is a selective antagonist of capsaicin on nociceptive neurones in vitro and in vivo and suggest that the effects of capsaicin were mediated by activation of a specific receptor. Since the antinociceptive effect produced by systemically administered capsaicin was antagonised by spinal intrathecal capsazepine this further supports the hypothesis that capsaicin exerts its antinociceptive effect by acting on specific receptors localized to sensory nerve fibres in the spinal cord.;
Enteral absorption of octreotide
Authors: Flicker G. , Drewe J. , Vonderscher J. , Kissel T. , Beglinger C. 
Published: July 2012

The somatostatin octapeptide‐analogue, octreotide, is absorbed as intact peptide from the gastrointestinal (GI) tract.
In situ absorption experiments in rats confirmed our recent intubation studies in human volunteers demonstrating that the peptide has preferential absorption sites in the small intestine. Absorption of octreotide was higher in the jejunum than in the duodenum or the ileum.
Experiments with bile‐duct cannulated rats demonstrated that the absorption of octreotide decreased in the presence of bile, reflecting a negative influence of biliary components on the absorption of the peptide.
Uptake experiments using rat jejunal brush border membranes were performed to analyse the absorption mechanisms. The transport of octreotide into jejunal brush border membranes was significantly higher than the uptake into membrane vesicles isolated from rat ileum. When initial uptake (0–15 s) rates into the membrane vesicles were calculated as a function of the peptide concentration, a saturable component could be observed, indicative of transport mechanisms different from simple diffusion.
ATP overflow from the mouse isolated vas deferens
Authors: Drake M. Eliane , Petersen S.A. 
Published: July 2012

A modified form of the highly specific luciferin‐luciferase assay was used to measure the overflow of adenosine 5′‐triphosphate (ATP) from the field‐stimulated mouse vas deferens in vitro. Precise timing of the stimulation, superfusate collection and assay minimized ATP degradation before assay, offering the opportunity for quantitative studies.
Stimulation with between 50 and 200 supramaximal pulses at 5 Hz increased ATP overflow by between 7 and 28 times over basal.
ATP overflow increased steadily with increasing numbers of stimuli from 50 to 200 pulses. Increasing the frequency of stimulation initially had no effect, but above 10 Hz there was increased overflow, suggesting an interaction between facilitated release and the rate of degradation by extracellular ATPases.
Contractions of the vas induced by exogenous (−)‐phenylephrine produced only a small increase in ATP overflow, suggesting that the stimulation induced increase in ATP overflow is mostly pre‐junctional in origin, though tetrodotoxin eliminated stimulation‐induced overflow only in a proportion of preparations.
Effectiveness of GABAB antagonists in inhibiting baclofen‐induced reductions in cytosolic free Ca concentration in isolated melanotrophs of rat
Authors: Shibuya I. , Kongsamut S. , Douglas W.W. 
Published: July 2012

The purpose of the present experiments was to assess the activities of GABAB receptor antagonists in mammalian isolated melanotrophs.
Cytosolic free Ca concentration ([Ca2+]i) in rat melanotrophs in primary culture was monitored with the fluorescent probe, fura‐2.
(−)‐Baclofen lowered [Ca2+]i in a concentration‐dependent manner with an EC50 of 0.96 μm. The reduction in [Ca2+]i produced by (−)‐baclofen at a maximally effective concentration (100 μm) was similar to that produced by the classic transmitter inhibitory to melanotroph secretion, dopamine, at a corresponding concentration (100 nm), or by perifusion with a nominally Ca‐free solution.
The GABAB receptor antagonists, 3‐aminopropyl(diethoxymethyl)phosphinic acid (CGP 35348), 2‐hydroxy saclofen, phaclofen and 4‐amino‐3‐(5‐methoxybenzo[b]furan‐2‐yl) butanoic acid (9H), had inhibitory effects on the reduction in [Ca2+]i produced by (−)‐baclofen (3 μm). Of the antagonists tested, CGP 35348 was the most potent with an IC50 of 60 μm, compared to 120 to 400 μm for the others. CGP 35348 acted competitively.
CGP 35348 alone had no effect on basal [Ca2+]i, or on the changes in [Ca2+]i produced by dopamine (10 nm) or the specific GABAA receptor agonist, muscimol (10 μm).
The evidence indicates that of the antagonists tested, CGP 35348 offers the greatest promise for pharmacological analysis of the functional significance of the GABAB receptors in melanotrophs.
Cardiovascular actions of a new selective postjunctional α.‐adrenoceptor antagonist, SK&F 104856, in normotensive and hypertensive dogs
Authors: Hieble J. Paul , Nichols Andrew J. , Fredrickson Todd A. , DePalma P. Dennis , Ruffolo Robert R. , Brooks David P. 
Published: July 2012

SK&F 104856 (2‐vinyl‐7‐chloro‐3,4,5,6‐tetrahydro‐4‐methylthieno[4,3,2ef][3]benzazepine) is a novel postjunctional α.1‐ and α.2‐adrenoceptor antagonist.
SK&F 104856 as well as prazosin and SK&F 86466 reduced blood pressure in the anaesthetized normotensive dog.
SK&F 86466 and rauwolscine but not SK&F 104856 or prazosin, produced a marked increase in myocardial contractility which corresponds with their ability to block prejunctional α.2‐adrenoceptors.
Intravenous or oral administration of SK&F 104856 resulted in dose‐dependent antihypertensive responses in 1‐kidney, 1‐clip (1‐K, 1‐C) Goldblatt hypertensive dogs with baseline blood pressure of approximately 140 mmHg. At 0.1 and 1 mg kg−1, i.v., mean arterial blood pressure fell by 11 ± 5 and 23 ± 5 mmHg, respectively. At 3 and 10 mg kg−1, p.o., blood pressure fell by 9 ± 3 and 22 ± 5 mmHg, respectively. At 10 mg kg−1, p.o., the antihypertensive effect of SK&F 104856 was still evident at 4 h.
The data indicate that SK&F 104856 shows selectivity in vivo for postjunctional versus prejunctional α.‐adrenoceptors and is a potent and long‐acting antihypertensive agent in 1‐K, 1‐C Goldblatt hypertensive dogs.
Pre‐clinical pharmacology of ICI D2138, a potent orally‐active non‐redox inhibitor of 5‐lipoxygenase
Authors: McMillan R.M. , Spruce K.E. , Crawley G.C. , Walker E.R.H. , Foster S.J. 
Published: July 2012

This paper describes the pre‐clinical pharmacology of ICI D2138, a potent orally‐active non‐redox inhibitor of 5‐lipoxygenase which is undergoing clinical evaluation.
ICI D2138 potently inhibited leukotriene synthesis in murine peritoneal macrophages (IC50 = 3 nm) and human blood (IC50 = 20 nm). In human and dog blood, ICI D2138 did not inhibit thromboxane B2 synthesis at a concentration of 500 μm, thus the selectivity ratio (cyclo‐oxygenase: 5‐lipoxygenase) was greater than 20,000. In contrast, zileuton (a 5‐lipoxygenase inhibitor also undergoing clinical evaluation) exhibited a selectivity ratio of 15–100.
ICI D2138 potently and dose‐dependently inhibited ex vivo leukotriene B4 (LTB4) synthesis by rat blood with ED50 values of 0.9, 4.0 and 80.0 mg kg−1 p.o. at 3, 10 and 20 h respectively after dosing. Similar activity was observed for inhibition of LTB4 production in a zymosan‐inflamed rat air pouch model. Zileuton produced ED50 values of 5 and 20 mg kg−1 at 3 and 10 h respectively.
Oral administration of 1, 3 or 10 mg kg−1 ICI D2138 to dogs produced maximal inhibition of ex vivo LTB4 synthesis by blood for 5, 9 and 31 h respectively. A dose of 5 mg kg−1 p.o. of zileuton caused maximal inhibition of LTB4 for 24 h.
Oral administration of 10 mg kg−1 ICI D2138 caused total inhibition of LTB4 production in zymosan‐inflamed rabbit knee joint.
Topical administration of ICI D2138 to rabbit skin caused a dose‐related inhibition of arachidonic acid‐induced plasma extravasation with an ID30 of 1.08 nmol per site. Zileuton was approximately 40 times less potent.
Oral anti‐inflammatory activity was assessed in an arachidonic acid‐induced mouse ear oedema model in animals treated with indomethacin to block pro‐inflammatory prostanoids. ICI D2138, given orally, caused dose‐dependent inhibition of oedema with an approximate ID50 of 1.8 mg kg−1. Zileuton was approximately 10 times less potent.
ICI D2138 caused a dose‐dependent inhibition of antigen‐induced broncho‐constriction in guinea‐pigs with an approximate ID50 of 0.1 mg kg−1, i.v. Zileuton was approximately 10 times less potent.
In view of the pharmacological profile described here, ICI D2138 has the potential to provide improved clinical efficacy compared to existing lipoxygenase inhibitors such as zileuton.