bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of hydrogen peroxide on guinea‐pig tracheal smooth muscle in vitro: role of cyclo‐oxygenase and airway epithelium
Authors: Rhoden K.J. , Barnes P.J. 
Published: July 2012

Hydrogen peroxide (H2O2) (0.1 μm‐3 mM) induced variable contractions of guinea‐pig isolated trachea which were attenuated by catalase (100 u ml−1) and mannitol (15 mM) suggesting that contractions were induced by H2O2 and/or the hydroxyl anion.
Epithelial removal potentiated contractile responses of tracheal preparations to H2O2 with a leftward shift of the concentration‐response curve and an increase in the maximal response.
Indomethacin (3 μm) inhibited contractions to H2O2 of intact preparations and preparations without epithelium suggesting that contractions may be mediated by cyclo‐oxygenase products. Intact preparations (but not preparations without epithelium) contracted in response to high concentrations (>0.1 mM) of H2O2 in the presence of indomethacin suggesting that other excitatory factor(s) released by the epithelium may induce contraction.
Preincubation of intact tracheal preparations with H2O2 (1 mM) for 1 h had no effect on responses to histamine or isoprenaline.
These results suggest that hydrogen peroxide generated during the inflammatory process may play a role in bronchoconstriction.
Effects of aerosolised substance P on lung resistance in guinea‐pigs: a comparison between inhibition of neutral endopeptidase and angiotensin‐converting enzyme
Authors: Lötvall Jan O. , Skoogh Bengt‐Eric , Barnes Peter J. , Chung K. Fan 
Published: July 2012

We have examined in guinea‐pigs, in vivo, the effects of inhibition of neutral endopeptidase (NEP) and angiotensin‐converting enzyme (ACE) on the airway response to aerosolised substance P (SP). We aerosolised captopril (4.6 mm, 60 breaths; 210 nmol) to inhibit ACE and acetorphan (0.3, 1 and 3 mm, 60 breaths; 9 nmol, 33 nmol and 110 nmol respectively) to inhibit NEP. We also examined the effect of the highest dose of acetorphan (110 nmol) on the response to aerosolised acetylcholine (ACh).
Responsiveness to SP (or ACh) was measured as the change in lung resistance (RL) induced by nebulisation of increasing concentrations of SP (or ACh) before and after treatment with the inhibitor. PC200, defined as the provocative concentration inducing an increase in RL of 200% above baseline, was calculated for each challenge.
Administration of acetorphan before the second SP‐challenge induced a dose‐dependent decrease in PC200 for SP amounting to 1.8 (±0.3) log units after treatment with 11 nmol acetorphan. Treatment with vehicle before the second SP‐challenge or with 3 mm acetorphan before the second ACh‐challenge had no significant effect on PC200.
Treatment with captopril (21 nmol) induced only a small, nonsignificant leftward shift of PC200 to SP (0.3 ± 0.2 log units).
We conclude that a NEP‐like enzyme, but not ACE, regulates the response to aerosolised SP. We suggest that the same is true for SP released endogenously from sensory nerve endings in the airway epithelial layer.
Effects of epithelium removal on relaxation of airway smooth muscle induced by vasoactive intestinal peptide and electrical field stimulation
Authors: Farmer Stephen G. , Togo James 
Published: July 2012

We have studied the effect of epithelium removal on relaxation of guinea‐pig isolated tracheal smooth muscle induced by vasoactive intestinal peptide (VIP) or stimulation of non‐adrenergic, non‐cholinergic (NANC) inhibitory nerves. Also examined were the effects of inhibitors of neutral endopeptidase (NEP) and angiotensin‐converting enzyme (ACE).
Epithelium removal produced a 3.6 ± 0.4 fold leftward shift in the VIP concentration‐response curve. The supersensitivity to VIP, following epithelium removal was abolished by phosphoramidon or thiorphan (NEP inhibitors), but unaffected by captopril (an ACE inhibitor). In intact trachea, the NEP inhibitors produced leftward shifts in the VIP curves similar to those produced by epithelium removal.
In contrast to responses to exogenous VIP, neurogenic NANC inhibitory responses to electrical field stimulation were affected neither by epithelial denudation nor by the peptidase inhibitors.
As in previous studies, epithelium removal increased tracheal sensitivity to isoprenaline. This was not altered by pretreatment with a cocktail of peptidase inhibitors. Thus, the effect of the NEP inhibitors on responses to VIP appears to be relatively specific.
These data indicate that exogenous VIP is a substrate for airway NEP, since inhibition of the enzyme potentiates the peptide. This is further evidence that the airway epithelium provides a source for the metabolism of mediators.
In guinea‐pig trachea the NEP responsible for cleaving VIP may be located largely in the epithelial layer, since NEP inhibition was without effect on sensitivity to VIP in epithelium‐denuded preparations. If VIP is a NANC inhibitory neurotransmitter in this tissue, its degradation endogenously does not appear to involve epithelial NEP.
The effects of cholecystokinin octapeptide on human isolated alimentary muscle
Authors: D'Amato M. , Stamford I.F. , Bennett A. 
Published: July 2012

We studied cholecystokinin octapeptide (CCK‐OP) for its motor effects and sites of action on human isolated muscle from stomach, small intestine and colon.
CCK‐OP induced a concentration‐dependent contraction of all the longitudinal muscles and of circular muscle from the stomach and large intestine. The peptide acted directly on these muscles at a site not involving muscarinic receptors.
CCK‐OP relaxed the circular muscle of the small intestine and/or reduced the contractions to acetylcholine, by stimulating intramural postganglionic inhibitory neurones.
Antigen induces leucopenia in non‐immunised guinea‐pigs injected with platelets from actively sensitized animals
Authors: Pretolani Marina , Randon Jacques , Vargaftig B. Boris 
Published: July 2012

Ovalbumin administration to animals injected with 0.5–5 × 106 washed platelets μl−1 from actively sensitized animals induced a marked decrease (maximum of around 50% at 60 min) in the number of circulating leucocytes, whereas platelet counts were unaffected. The intensity of the decrease in leucocyte counts was dependent upon the concentration of the injected platelets.
No drop in leucocyte counts was measured upon antigen challenge of guinea‐pigs injected with platelets from non‐sensitized animals.
This phenomenon was unaffected by pretreatment of the recipient animals with a platelet‐activating factor (PAF) antagonist WEB 2086 (3 mg kg−1 i.v.) but was markedly reduced (around 50% inhibition) by the anti‐allergic drug nedocromil sodium (100 mg kg−1 i.v.). By contrast, indomethacin (5 mg kg−1 i.v.) caused a significant (P < 0.01) enhancement of the antigen‐induced leucopenia, whereas the mixed cyclooxygenase and lipoxygenase inhibitor, BW 755C (10 mg kg−1 i.v.) suppressed the drop in leucocyte counts evoked by ovalbumin administration.
These results indicate that platelets from actively sensitized guinea‐pigs transferred to normal animals still responds to the specific antigen with the activation of circulating leucocytes. This phenomenon appears to be independent of the production of PAF and of cyclo‐oxygenase metabolites. By contrast, the production of the metabolites of the lipoxygenase pathway by platelets could account for the marked leucopenia observed following the immunological stimulation.
Pharmacological estimation of agonist affinity: detection of errors that may be caused by the operation of receptor isomerisation or ternary complex mechanisms
Authors: Leff P. , Harper D. , Dainty I.A. , Dougall I.G. 
Published: July 2012

Recent theoretical studies have questioned the pharmacological estimation of agonist affinity. They showed that when receptor isomerisation or ternary complex mechanisms operate, the receptor inactivation method can substantially overestimate affinity, whereas methods for partial agonist analysis are more accurate. We previously suggested that the operation of such mechanisms and therefore the presence of errors could be detected by analysing the same partial agonist by the receptor inactivation and comparative methods. This paper describes the practical application of this test.
The ternary complex mechanism was simulated for a partial agonist under various conditions relating receptor (R) and transducer (T) concentrations, one of which also corresponds to the receptor isomerisation mechanism. The theoretical data so generated were then analysed by the inactivation and comparative methods to quantify the magnitude of error of affinity estimation that could occur.
This analysis showed that for a partial agonist with approximately 85% of the activity of a full agonist, the inactivation method could produce an affinity (pKA) estimate up to 0.7 log10 units higher than that produced by the comparative method. This difference would occur when the total receptor concentration ([R0]) is less than or equal to the total transducer concentration ([T0]). It also showed that the over‐estimation of affinity by the inactivation method was accompanied by drastic overestimation of Em, the maximal effect parameter.
The test was then exemplified using the muscarinic receptor system in the guinea‐pig isolated left atrial preparation, where there is evidence that a ternary complex mechanism operates. The test agonist was pilocarpine, which produced on average 83% of the activity of the full agonist, carbachol. Pilocarpine was analysed in comparison with carbachol and by receptor inactivation in the same tissue resulting in small and statistically insignificant differences in Em (96.7% and 97.3% respectively) and pKA (5.03 and 4.95 respectively).
In conclusion, in this experimental system, there was no evidence for the errors in agonist affinity estimation predicted by theory. Although this conclusion only applies to this system and application of the test to others is necessary to establish the generality of the present results, further examination of the theoretical basis for the predicted errors is required.
Pharmacological evidence for the existence of a local renin‐angiotensin system in porcine interlobar renal arteries
Authors: Müller‐Schweinitzer Else , Olea‐Baza Itziar 
Published: July 2012

Changes in tension in response to cumulative additons of angiotensins (i.e., angiotensinogen, angiotensin I and angiotensin II), bradykinin and acetylcholine were monitored isometrically on ring preparations from porcine interlobar renal arteries.
Angiotensins consistently elicited contractile responses, whereas both bradykinin and acetylcholine produced relaxation of the arterial rings when active tone was induced by prostaglandin F2α.
Contractile responses to angiotensin II could be completely blocked by the combined action of the cyclo‐oxygenase inhibitor, indomethacin (1 μm) and the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA, 10 μm).
Relaxant responses to bradykinin were unchanged during blockade of thromboxane A2 synthesis by dazoxiben (30μm) and proved to be largely resistant to blockade by indomethacin (1 μm) and the prostaglandin I2 (prostacyclin) synthesis inhibitor, tranylcypromine (40 μm).
The angiotensin receptor blocker, saralasin (10 and 100 nm) antagonized responses to angiotensinogen, angiotensin I and angiotensin II effectively and with similar potency. Enalaprilic acid, the active metabolite of the converting enzyme inhibitor enalapril (300 nm), attenuated responses to angiotensin I but failed to inhibit those to angiotensinogen up to 1 μm. The serine protease kallikrein (0.001 to 1 u ml−1) produced a dose‐dependent shift to the left of the concentration‐response curve for angiotensinogen.
It is suggested that the porcine interlobar renal artery possesses a local renin‐angiotensin system with activatable angiotensin II forming enzyme(s) within the vessel wall.
Alterations in regional blood flow in rats following sensitization to the nematode Nippostrongylus brasiliensis: effects of PAF antagonists
Authors: Mathison Ronald , Rimmer Carol , Davison Joseph S. , Wallace John L. , Befus A. Dean 
Published: July 2012

Changes in tissue and organ blood flow associated with sensitization of rats to the nematode parasite, Nippostrongylus brasiliensis, were studied 30 to 35 days after infection, a time when very few worms remain in the animal.
Neither active nor passive sensitization modified heart rate, mean arterial blood pressure, cardiac output or total peripheral resistance. Passive sensitization and administration of non‐immune sera did not modify blood flow to any of the tissues studied.
Active sensitization increased hepatic arterial blood flow, but decreased blood flow to the stomach, duodenum, jejunum and the submandibular glands. These effects cannot be attributed to residual nematode infections as treatment with the anthelmintic, thiabendazole, did not alter blood flow relative to untreated, actively sensitized rats.
The effects of active sensitization on blood flow were probably due to an action of platelet‐activating factor (PAF) since treatment of actively sensitized animals with the selective antagonists, WEB‐2086 and BN 52021, reversed the decrease in flow seen to the intestinal regions. The PAF antagonists increased blood flow to the kidneys and the trachea of sensitized animals.
These results suggest that the PAF released from undetermined sources in nematode‐sensitized rats, produces altered blood flow, primarily to the stomach and proximal small bowel.
Dihydropyridines alter adenosine sensitivity in the rat hippocampal slice
Authors: Bartrup J.T. , Stone T.W. 
Published: July 2012

The effects of adenosine and a range of adenosine analogues, which are resistant to uptake processes, were studied in the presence of dihydropyridines and verapamil on the population spike potential recorded from the CA1 area of the hippocampal slice.
Nifedipine and Bay K 8644, a calcium channel antagonist and activator respectively, enhanced the inhibitory action of adenosine in a concentration‐dependent manner. This was in contrast to their effect on adenosine analogues where the inhibition of the population potential was significantly attenuated. Similiar interactions between the adenosine compounds and the dihydropyridines were also displayed in studies on spontaneous epileptiform activity in the CA3 region.
This effect of nifedipine and Bay K 8644 was not shown by the dihydropyridines, nimodipine or nitrendipine, or by the phenylalkylamine, verapamil.
Addition of the adenosine uptake blocker dipyridamole reversed the action of nifedipine on adenosine, so that inhibition by adenosine was now attenuated by nifedipine in a similar manner to that observed with the adenosine analogues.
These results can be explained with reference to binding studies that show displacement of adenosine analogues from the adenosine receptor by dihydropyridines. An action at the adenosine uptake site by the dihydropyridines explains the enhancement of adenosine inhibition.
The possible sites for this interaction are discussed.
Endothelium modulation of the effects of nitroglycerin on blood vessels from dogs with pacing‐induced heart failure
Authors: Forster Christine , Main Jeffrey S. , Armstrong Paul W. 
Published: July 2012

The relaxant actions of nitroglycerin (previously considered to be an endothelium‐independent relaxing agent) and acetylcholine (an endothelium‐dependent relaxing agent) were compared on 4 vascular preparations (dorsal pedal artery, saphenous vein, left anterior descending coronary artery and circumflex coronary artery) from dogs with and without pacing‐induced congestive heart failure (CHF).
Responses of the coronary arteries to acetylcholine were unaltered in endothelium‐intact rings from dogs with and without heart failure. Similarly no such changes were observed in the peripheral vessels. The maximum relaxation produced by acetylcholine was always greater in the coronary vessels compared to the peripheral vessels.
Before heart failure, the coronary vessels were more sensitive and reactive to nitroglycerin compared to the peripheral vessels.
Removal of the endothelium in both the control (dogs without CHF) and experimental (dogs with CHF) rings enhanced the relaxant effects of nitroglycerin, such that the EC50 for nitroglycerin became significantly lower in all denuded rings, with the exception of the saphenous vein and the left anterior descending coronary artery, before the development of CHF.
When CHF was maximally developed, vascular sensitivity to nitroglycerin was increased in peripheral vessels with an intact endothelium, but not in the coronary vessels.
These findings indicate that relaxation produced by nitroglycerin cannot be considered as entirely endothelium‐independent but should be considered endothelium‐modulated.
Phentolamine and yohimbine inhibit ATP‐sensitive K+ channels in mouse pancreatic β‐cells
Authors: Plant T.D. , Henquin J.C. 
Published: July 2012

The effects of phentolamine and yohimbine on adenosine 5‐triphosphate (ATP)‐sensitive K+ channels were studied in normal mouse β‐cells.
In the presence of 3 mM glucose, many ATP‐sensitive K+ channels are open in the β‐cell membrane. Under these conditions, phentolamine inhibited 86Rb efflux from the islets. This inhibition was faster with 100 than with 20 μm phentolamine but its steady‐state magnitude was similar with both concentrations. Yohimbine (20–100 μm) also inhibited the efflux rate but was not as potent as phentolamine.
In the presence of 6 mM glucose, most ATP‐sensitive K+ channels are closed in the β‐cell membrane. Their opening by 100 μm diazoxide caused a marked acceleration of 86Rb efflux from the islets. This acceleration was almost entirely prevented by 20 μm phentolamine. It was barely affected by 20 μm yohimbine and reduced by 50% by 100 μm yohimbine.
ATP‐sensitive K+ currents were studied in single β‐cells by the whole cell patch‐clamp technique. Phentolamine (20–100μm) caused a progressive but almost complete and irreversible inhibition of the current. The effects of yohimbine were faster but smaller; the inhibition was still incomplete with 100 μm yohimbine.
The increase in ATP‐sensitive K+ current produced by 100 μm diazoxide was prevented by 100 μm phentolamine but only partially attenuated by 100 μm yohimbine.
It is concluded that phentolamine inhibits ATP‐sensitive K+ channels in pancreatic β‐cells. This novel effect of phentolamine resembles that of hypoglycaemic sulphonylureas. It may account for previously unexplained effects of the drug. These observations also call for reinterpretation of many studies in which phentolamine was used as an allegedly specific blocker of α‐adrenoceptors.
Differential regulation of 5‐lipoxygenase and cyclo‐oxygenase pathways of arachidonate metabolism in rat peritoneal leukocytes
Authors: Moroney M.A. , Forder R.A. , Carey F. , Hoult J.R.S. 
Published: July 2012

Simultaneous activation of the 5‐lipoxygenase and cyclo‐oxygenase pathways of arachidonate metabolism in rat peritoneal mixed leukocytes in response to A23187, chemoattractant N‐formyl‐methionineleucine‐phenylalanine (FMLP) and arachidonic acid (AA) was studied by radioimmunoassay of leukotriene B4 (LTB4) and thromboxane B2 (TXB2) respectively.
FMLP and AA preferentially activated cyclo‐oxygenase and A23187 preferentially activated 5‐lipoxygenase. Release of TXB2 preceded that of LTB4. A threshold amount of A23187 enhanced FMLP‐and AA‐induced LTB4 production but not that of TXB2.
Phorbol myristate acetate (PMA) abolished LTB4 generation in response to FMLP with much less effect on TXB2, but did not inhibit the formation of either eicosanoid caused by A23187 or AA. Instead, PMA caused a dose‐dependent but modest stimulation of TXB2 generation either on its own or when added with A23187 or AA.
These results show that the 5‐lipoxygenase and cyclo‐oxygenase pathways in rat peritoneal leukocytes are regulated differently and that functional compartmentalisation of the stimulus‐generation sequence operates in these cells.
Volatile anaesthetics inhibit a cyclic AMP‐dependent sodium‐potassium current in cultured sensory neurones of bullfrog
Authors: Tokimasa T. , Sugiyama K. , Akasu T. , Muteki T. 
Published: July 2012

Cultured dorsal root ganglion cells of the bullfrog were voltage‐clamped in the whole‐cell configuration.
An adenosine 3′:5′‐cyclic monophosphate (cyclic AMP)‐dependent cationic inward rectifier (IH) was inhibited by bath application of enflurane (0.2‐0.8 mm) and halothane (0.2‐0.5 mm), which thereby induced an outward current at the resting potential, and a membrane hyperpolarization in undamped cells.
The main effect of enflurane (0.5 mm) was to displace the steady‐state IH activation curve to a hyperpolarizing direction by about 10 mV, as well as to reduce the maximum H‐conductance to about 20%.
Forskolin (1–10 μm), which enhances IH by producing a depolarizing shift in the IH activation curve and increasing the maximum H‐conductance, recruited IH even when the current had already been eliminated by enflurane (1 mm).
Contractile and relaxant responses of the canine isolated spinal artery to vasoactive substances
Authors: Shirai K. , Kawai Y. , Ohhashi T. 
Published: July 2012

Effects of vasoactive substances were investigated in the canine isolated spinal branch of the intercostal artery (SBICA).
Addition of angiotensin II (AII), vasopressin, noradrenaline (NA), adrenaline, 5‐hydroxytryptamine (5‐HT), and dopamine each produced concentration‐dependent contraction in the SBICA, whereas prostaglandin F2α, histamine, and tyramine caused only slight contraction. The decreasing order of the potency of contractile agents was AII ≫ vasopressin = NA > 5‐HT > adrenaline ≫ dopamine.
Although the pD2 value for phenylephrine (5.31 ± 0.36) was smaller than that for NA (6.48 ± 0.13), there was no significant difference in Emax value between these two agonists in the SBICA. On the other hand, xylazine produced only a slight contraction, the pD2 value being 3.59 ± 0.08. Phentolamine (10−8–10−6m) and prazosin (10−8–10−6m) competitively inhibited the NA‐induced contraction, while yohimbine (10−8–10−6m)did not.
Acetylcholine (ACh), sodium nitroprusside (SNP), ATP, ADP, and adenosine caused concentration‐dependent relaxations in SBICA following contraction with NA. On the other hand, isoprenaline up to 10−4m did not produce any relaxation. The decreasing order of potency of the relaxant agents was ACh > SNP ≫ ATP = ADP = adenosine.
The ACh‐induced relaxation was competitively inhibited by atropine and was abolished by mechanical removal of the endothelium. Aspirin (5 × 10−5m) did not affect the relaxant response to ACh, while oxyhaemoglobin (10−5m) and methylene blue (10−5m) produced significant attenuation.
These results suggest that NA produces contraction of the isolated canine SBICA which is mainly mediated via α1‐adrenoceptors and that ACh causes a relaxation of the SBICA due to release of endothelium‐derived relaxing factor (EDRF) from the endothelial cells.
Haemodynamic alterations in anaesthetized and acutely intoxicated newborn piglets
Authors: Chandler Cara J. , Ong Bill Y. , Sitar Daniel S. 
Published: July 2012

We investigated the haemodynamic alterations in 2‐day old anaesthetized piglets after acute ethanol intoxication using the microsphere technique.
After ethanol infusion, mean arterial blood pressure (MABP) decreased by 6%, cardiac output (CO) decreased by 26%, heart rate (HR) increased by 20% and systemic vascular resistance (SVR) increased by 36%.
Arterial perfusion to the kidneys, gastrointestinal (GI) organs and carcass decreased by 39%, 34% and 26%, respectively.
In piglets pretreated with 4‐methylpyrazole (4‐MP), an alcohol dehydrogenase inhibitor, the decrease in MABP and increase in HR were not observed after ethanol infusion, but the reduction in CO and increase in SVR were maintained.
Arterial blood flow to the GI organs and carcass, but not the kidneys, remained at significantly reduced levels.
These observations indicate that ethanol can adversely affect CO and arterial perfusion to GI and musculoskeletal structures while metabolites of ethanol, such as acetaldehyde, affect MABP and HR. Therefore, the clinical effects observed after acute ethanol intoxication in neonates may vary with their rate of ethanol metabolism.