bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effect of CCKB/gastrin antagonists on stimulated gastric acid secretion in the anaesthetized rat
Authors: Hayward N.J. , Harding M. , Lloyd S.A.C. , McKnight A.T. , Hughes J. , Woodruff G.N. 
Published: July 2012

The urethane‐anaesthetized, vagotomised rat preparation was used to investigate the effects of the histamine H2‐antagonist ranitidine, the proton pump inhibitor omeprazole and the CCKB/gastrin antagonists CI‐988, PD 136450 and L‐365,260 on pentagastrin‐, histamine‐ and bethanechol‐induced gastric acid secretion.
The novel CCKB/gastrin antagonists CI‐988 and PD 136450, and L‐365,260 dose‐dependently inhibited pentagastrin‐induced secretion. The ED50 value for PD 136450 was 0.05 μmol kg−1, the same following intravenous or subcutaneous administration.
CI‐988 and PD 136450 administered subcutaneously at dose levels highly effective for antagonism of pentagastrin responses had no effect on basal acid secretion.
Ranitidine inhibited pentagastrin‐, bethanechol‐, and histamine‐induced acid secretion, whereas the CCKB/gastrin antagonists inhibited only the secretory response to pentagastrin.
The selective CCKA antagonist, devazepide, was inactive at up to 300 μmol kg−1 i.p. against the three stimulants of acid secretion.
CI‐988 and PD 136450 will be useful research tools with which to investigate the role of CCKB/gastrin receptors in gastric acid secretion and the trophic activities of gastrin and cholecystokinin (CCK) on the gastrointestinal tract.
Increased endothelin excretion in rats with renal failure induced by partial nephrectomy
Authors: Brooks David P. , Contino Lisa C. , Storer Barbara , Ohlstein Eliot H. 
Published: July 2012

Six weeks following partial nephrectomy in rats, significant increases in serum urea nitrogen and serum creatinine concentration and a significant decrease in creatinine clearance were observed.
Measurement of systolic blood pressure by tail plethysmography indicated that animals that had undergone partial nephrectomy were hypertensive.
Compared to sham‐operated animals, there were 4 fold increases in both urinary protein excretion and urinary endothelin excretion.
There was a significant correlation between urinary protein and urinary endothelin excretion (r = 0.77). There was also a correlation (r = 0.65) between urinary endothelin excretion and systolic blood pressure.
Plasma endothelin concentrations were not different in sham‐operated and partially nephrectomized rats.
The data indicate that there is an increased renal endothelin production in rats with chronic renal failure.
Protective action of clonidine against the arrhythmogenic and lethal effects of ouabain in guinea‐pigs
Authors: Thomas George P. , Stephen P.M. 
Published: July 2012

Clonidine (1.25, 2.5 and 5.0 μg kg−1) was studied for its effect on the cardiac arrhythmias and lethality induced by slow intravenous infusion of ouabain in guinea‐pigs.
Clonidine produced significant delays in the onset of the arrhythmic stages and lethality. However, clonidine did not offer any such protection in reserpinised guinea‐pigs, whereas its effects were unaltered in atropinized guinea‐pigs.
Idazoxan (100 μg kg−1, i.v.) abolished the antiarrhythmic effect of clonidine whereas corynanthine (1 mg kg−1, i.v.) had no such effect.
Clonidine inhibited the rate of the ouabain‐induced rise in blood pressure and the peak pressor response.
In isolated paced left atria of the guinea‐pig, clonidine (3.75 × 10−4 m) did not offer any protection against rapid and/or irregular extrasystolic contractions induced by ouabain.
It is concluded that the antiarrhythmic effect of clonidine is due to its effects on the indirect neural components of digitalis toxicity mediated by the stimulation of α2‐adrenoceptors, without any direct antiarrhythmic effect on the myocardium.
Mechanisms of the anticholinergic effect of SUN 1165 in comparison with flecainide, disopyramide and quinidine in single atrial myocytes isolated from guinea‐pig
Authors: Inomata Norio , Ishihara Takafumi , Akaike Norio 
Published: July 2012

The mechanism of the anticholinergic effect of SUN 1165 on the acetylcholine (ACh)‐induced K+ current (IK.ACh) was examined and compared with those of flecainide, disopyramide and quinidine in single atrial myocytes, in a whole‐cell configuration by use of the concentration‐jump technique. This technique combines an intracellular perfusion and a rapid exchange of external solution surrounding the voltage‐clamped single myocyte within 2 ms.
In the cells loaded with guanosine‐5′‐triphosphate (GTP), 100 μm, the muscarinic ACh response, (IK.ACh), was mediated by GTP‐binding proteins. The concentrations of the test drugs that produced a half‐maximal inhibition of ACh (1 μm)‐induced IK.ACh (IC50) were 29 μm for SUN 1165, 3.6 μm for flecainide, 1.7 μm for disopyramide, and 1.6 μm for quinidine. The blockade of IK.ACh by SUN 1165 and its recovery from the inhibition occurred within a few seconds. Disopyramide had a similar rapid action, while the effects of flecainide and quinidine occurred much more slowly within a few tens of seconds.
In cells loaded with 100 μm guanosine‐5′‐O‐(3‐thio triphosphate) (GTPγS, a nonhydrolysable GTP analogue), the K+ channel was uncoupled from the muscarinic receptors and activated irreversibly due to direct activation of GTP‐binding proteins by GTPγS. SUN 1165 and disopyramide had a weak inhibitory effect (IC50 > 100 μm for both), while flecainide and quinidine depressed the GTPγS‐induced K+ current with similar potencies to the cases of ACh‐induced currents; IC50 was 5.3 μm for flecainide and 4.4 μm for quinidine.
These results suggest that the mechanisms underlying the anticholinergic effects of these antiarrhythmic drugs are different; disopyramide and high concentrations of SUN 1165 mainly block muscarinic ACh receptors in atrial myocytes, while flecainide and quinidine inhibit the K+ channel itself and/or GTP‐binding proteins.
Inhibition by salmeterol of increased vascular permeability and granulocyte accumulation in guinea‐pig lung and skin
Authors: Whelan C.J. , Johnson M. 
Published: July 2012

The long‐acting β2‐adrenoceptor agonist, salmeterol has been evaluated for its anti‐inflammatory effects in the guinea‐pig lung and skin.
Salmeterol, administered in bronchodilator doses to conscious guinea‐pigs by both oral (0.01–1.0 mg kg−1) and inhaled (nebulizer concentration, 0.001–1.0 mg ml−1) routes, inhibited histamine‐induced plasma protein extravasation (PPE) into the airway lumen.
Inhibition of PPE by salmeterol was long‐lasting (>6 h) and was inhibited by prior administration of propranolol (1 mg kg−1, s.c.), indicating an effect mediated by β‐adrenoceptors.
Inhaled salbutamol (nebulizer concentration, 0.001 — 1.0 mg ml−1) also inhibited PPE in guinea‐pig lung but, in contrast to salmeterol, this effect was short‐lived with substantial loss of activity 2 h after administration.
Inhaled salmeterol (0.1 mg ml−1) and salbutamol (1.0 mg ml−1) inhibited the accumulation of neutrophils in guinea‐pig lung in response to lipopolysaccharide (100 μg ml−1). Salmeterol, but not salbutamol, inhibited the infiltration of eosinophils into the airway lumen in response to platelet activating factor (100 μg ml−1). These effects of salmeterol were blocked by prior administration of propranolol (5 mg kg−1, s.c.), indicating that they were also β‐adrenoceptor‐mediated.
Oral salmeterol (10 mg kg−1, p.o.), but not salbutamol (10 and 100 mg kg−1, p.o.), inhibited zymosan‐induced granulocyte accumulation and PPE in guinea‐pig skin. Lower doses of salmeterol (0.1 and 1 mg kg−1) inhibited PPE, but not granulocyte accumulation. The effects of salmeterol were blocked by prior administration of propranolol (1 mg kg−1, s.c.). Both salmeterol and salbutamol inhibited histamine‐induced PPE in guinea‐pig skin.
Intradermal salmeterol (10−8 mol per site), but not salbutamol, was also effective in inhibiting zymosan‐induced granulocyte accumulation and PPE in guinea‐pig skin.
It is concluded that salmeterol, at bronchodilator doses in the guinea‐pig, inhibits granulocyte accumulation and PPE, possibly by an action on the vasculature. As this profile of activity is not shared by the shorter‐acting compound, salbutamol, it would seem that anti‐inflammatory activity is associated with β‐adrenoceptor agonism of long duration. The implications of these findings for the use of salmeterol in the treatment of bronchial asthma are discussed.
Evidence for an atypical, or β3‐adrenoceptor in ferret tracheal epithelium
Authors: Webber S.E. , Stock M.J. 
Published: July 2012

A preparation of the ferret trachea in vitro was used to examine the effects of three selective β‐adrenoceptor agonists on lysozyme secretion from submucosal gland serous cells and epithelial albumin transport into tracheal mucus following sustained, submaximal stimulation of mucus production with methacholine (20 μm)
Prenalterol, salbutamol and BRL 37344 all enhanced methacholine‐induced albumin output. BRL 37344 was 10,000 times more potent than salbutamol, and salbutamol was slightly more potent than prenalterol. The concentrations required to increase albumin output by 100% (EC100%) were 1.4 nm, 0.7 mm and approximately 1.0 mm for BRL 37344, salbutamol and prenalterol, respectively. All three agonists inhibited methacholine‐induced lysozyme output, with salbutamol being 60 times more potent than BRL 37344, and BRL 37344 being approximately 100 times more potent than prenalterol.
The selective β2‐adrenoceptor antagonist, ICI 118551, inhibited the increase in albumin output produced by BRL 37344, but was much more potent at inhibiting the response to salbutamol; the pA2 for ICI 118551 was 5.55 and 7.18 (P < 0.001) when the agonist was BRL 37344 and salbutamol, respectively. ICI 118551 also attentuated the inhibition of lysozyme output produced by the two agonists, but was 10–30 times more potent at inhibiting this response than the albumin response to BRL 37344 and salbutamol.
The greater potency (4–5 orders of magnitude) of BRL 37344, compared to the β1‐ (prenalterol) and β2 ‐ (salbutamol) adrenoceptor selective agonists, in stimulating methacholine‐induced albumin transport suggests that tracheal epithelium possess an atypical, or β3‐adrenoceptor similar to that previously reported for adipocytes and gastrointestinal smooth muscle. The weak antagonism of the response to BRL 37344 by ICI 118551 would also be consistent with an atypical adrenoceptor mediating the albumin transport response. Inhibition of methacholine‐induced serous cell lysozyme output would appear to be mediated predominantly by β2‐adrenoceptors.
In view of the possible beneficial protective effects of albumin in airway surface liquid, selective β3‐agonists like BRL 37344 might have potential value in the prevention and/or treatment of inflammatory airway disease.
Characterization of the receptor mediating relaxation to substance P in canine middle cerebral artery: no evidence for involvement of substance P in neurogenically mediated relaxation
Authors: Stubbs C.M. , Waldron G.J. , Connor H.E. , Feniuk W. 
Published: July 2012

The aim of this study was to characterize the neurokinin receptor which mediates relaxation of dog isolated middle cerebral artery by the use of selective agonists and antagonists and to establish whether substance P is involved in the neurogenically mediated relaxant response in this vessel.
Substance P caused concentration‐related, endothelium‐dependent relaxations of dog isolated middle cerebral artery, contracted with prostaglandin F2α. The selective NK1 receptor agonists, GR73632 and substance P methyl ester (SPOMe), also caused relaxation with similar maximum effects to those of substance P. GR73632 and SPOMe were approximately 20 times and 6 times less potent respectively than substance P. The selective NK2 and NK3 receptor agonists, GR64349 and senktide, were only weakly active in causing relaxation being at least 425 times and 245 times less potent respectively than substance P.
The selective NK1 receptor antagonist, GR82334, was a potent, specific, competitive antagonist of the relaxant effects of substance P. In contrast, the selective NK2 receptor antagonist, R396 (10 μm) had no effect on the response to substance P.
Electrical field stimulation of dog isolated middle cerebral artery, contracted with prostaglandin F2α, caused neurogenically mediated, non‐adrenergic non‐cholinergic (NANC) relaxations. These NANC relaxations were unaffected by endothelium removal, GR82334 (10 μm) or by capsaicin (10 μm) treatment. However, the nitric oxide synthesis inhibitor, L‐NG‐monomethyl arginine methyl ester (L‐NMMA) (100 μm) markedly attenuated the response to electrical stimulation.
These results suggest that substance P causes relaxation of dog isolated middle cerebral artery via activation of NK1 receptors. However, substance P does not appear to be involved in NANC neurotransmission. In contrast, the marked inhibitory effect of L‐NMMA on NANC relaxations implicates nitric oxide in NANC neurotransmission in this vessel.
Bradykinin stimulation of phosphoinositide hydrolysis in guinea‐pig ileum longitudinal muscle
Authors: Ransom Richard W. , Goodman Carl B. , Young Gretchen S. 
Published: July 2012

Bradykinin (BK)‐induced contraction of ileal smooth muscle is assumed to be due to phosphoinositide hydrolysis but this has never been reported. We have investigated whether BK receptors are linked to this transduction mechanism in guinea‐pig ileum longitudinal muscle and determined whether these receptors are equivalent to those labelled in [3H]‐BK binding assays.
In membranes prepared from longitudinal muscle, [3H]‐BK bound to a single class of sites with high affinity. Characterization of the binding with BK analogues indicated that the radioligand selectivity labelled a B2 type receptor.
BK significantly elevated tissue levels of [3H]‐inositol phosphates in longitudinal muscle slices preincubated with [3H]‐myo‐inositol. The agonists potencies of BK, Lys‐BK, Met‐Lys‐BK, Tyr5‐BK and Tyr8‐BK were in agreement with their relative potencies in the binding assay. The B1 receptor agonist des‐Arg9‐BK, did not stimulate inositol phosphate production. The response to BK was blocked by known B2 receptor antagonists but not by the B1 antagonist des‐Arg9, Leu8‐BK.
BK‐induced phosphoinositide hydrolysis was unaffected by exposure of muscle slices to either atropine or indomethacin.
The results indicate that the B2 receptors linked to phosphoinositide turnover in ileal longitudinal muscle exhibit properties similar to those involved in contractile responses. Also, the receptor mediating the phosphoinositide response is likely to be that labelled in the [3H]‐BK binding studies.
Phosphoramidon potentiates the contractile response to endothelin‐3, but not endothelin‐1 in isolated airway tissue
Authors: McKay K.O. , Black J.L. , Armour C.L. 
Published: July 2012

Phosphoramidon (10 μm) markedly increased the contractile response to endothelin‐3 in human and rabbit bronchus in vitro. In human tissue the contractile response to 0.3 μm endothelin‐3 was significantly increased from 54 ± 12% to 137 ±34% (of the response to 1 mm acetylcholine) in the presence of phosphoramidon. Similarly, in rabbit isolated bronchus, the endothelin‐3‐induced response was increased from 34 ± 5% to 61 ± 7%.
In addition, the potency (as measured by EC30 values) of this peptide in human and rabbit airways was significantly augmented in the presence of the enzyme inhibitor. The geometric mean EC30 value was decreased from 53 nm (95% CI:15, 190) to 8 nm (95% CI:3, 23) in human bronchus and from 150 nm (95% CI:89, 250) to 23 nm (95% CI:11, 50) in rabbit tissue.
Neither the potency nor the response (at 0.3 μm) to endothelin‐3 in canine bronchial rings was altered after incubation of the tissue in phosphoramidon.
A previous study carried out in human airways has implied that the difference in potency between endothelin‐1 and endothelin‐3 may be attributed to a heterogeneous endothelin receptor population. The results of our study, while also demonstrating this difference in potency, have shown that this marked difference, as well as that obvious in rabbit airway tissue can be abolished in the presence of phosphoramidon.
Phosphoramidon produced no change in the cumulative concentration‐response curve for endothelin‐1 in airway tissue from the three species studied.
These results suggest that a phosphoramidon‐sensitive enzyme (probably neutral endopeptidase) found in lung, may be responsible for local degradation of endothelin‐3, but not endothelin‐1 in human and rabbit isolated bronchus.
Effects of monoamine uptake inhibitors on extracellular and platelet 5‐hydroxytryptamine in rat blood: different effects of clomipramine and fluoxetine
Authors: Ortiz Jordi , Artigas Francesc 
Published: July 2012

The concentration of 5‐hydroxytryptamine (5‐HT) in rat platelet‐free plasma increased significantly 30 min after a single i.p. injection (10 mg kg−1) of each of six inhibitors of the high‐affinity 5‐HT uptake (fluvoxamine, fluoxetine, alaproclate, paroxetine, sertraline and clomipramine). The increases ranged from 226% to 776% of control values. In contrast, imipramine, desipramine and femoxetine had no significant effect. The increase elicited by paroxetine was dependent on the dose (1, 5 and 10 mg kg−1) and returned to control values after 4 h. That observed after clomipramine was also transient and paralleled the plasma concentration of the drug (Spearman‐rank correlation r = 0.43).
In vivo, the rat pulmonary vascular endothelium removed trace amounts (8.8 nmol in a bolus) of intravenously injected [14C]‐5‐HT. Paroxetine pretreatment (10 mg kg−1, 30 min before‐hand) reduced this uptake by 73%.
Repeated fluoxetine treatments reduced rat whole blood 5‐HT concentration (ca. − 60% after daily 2× 5 mg kg−1, i.p. during 14 days). However, plasma (extracellular) 5‐HT was not increased.
Various repeated treatments with clomipramine (i.p. injections or osmotic minipumps, up to 30 mg kg−1 day−1), failed to decrease rat whole blood 5‐HT concentrations. Platelet‐free plasma 5‐HT was also unchanged, even after treatments yielding plasma clomipramine levels 2.7 times higher than those that increased it acutely.
These results indicate that the extracellular pool of 5‐HT in rat blood (measured in the platelet‐free plasma) is physiologically under the control of high‐affinity 5‐HT uptake systems. The sustained 5‐HT uptake inhibition does not result in an increase of 5‐HT in platelet‐free plasma, suggesting that adaptative mechanisms are triggered. The distinct long‐term effects of the two antidepressants clomipramine and fluoxetine on rat whole blood 5‐HT suggest a differential in vivo action on the rat 5‐HT uptake.
Potassium channel modulation in rat portal vein by ATP depletion: a comparison with the effects of levcromakalim (BRL 38227)
Authors: Noack Thomas , Edwards Gillian , Deitmer Petra , Weston Arthur H. 
Published: July 2012

The effects of levcromakalim and of adenosine 5′‐triphosphate (ATP) depletion on membrane potential and ionic currents were studied in freshly‐dispersed smooth muscle cells of rat portal vein by use of combined voltage‐ and current‐clamp techniques.
Levcromakalim (1 μm) induced a glibenclamide‐sensitive, non‐inactivating K‐current (IKCO) and simultaneously inhibited the slow, transient outward, delayed rectifier K‐current (ITO). Levcromakalim also hyperpolarized the portal vein cells by approximately 20 mV.
Reduction of intracellular ATP by removal of glucose and carboxylic acids from the recording pipette and of glucose from the bath fluid, induced a slowly‐developing, non‐inactivating and glibenclamide‐sensitive K‐current (Imet) within 60–300 s after breaking the membrane patch. Imet reached peak amplitude after 300–900 s, remained at a plateau for 200–800 s and then slowly ran down. At the peak of Imet, the cells were hyperpolarized by approximately 20 mV and their input conductance was increased by 42%.
At the time of maximum development of Imet, the delayed rectifier current, ITO, was reduced by 48%.
In the absence of glucose and carboxylic acids, addition of 1 μm free ATP to the recording pipette almost doubled the magnitude of Imet. At a holding potential of −10 mV, Imet was increased from 124 ± 11 pA to 228 ± 54 pA whereas the time‐course of development and run‐down of Imet was unaffected.
During the development and after the run‐down of Imet, levcromakalim (1–10 μm) failed to induce IKCO.
Stationary fluctuation analysis of the current noise associated with Imet revealed a unitary conductance of between 10–20 pS in a physiological potassium gradient. A second contaminating current with an underlying unitary conductance of approximately 150 pS remained after Imet had run down.
It is concluded that IKCO induced by levcromakalim and Imet are carried by the same population of relatively small conductance, glibenclamide‐sensitive K‐channels. The open state of these is increased by procedures designed to lower intracellular ATP concentrations.
The simultaneous inhibition of the delayed rectifier current (ITO) by both levcromakalim and during the development of Imet is highly significant. It suggests that levcromakalim could modify the interaction of ATP with sites linked to more than one type of K‐channel. This results in the opening of those channels which underlie IKCO (and which are normally inhibited by ATP binding) together with the modulation of phosphorylation‐dependent channels such as those which underlie ITO.
Inhibitors of nitric oxide synthase selectively reduce flow in tumour‐associated neovasculature
Authors: Andrade Silvia P. , Hart Ian R. , Piper Priscilla J. 
Published: July 2012

The effects of l‐arginine analogues, NG‐nitro‐l‐arginine methyl ester (l‐NAME) and NG‐monomethyl‐l‐arginine (l‐NMMA) and methylene blue on blood flow in a murine adenocarcinoma and melanoma have been investigated.
Sponge implants in Balb/c and C57/BL mice were used to host proliferating tumour cells while the washout of 133Xe was employed to assess local blood flow in the implanted sponges.
Pharmacological inhibition of nitric oxide (NO) reduced blood flow in both tumours but this effect was reversed by administration of l‐arginine.
In marked contrast, the effect of these same NO inhibitors on the blood flow in sponge‐induced non‐neoplastic granulation tissue was negligible.
These results strongly suggest that: (a) flow in tumour vessels is modulated by nitric oxide which maintains a dilator tone in neoplastic tissue; (b) the constrictor activity (as monitored by an increase in t½ of 133Xe) of NO inhibitors may be attributed to the removal of such dilator tone; (c) many of the abnormalities described in tumour vasculature, such as hyporeactivity or unresponsiveness to vasoactive mediators and maximum vasodilatation, may be due to an increase in NO synthesis in cancers.