bluuebunny/crossref_metadata_2025_split huggingface dataset:
The influence of atropine and atenolol on the cardiac haemodynamic effects of NG‐nitro‐l‐arginine methyl ester in conscious, Long Evans rats
Authors: Widdop R.E. , Gardiner S.M. , Kemp P.A. , Bennett T. 
Published: July 2012

In the present study, the extent to which baroreflexes contribute to the cardiac effects of NG‐nitro‐l‐arginine methyl ester (l‐NAME) was assessed in conscious, Long Evans rats chronically instrumented with thoracic electromagnetic flow probes for the measurement of cardiac haemodynamics.
l‐NAME (10 mg kg−1, i.v.) was administered in the absence (n = 6) and in the presence (n = 7) of atropine (1 mg kg−1) and atenolol (1 mg kg−1).
l‐NAME caused a marked increase in mean arterial pressure and marked reductions in total peripheral conductance, cardiac output, heart rate, stroke volume, peak thoracic flow and the maximum rate of rise of aortic flow.
Administration of atropine, after the maximal bradycardic effect of l‐NAME was established, restored the heart rate to resting levels. Concurrently, there was a reduction in stroke volume, such that cardiac output, although transiently elevated, did not show a sustained increase. No other variables were significantly affected by atropine. Additional administration of atenolol had no effect other than to cause a slight bradycardia, such that in the presence of atropine and atenolol, heart rate was not different from that in animals receiving atropine and atenolol before l‐NAME.
In the presence of atropine and atenolol, l‐NAME had similar pressor, vasoconstrictor and cardiac haemodynamic effects to those in untreated animals, although the bradycardia was significantly attenuated. However, there was still a significant reduction in heart rate following l‐NAME in the presence of atropine and atenolol.
These results indicate that the major component of the bradycardia following l‐NAME is indirect and mediated through an increase in vagal efferent activity. However, the substantial reduction in cardiac function caused by l‐NAME is not dependent on the autonomic control of the heart but rather, may depend on the increase in afterload and/or a direct effect of l‐NAME on the heart and/or its vasculature.
α4‐β2 and other nicotinic acetylcholine receptor subtypes as targets of psychoactive and addictive drugs
Authors: Connolly John , Boulter Jim , Heinemann Stephen F. 
Published: July 2012

Xenopusoocytes were injected with various muscle and neuronal nicotinic acetylcholine receptor (ACh receptor, cholinoceptor) subunit RNA combinations and their pharmacological properties studied using two‐electrode voltage clamp. The functional expression of one of these combinations, rat α4–2β2, has not been previously described. The α4–2 mRNA is a splicing variant transcribed from the α4 gene. In the experiments reported here, the α4–2β2 subtype was functionally indistinguishable from the α4–1β2 subtype.For each subtype, the relative potency of nicotine compared with acetylcholine was obtained by estimating the relative concentration of nicotine which would elicit the same current response as 0.1 μmACh. The ratios of these concentrations (nicotine: ACh) for the mouse muscle ACh receptor‐(α1β1γδ) was 96.1:1. In contrast, the ratios for the rat neuronal subtypes were: α2β2, 1.01:1; α3β2, 2.01:1; α4β2, 0.76:1 and α4–2β2, 0.76:1. The much greater relative nicotine sensitivity of the neuronal subtypes as compared with muscle receptors illustrates their potential to mediate the psychoactive and addictive effects of nicotine. However, it does not appear that the differences in relative nicotinic sensitivity among the neuronal receptors themselves can be used as a simple discriminative tool in neuronal tissue.The slopes of the log dose‐log response curves at low ACh concentrations were all greater than 1 but less than 2, suggesting that at least two agonist binding sites mediate the functional response of each hetero‐oligomer.The response of all the neuronal subtypes to ACh could be inhibited by the psychoactive drugs mecamylamine, amitriptyline, phencyclidine, trifluoperazine and promethazine. With the exception of the very potent antagonist, mecamylamine, the degree of block of the peak current to ACh produced by 10 μmconcentrations of these drugs was remarkably similar (around 50%).The degree of inhibition produced when the antipsychotic drug, trifluoperazine, was co‐applied with ACh increased as the duration of application increased. Such an effect was not observed with promethazine, a related phenothiazine derivative which does not have antipsychotic actions.
8‐Hydroxy‐2‐(di‐n‐propylamino)tetralin impairs spatial learning in a water maze: role of postsynaptic 5‐HT1A receptors
Authors: Carli M. , Samanin R. 
Published: July 2012

The effect of 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), a 5‐HT1A receptor agonist, on place navigation was studied by use of two spatial tasks in a water maze.
In the first experiment, rats treated subcutaneously with 100 and 300 (but not 30) μg kg−1 8‐OH‐DPAT were impaired in their ability to locate a hidden platform. The probe test confirmed the impairment of spatial navigation but the effect (time spent in the training quadrant) was quantitatively different, depending on whether 8‐OH‐DPAT was administered only before each training session, only before the probe test or in both conditions.
In the second experiment, rats received 150 μg 5,7‐dihydroxytryptamine (5,7‐DHT) intracerebroventricularly to destroy 5‐hydroxytryptamine (5‐HT)‐containing neurones and 24 days later were examined for choice accuracy in a two‐platform spatial discrimination task.
At 100 (but not 30) μg kg−1 8‐OH‐DPAT impaired rats' accuracy with no effect on latency and no errors of omission. In 5,7‐DHT‐treated rats, this dose had a greater effect, including errors of omission. Sham‐operated rats injected with 300 μg kg−1 8‐OH‐DPAT were markedly impaired in accuracy but they had longer latencies and made more errors than controls. All the effects were increased in 5,7‐DHT treated rats.
The results suggest that, at doses causing no apparent changes in motor behaviour or motivation, 8‐OH‐DPAT impairs spatial navigation by stimulating postsynaptic 5‐HT1A receptors in the rat brain.
Effect of K+ channel‐modulating drugs on the vasoconstrictor responses of leukotrienes C4, D4 and angiotensin II in the guinea‐pig isolated perfused heart
Authors: McLeod J.D. , Piper P.J. 
Published: July 2012

The vascular actions of leukotrienes C4 (LTC4) and LTD4 in the guinea‐pig isolated perfused heart were studied in the presence of potassium (K+) channel modulatory compounds.
Cromakalim (0.35–10 μm), a K+ channel activator, inhibited the vasoconstrictor responses of LTC4 (30 pmol), LTD4 (30 pmol) and angiotensin II (AII) (100 pmol) in a concentration‐dependent manner.
Glyceryl trinitrate (10 mgl−1) and vasoactive intestinal peptide (10 nm) induced a similar vasodilator action to cromakalim in the isolated heart but had no effect on responses to LTC4 and LTD4.
The inhibitory action by cromakalim (10 μm) on the LTC4 (30 pmol) response could be reversed in the presence of an equimolar concentration of glibenclamide. However, glibenclamide (10 μm) only partially restored the LTD4 (30 pmol) actions.
Galanin (10 nm) and charybdotoxin (60 nm) had no effect on the vascular responses to LTC4 and LTD4 (30 pmol).
Inhibition by cromakalim of coronary vasospasm induced by vascular LTC4, LTD4 and AII appears to be separate from its vasodilator action and it is postulated that a cromakalim‐sensitive mechanism in the coronary vasculature is important in the vasoconstrictor responses to LTC4, LTD4 and AII.
The effect of adrenoceptor antagonists on the ileal brake mechanism in the rat
Authors: Brown Nicola J. , Rumsey R.D.E. , Bogentoft C. , Read N.W. 
Published: July 2012

Studies were carried out in the rat to investigate the effect of adrenoceptor antagonists on stomach to caecum transit time under control conditions and during ileal infusion of Intralipid. Stomach to caecum transit time (SCTT) of the head of the meal was measured by use of environmental hydrogen analysis and the distribution of the meal was assessed by a scintigraphic technique.
Four adrenoceptor antagonists were used in these studies, the α1 antagonist prazosin, the α2 antagonist, idazoxan, the β1 antagonist atenolol and the β2 antagonist ICI 118551.
None of the antagonists affected SCTT of the head of the meal during ileal infusion of saline. However, the α1 and β1 antagonists significantly reversed (P < 0.05) the delay in SCTT induced by ileal infusion of Intralipid whereas the α2 antagonist, idazoxan, potentiated this delay (P < 0.05).
Study of the distribution of the radiolabelled meal showed that the Intralipid delayed SCTT by slowing both gastric emptying (P < 0.05) and small bowel transit (P < 0.05).
Prazosin delayed gastric emptying under control conditions (P < 0.001) but did not alter significantly the effect of ileal lipid on the distribution of the meal, 100 min or 200 min after gavage. Idazoxan delayed gastric emptying during ileal infusion of saline (P < 0.05) and produced a proximal shift in the geometric centre of the meal in the small intestine (P < 0.001) and despite the apparent potentiation of the ileal brake effect indicated by the hydrogen analysis, idazoxan increased the amount of radioactivity in the colon 200 min after gavage (P < 0.05).
The meal distribution was more compatible with the hydrogen analysis after administration of the β‐adrenoceptor antagonists. The reversal of the lipid‐induced delay in SCTT caused by atenolol was associated with more radioactivity in the large intestine 200 min after the gavage. ICI 118551 had no significant effects on either the distribution of the meal or the SCTT of the head of the meal.
In conclusion, the data confirm that the sympathetic nervous system normally modulates or mediates the mechanisms that influence gastrointestinal transit in the rat and suggest that these mechanisms may be involved in the ileal brake effect. Nevertheless the data also suggest that simple measurement of the transit of the head of the meal by use of environmental hydrogen analysis may sometimes give a misleading impression of the action of drugs on gastrointestinal transit of the bulk of a test meal.
Short‐term desensitization of the histamine H1 receptor in human HeLa cells: involvement of protein kinase C dependent and independent pathways
Authors: Smit M.J. , Bloemers S.M. , Leurs R. , Tertoolen L.G.J. , Bast A. , de Laat S.W. , Timmerman H. 
Published: July 2012

In this study we have investigated the effects of short‐term exposure of cells to histamine on the subsequent H1 receptor responsiveness in HeLa cells, using Ca2+ fluorescence microscopy and video digital imaging.
In HeLa cells, histamine (100 μm) induces an immediate H1 receptor‐mediated biphasic elevation of the intracellular Ca2+ concentration ([Ca2+]i) (basal [Ca2+]i: 81 ± 30 nm, histamine‐induced Ca2+ response: first phase: 1135 ± 79 nm; second phase: 601 ± 52 nm, n = 11).
The histamine H1 receptors on HeLa cells are readily susceptible to desensitization since repetitive exposure of the same group of cells to histamine (100 μm) markedly affected the release and influx component of the induced Ca2+ response (second application of histamine: first phase: 590 ± 92 nm, second phase: 279 ± 47 nm; third application of histamine: first phase: 454 ± 127 nm, second phase: 240 ± 45 nm, n = 6). Video digital imaging revealed an increase in the lag time between stimulation and monitoring of the Ca2+ response and a reduced increase in [Ca2+]i after desensitization with histamine.
Neither the release component of the ATP response (50 μm) nor the caffeine (3 mm)‐induced Ca2+ release were found to be affected by desensitization with 100 μm histamine. However, the second phase of the ATP response was significantly reduced after desensitization with histamine (control cells: 516 ± 33 nm; desensitized cells: 331 ± 96 nm, n = 4, P < 0.05).
Activation of protein kinase C (PKC) by phorbol‐12‐myristate‐13‐acetate was found to inhibit the histamine as well as ATP‐induced Ca2+ response in a dose‐dependent manner.6 In PKC downregulated cells the second phase of the histamine‐induced Ca2+ response was significantly elevated, indicating the involvement of PKC in the negative feedback on the Ca2+ influx (control cells: second phase: 601 ± 52 nm (n = 11); PKC downregulated cells: second phase: 890 ± 90 nm, n = 10, P < 0.05).7 Homologous desensitization of H1 receptor responsiveness was still observed in PKC downregulated cells, implying the rapid activation of a regulatory mechanism other than PKC.8 Based on our experimental data we suggest that short‐term desensitization of the histamine H1 receptor evolves from two different processes: a selective reduction of the histamine‐induced Ca2+ release, mediated by a PKC‐independent pathway, and a non‐selective inhibition of the receptor‐mediated Ca2+ influx activated by a PKC‐dependent pathway.
Pharmacological modulation of inhaled sodium metabisulphite‐induced airway microvascular leakage and bronchoconstriction in the guinea‐pig
Authors: Sakamoto Tatsuo , Elwood Wayne , Barnes Peter J. , Chung K. Fan 
Published: July 2012

We have investigated the effects of chlorpheniramine, atropine and capsaicin pretreatment on inhaled sodium metabisulphite (MBS)‐induced airway microvascular leakage and bronchoconstriction in anaesthetized guinea‐pigs in order to clarify the mechanisms involved in these responses. The effects of frusemide and nedocromil sodium were also examined.
Lung resistance (RL) was measured for 6 min after inhalation of MBS (20, 40, 80 and 200 mm; 30 breaths), followed by measurement of extravasation of Evans blue dye into airway tissues, used as an index of airway microvascular leakage. MBS caused an increase in RL and leakage of dye at all airway levels in a dose‐dependent manner.
Chlorpheniramine (10 mg kg−1, i.v.), atropine (1 mg kg−1, i.v.), their combination or inhaled nedocromil sodium (10 mg ml−1, 7 min) had no effect against the airway microvascular leakage induced by 80 mm MBS (30 breaths). Capsaicin pretreatment (50 mg kg−1, s.c.) caused a significant decrease in the leakage of dye in the main bronchi and inhaled frusemide (10 mg ml−1, 7 min) also in the main bronchi and proximal intrapulmonary airway.
Chlorpheniramine, atropine, their combination, capsaicin pretreatment and frusemide, but not nedocromil sodium, inhibited significantly the peak RL induced by 80 mm MBS (30 breaths) by approximately 50%.
We conclude that a cholinergic reflex and neuropeptides released from sensory nerve endings may participate in the mechanisms of MBS‐induced airway responses. Frusemide but not nedocromil sodium may have an inhibitory effect on these neural mechanisms. The inhibitory effect of nedocromil sodium against lower doses of MBS is not excluded.
Lack of effect of the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine on arteriovenous anastomotic shunting in the dura mater of the pig
Authors: den Boer Marinus O. , Somers Judith A.E. , Saxena Pramod R. 
Published: July 2012

In anaesthetized animals, the antimigraine drugs, sumatriptan, ergotamine and dihydroergotamine, reduce carotid arteriovenous anastomotic shunting. Within the carotid vascular bed arteriovenous anastomoses are located, amongst other places in the dura mater, which is a putative site of the pain during a migraine attack.
In this investigation, we have localized and measured the arteriovenous shunting within the carotid vascular bed of the pig by using simultaneous intracarotid injections of radiolabelled microspheres of three different sizes (10, 15 and 50 μm), which provides an index of blood flow via arteriovenous anastomoses larger than approximately 14, 27 and 90 μm diameter, respectively. The effects of sumatriptan (0.3 mg kg−1), ergotamine (0.02 mg kg−1), dihydroergotamine (0.1 mg kg−1) and saline were studied by repeating the injections of 15 and 50 μm spheres after the treatments.
There was no difference in shunting or entrapment between the 10 and 15 μm microsphere, indicating the absence of arteriovenous anastomoses with a diameter between 14 and 27 μm.
Arteriovenous anastomoses with a diameter between 27 and 90 μm, as indicated by the difference in blood flow measured by 15 and 50 μm spheres, were located in the dura mater, ears, skin, fat and, to a lesser extent, in the skeletal muscles and eyes.
Sumatriptan, ergotamine and dihydroergotamine reduced the overall flow in the smaller arteriovenous anastomoses (diameter between 27 and 90 μm), and even more in larger shunts (wider than 90 μm).
Locally, blood flow in the smaller arteriovenous shunts was reduced in the skin and fat, but not in the dura mater, ears, eyes and muscles. It is not possible to determine in which tissues blood flow in the larger arteriovenous anastomoses was reduced.
Tissue blood flow measured with 15 μm microspheres remained unchanged after the three antimigraine drugs, implying a lack of effect on capillary flow.
It is concluded that in the anaesthetized pigs the only evident effect of these antimigraine drugs on carotid haemodynamics is a decrease in blood flow in both smaller and larger arteriovenous anastomoses; the smaller arteriovenous anastomoses were affected in the skin and fat, but not in other tissues.
Endothelial‐dependent sexual dimorphism in vascular smooth muscle: role of Mg2+ and Na+
Authors: Zhang Aimin , Altura Bella T. , Altura Burton M. 
Published: July 2012

Summary
. In isolated aortae of the male rat [Mg2+]o withdrawal and concomitant reduction in [Na+]o (to 84 mm) induced significant increases of basal tone, but, surprisingly, this did not occur in intact aortae removed from female rats. Such tension development, however, was observed in endothelium‐denuded aortic preparations from both sexes. These observed gender‐related differences were not dependent on animal strain or types of tissue preparations.
. No tension development was observed in aortae obtained from castrated males treated with oestradiol. Aortic tissues of sexually‐immature male and female rats exhibited marked tension development when exposed to 0 mm [Mg2+]o and low [Na+]o.
. Tension development in Mg2+‐free, low‐Na+ media was not tachyphylactic and completely dependent on extracellular Ca2+; addition of 1.2 mm Mg2+ to the Mg2+ and Na+‐deficient incubation media relaxed the increase in tension to a normal basal level.
. Two known endothelial‐derived relaxant factor (EDRF) inhibitors, methylene blue and haemoglobin, induced tension development in female aortae with intact endothelium exposed to Mg2+‐Na+ deficient media, while use of a specific inhibitor of EDRF‐derived nitric oxide, viz., NG‐monomethyl‐l‐arginine (l‐NMMA), resulted in potentiation of tension development in male, but not in female, aortae. This effect of l‐NMMA was antagonized by l‐arginine.
. The Ca ionophore, A23187, partially relaxed contractile responses in male aortae (with intact endothelium) which were followed by potentiated contractions. Endothelium‐dependent vasodilator responses to A23187 (10−10−10−6 m) of aortic rings from male or female rats in normal Krebs‐Ringer bicarbonate solution were not different.
. These results suggest that: (a) as in vascular smooth muscle cells, Mg2+ plays an important role in Ca2+ homeostasis in endothelial cells, probably via Na+‐Ca2+ exchange; and (b) sex steroid hormones, probably the female sex hormone, 17‐β‐oestradiol, may regulate contractile responses of intact vascular smooth muscle by modifying endothelium functions through such Mg2+‐regulated internal Na+‐dependent Ca2+ entry. These data may help to explain why female subjects, despite Mg deficiency, unlike male subjects, are protected against ischaemic heart disease and cerebrovascular disease until menopause.
M‐currents in frog sympathetic ganglion cells: manipulation of membrane phosphorylation
Authors: Chen Hsinyo , Smith Peter A. 
Published: July 2012

Summary
. The inward current and the M‐current (IM) suppression produced when muscarine is applied to frog sympathetic ganglion cells was recorded by means of the whole‐cell patch‐clamp technique. The holding potential was −30 mV and [K+]o was 6 mm.
. The steady‐state IM was maintained for at least 20 min when the patch pipette contained neither adenosine 5′‐triphosphate (ATP) nor adenosine 3′:5′‐cyclic monophosphate (cyclic AMP). Inclusion of these substances or the ATP antagonst, β,γ‐methyleneadenosine 5′‐triphosphate (β,γ‐MethATP; 1 or 2 nm) (failed to alter the rate of IM ‘run down’. By contrast, inclusion of adenosine‐5′‐O‐(3‐thiotriphosphate) (ATP‐γ‐S, 1 or 2 mm) resulted in a 60% reduction of the current within 18 min.
. Despite the inability of ATP‐γ‐S to maintain steady‐state IM, it had no effect on the ability of muscarine (2–100 μm) to suppress a constant fraction of the available current. ATP‐γ‐S and β,γ‐MethATP increased the rise time and duration of the response to muscarine.
. Inclusion of a phosphatase inhibitor, diphosphoglyceric acid (DPG, 1–2.5 mm) or alkaline phosphatase (100 μg ml−1) failed to affect the amplitude of muscarinic responses.
. These results question the role of the phosphorylation and/or dephosphorylation reactions in the transduction mechanism for muscarine‐induced IM suppression but are consistent with the possibility that M‐channels are ‘directly coupled’ via G‐protein to the muscarinic receptor.
An ubiquitous modulating function of rabbit tracheal epithelium: degradation of tachykinins
Authors: Inoue Kazuaki , Sakai Yasushi , Homma Ikuo 
Published: July 2012

To examine the role of epithelium in the responsiveness of tracheal smooth muscle in rabbit, we measured the contractile responses to acetylcholine (ACh), KCl, 5‐hydroxytryptamine (5‐HT), histamine, substance P (SP), neurokinin A (NKA), and electrical field stimulation (EFS) in intact and epithelium‐denuded preparations.
Removal of epithelium did not alter the contractile response to any agonist examined, except SP.
Removal of epithelium enhances the contractile response to SP. In the presence of phosphoramidon, the contractile response to SP was not significantly different in either group. The results suggest that the effect of epithelium is largely due to degradation of SP by enzymes in the epithelium.
Arachidonic acid metabolites did not seem to be related to the responses induced by contractile agonists or EFS.
In the presence of SP, the contractile responses and [3H]‐choline outflow evoked by EFS were dose‐dependently enhanced. Contractile responses to EFS and [3H]‐choline outflow evoked by EFS were enhanced by SP significantly more than by NKA. Both were abolished by atropine or tetrodotoxin.
These results suggest that rabbit tracheal epithelium may modulate SP‐induced contractions, both direct and indirect, by inactivation of SP. This phenomenon is widespread in mammals. The rabbit may be a useful model to examine airway cholinergic functions.