bluuebunny/crossref_metadata_2025_split huggingface dataset:
The key role of sodium in the ouabain‐mediated potentiation of potassium‐evoked catecholamine release in cat adrenal glands
Authors: Abajo Francisco J. , Castro Maria Antonia S. , Sánchez‐García Pedro 
Published: July 2012

The effect of [Na]o on the catecholamine release evoked by K in ouabain pretreated, isolated adrenal glands of the cat, was investigated.
Reduction of [Na]o to 70, 50 and 25 mM, with sucrose as a substitute, did not modify the spontaneous catecholamine release but progressively increased the K (17.7 mm)‐evoked secretory response.
Ouabain pretreatment (100 μm; 10 min) greatly increased the K (17.7 mm)‐evoked catecholamine secretory response in glands perfused with normal Krebs. Such an increase was still seen in glands perfused with 70 mM Na‐containing solution but disappeared when [Na]o was reduced to 25 and 10 mM.
Preperfusion of non‐ouabain treated glands with Li‐enriched Krebs, for a 40 min period, caused an increase in the K (17.7 mm)‐evoked secretory response which was dependent on [Li]o and essentially similar to that induced by ouabain, pretreatment.
Ouabain treatment (100 μm; 10 min) of glands perfused with normal Krebs evoked a long lasting catecholamine release, which reached a plateau at about 36 min and amounted to 0.68 ± 0.25 μg 2 min−1 (n = 9). Such a secretory response was dramatically increased, and its shape modified, when glands were preperfused with K (17.7 mm)‐Krebs: a peak of 3.77 ± 0.42 μg 2 min−1 (n = 7) was reached at 18 min. This response was drastically reduced in the presence of nitrendipine (1μm).
In summary, our results indicate that both [Na]o reduction or Na accumulation into the chromaffin cell by inhibition of the Na pump with ouabain, greatly enhance the secretory efficacy of small increments of [K]o, and suggest that sodium may play a role in the regulation of catecholamine release mediated by voltage‐dependent Ca channels in adrenal glands.
The interaction of hexamethonium with muscarinic receptor subtypes in vitro
Authors: Eglen R.M. , Michel A.D. , Cornett C.M. , Kunysz E.A. , Whiting R.L. 
Published: July 2012

The action of hexamethonium has been studied at a range of muscarinic receptors in vitro by use of both functional and radioligand binding studies.
In functional studies, hexamethonium exhibited little or no significant (P < 0.05) antagonism of contractile responses to carbachol at muscarinic receptors in the guinea‐pig ileum, oesophageal muscularis mucosae, urinary bladder and trachea. However, antagonism was observed at muscarinic receptors in the guinea‐pig left atria mediating negative inotropic responses and the calculated pKB value was 3.80. Hexamethonium also antagonized contractile responses to carbachol in the canine saphenous vein. The pKB value at these receptors was 3.75.
In the presence of 3.2 mM hexamethonium, the pA2 value for methoctramine at atrial muscarinic receptors was reduced by approximately 10 fold (control pA2 value was 7.81 ± 0.05; pA2 value in hexamethonium was 6.73 ± 0.04). In contrast at tracheal muscarinic receptors, the pA2 values for methoctramine were unaffected in the presence of 3.2 mM hexamethonium (control pA2 = 5.58 ± 0.07; pA2 value in hexamethonium was 5.63 ± 0.12). All values quoted are mean ± s.e.mean, n = 8.
In competition radioligand binding studies, hexamethonium exhibited a higher affinity for cardiac M2 receptors (pKi = 3.68) than for cerebrocortical M1 receptors (pKi = 3.28) or for submaxillary gland M3 receptors (pKi = 2.61). At M2 receptors hexamethonium at concentrations of 0.1–10 mM, increased the half life of the dissociation rate of [3H]‐N‐methylscopolamine 1.6‐4.3 fold. This was observed at M3 receptors only at 10 mM, when the half life was increased 1.7 fold.
We conclude that hexamethonium, in addition to its well characterized nicotinic antagonist properties, can act as a weak muscarinic antagonist and differentiates between cardiac M2 receptors and glandular/smooth muscle M3 receptors. However, hexamethonium differentiates less clearly between M1 and M2 receptors. The selectivity between M2 and M3 receptors observed in the present study with hexamethonium is comparable to other M2 selective antagonists such as AF‐DX 116 and himbacine.
Caution should be exercised with regard to the inclusion of hexamethonium in functional studies of M2 muscarinic receptor subtypes at concentrations of 0.1 mM and above.
Metabolism of amines in the isolated perfused mesenteric arterial bed of the rat
Authors: Elliott Jonathan , Callingham Brian A. , Sharman Dennis F. 
Published: July 2012

Semicarbazide‐sensitive amine oxidase (SSAO) activity has been demonstrated in the isolated mesenteric arterial bed of the rat in vitro by studying the metabolism of benzylamine (Bz) and tyramine (Tyr) added to the perfusing fluid.
Pretreatment of rats with (E)‐2‐(3′,4′‐dimethoxyphenyl)‐3‐fluoroallylamine (MDL72145), a potent inhibitor of SSAO in rat mesenteric blood vessels, reduced the amount of metabolites, following the addition of Bz (25 μm) or Tyr (100 μm) to the perfusing fluid, by 83% and 52% respectively. Inactivation of monoamine oxidase type A (MAO‐A) by the addition of clorgyline (10 μm) to the perfusing fluid, had little effect on the appearance of metabolites from Tyr.
The presence of 3 μm cocaine in the perfusing fluid increased the amount of metabolites produced from Tyr.
The metabolites of Tyr appearing in the perfusion fluid from control preparations were 85% p‐hydroxyphenylacetic acid and the remainder consisted of a mixture of p‐hydroxyphenylacetaldehyde and, possibly, p‐hydroxyphenylethanol.
The metabolism of Tyr by homogenates of the rat mesenteric vascular bed was carried out by SSAO (60%) and MAO‐A (40%) with very little contribution from MAO‐B. Homogenates from rats pretreated with MDL 72145 showed metabolism of Tyr by MAO‐A only.
These data indicate that SSAO is capable of metabolizing amines present in the fluid perfusing blood vessels to metabolites that are readily released. Histochemical evidence has shown that whereas MAO‐A is present in the mitochondria of smooth muscle cells and nerve endings, SSAO is located in the plasma membrane of the smooth muscle cells. This subcellular distribution may explain the differences found between metabolites released from intact vessels and the metabolism seen in homogenates. The identity of the Tyr metabolizing activity in intact vessels that is resistant to both MDL 72145 and clorgyline remains to be determined.
Spinal antinociceptive actions and naloxone reversibility of intravenous μ‐ and κ‐opioids in spinalized rats: potency mismatch with values reported for spinal administration
Authors: Parsons Chris G. , West David C. , Headley P. Max 
Published: July 2012

The relative spinal effectiveness of μ‐ and κ‐opioids has been assessed by their intravenous potencies on nociceptive responses (heat and/or pinch) of single motoneurones recorded in α‐chloralose anaesthetized, spinalized rats.
The depressant actions of both μ‐ and κ‐opioids were reversed by low intravenous doses of naloxone (10 to 100 μg kg−1). When tested at a dose of 1 μg kg−1 i.V., naloxone antagonized the effects of the μ‐agonist morphine but had no effect on the κ‐opioid U‐50,488. This provides further support for the theory that the actions of μ‐ and κ‐ligands were mediated at different subclasses of opioid receptor but highlights the difficulties in using antagonists with poor receptor selectivity to differentiate between μ‐ and κ‐receptor‐mediated effects in vivo.
The molar potency ratios of fentanyl: morphine: U‐50,488: tifluadom for thermal and mechanical nociceptive responses were 620:1.0:0.74:5.7 and 520:1.0:0.56:7.7 respectively. These potency ratios, as well as the absolute potencies, agree well with those reported in several behavioural studies in which systemic administration of agonists was used in non‐thermal tests.
The agonist potency values obtained in this study contrast with those reported for local spinal administration. By this route, the potency of lipophilic opioids (e.g. fentanyl, U‐50,488 and tifluadom) relative to hydrophilic opioids (e.g. morphine) is much reduced, implying that activity of intrathecally administered opioids is more dependent on the physico‐chemical properties of the agonists used than on the relative abundance in the spinal cord of functional opioid receptors of the μ‐ and κ‐subtypes. This conclusion indicates that the results with locally applied opioids should not be used to assess spinal opioid receptor function.
On the selectivity of intravenous μ‐ and κ‐opioids between nociceptive and non‐nociceptive reflexes in the spinalized rat
Authors: Parsons Chris G. , Headley P. Max 
Published: July 2012

In electrophysiological experiments in spinalized, α‐chloralose anaesthetized rats, opioids and anaesthetics were tested intravenously (i.v.) on the responses of individual motoneurones to alternating noxious (heat or pinch) and non‐noxious (tap or vibration) stimuli.
On cells that were sensitive to low doses of μ‐opioids, both fentanyl (0.5–4 μg kg−1 i.v.) and morphine (0.5 mg kg−1 i.v.) selectivity reduced reflexes to noxious stimuli to a greater degree than reflexes to non‐noxious stimuli. In contrast, on cells that were relatively resistant to these agonists, the higher doses required to reduce nociceptive reflexes (fentanyl 8 μg kg−1 i.v.; morphine 1–8 mg kg−1 i.v.) depressed non‐nociceptive reflexes to a similar degree.
A similar spectrum of selectivity was seen with U‐50,488 (0.5–16 mg kg−1 i.v.) although statistically significant selective depression of reflexes was only evident at the lowest dose tested (0.5 mg kg−1 i.v.). All effects of U‐50,488 were readily reversed by low doses of the opioid antagonist, naloxone (10–100 μg kg−1 i.v.).
The dissociative anaesthetic/PCP ligand ketamine (0.5–4 mg kg−1 i.v.) was similar in having selective actions at low doses on sensitive cells but non‐selective actions when higher doses were required. In contrast, the general anaesthetics methohexitone (4 mg kg−1 i.v.) and alphadolone/alphaxalone (1 mg kg−1 i.v.) were consistently non‐selective between reflexes to noxious and non‐noxious stimuli. α‐Chloralose (20–40 mg kg−1 i.v.) had very little effect on reflexes to any of the synaptic inputs tested.
The sensitivity of nociceptive reflexes to depression by opioids and dissociative anaesthetics thus determines the selectivity of these agents between nociceptive and non‐nociceptive reflexes. The same is not true for the general anaesthetics tested.
Taken together with our previous findings that κ‐ as well as μ‐agonists reduce thermal and mechanical nociceptive reflexes in parallel, these results indicate a general similarity of spinal μ‐ and κ‐opioid actions in the spinal cord of the rat.
Simultaneous measurement of endothelium‐derived relaxing factor by bioassay and guanylate cyclase stimulation
Authors: Kondo Kigen , Mitchell Jane Allison , de Nucci Gilberto , Vane John Robert 
Published: July 2012

Endothelium‐derived relaxing factor (EDRF) released by cultured endothelial cells (EC) from bovine aortae was measured by bioassay using pre‐contracted strips of rabbit aorta and by radioimmunoassay of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) produced by stimulation of bovine lung soluble guanylate cyclase.
Bradykinin (Bk, 3 and 30 pmol) injected through a column of EC caused release of EDRF as detected by bioassay and increased cyclic GMP concentrations. Superoxide dismutase (SOD, 15 u ml−1) increased the amount of EDRF detected by the activation of soluble guanylate cyclase.
In the absence of endothelial cells, nitric oxide (NO, 1–2 μm), arachidonic acid (AA, 3–30 μm) or sodium nitröprusside (SNP, 1–100 μm) stimulated guanylate cyclase. Superoxide dismutase strongly increased the stimulation of guanylate cyclase induced by NO, but had little effect on the stimulation induced by SNP and no effect on the stimulation induced by AA.
Oxyhaemoglobin (10–300 μm) abolished the stimulation of guanylate cyclase by EDRF, NO or SNP but was much less effective as an inhibitor of AA‐induced stimulation of guanylate cyclase.
These results demonstrate that measurement of guanylate cyclase stimulation by radioimmunoassay is a viable method for detecting EDRF release, especially useful when the drugs used interfere with bioassay tissues.
Endothelium‐dependent calcium‐induced relaxation in the presence of Ca2+ ‐antagonists in canine depolarized coronary arteries
Authors: Kikkawa Kohei , Murata Sakae , Nagao Taku 
Published: July 2012

We examined the mechanisms underlying Ca2+‐induced relaxation in the presence of clentiazem, a new Ca2+‐antagonist, in depolarized coronary arteries of the dog.
Ca2+ (3 × 10−5−3 × 10−3m) caused an unexpected relaxation in the presence of a high concentration of clentiazem (10−6m) in coronary, but not in mesenteric or renal arteries.
The Ca2+‐induced relaxation was also observed in the presence of established Ca2+‐antagonists such as diltiazem (3 × 10−6m), nifedipine (3 × 10−8m) and verapamil (3 × 10−6m).
The Ca2+‐induced relaxation was inhibited by removal of the endothelium, treatment with oxyhaemoglobin (1.5 × 10−6m) or methylene blue (10−5m), but not by treatment with indomethacin (5 × 10−6m).
The Ca2+‐induced relaxation was observed in an endothelium‐denuded coronary artery segment when closely apposed to an endothelium‐containing segment of coronary or mesenteric artery.
These results suggest that Ca2+‐induced relaxation in the presence of high concentrations of Ca2+‐antagonists is mediated through endothelium‐derived relaxing factor (EDRF). In addition, Ca2+‐antagonists do not affect the Ca2+‐influx necessary for the release and/or synthesis of EDRF.
Mechanisms underlying the antiarrhythmic properties of β‐adrenoceptor blockade against ischaemia‐induced arrhythmias in acutely prepared rats
Authors: Paletta M.J. , Abraham S. , Beatch G.N. , Walker M.J.A. 
Published: July 2012

The mechanism underlying the limited antiarrhythmic effects of β‐adrenoceptor blocking agents against occlusion‐induced arrhythmias in acutely prepared, pentobarbitone‐anaesthetized rats has been investigated.
Atenolol, ICI 111,581 and propranolol were given at low, medium and high doses calculated to shift dose‐response curves to exogenous agonists by factors of 10–30, 100–300 and 1000–3000, respectively.
Arrhythmias, blood pressure, heart rate, ECG changes and serum K+ were measured.
Antiarrhythmic activity was seen with β‐blocker treatment. This was minimal with atenolol (0.1, 1 and l0 mg kg−1) and only statistically significant with the highest dose of ICI 111,581 (5 mg kg−1), and propranolol (10 mg kg−1).
Treatment with β‐adrenoceptor blockers elevated serum potassium concentrations, as compared with saline controls, especially when measured at 30 min post‐occlusion.
Only ICI 111,581 (5 mg kg−1) and propranolol (1 and 10 mg kg−1) prolonged P‐R interval.
In order to evaluate possible mechanisms of antiarrhythmic action, attempts were made to correlate antiarrhythmic activity with β‐blockade, serum potassium concentrations, and/or with changes in the P‐R interval of the ECG.
Reductions in arrhythmias did not correlate well with presumed β‐blockade. Better correlation was obtained with elevations of serum potassium concentration, and with prolongation of P‐R interval (a presumed Class I antiarrhythmic action).
These results suggested that antiarrhythmic effects of adrenoceptor blocking agents in acutely‐prepared anaesthetized rats, subjected to occlusion of a coronary artery, are unrelated to cardiac β‐blockade. The limited antiarrhythmic effects which were observed could be attributed to elevations in serum potassium concentration (due to peripheral β‐blockade) and/or possible Class I antiarrhythmic actions.
Nicotinic excitation of rat ventral tegmental neurones in vitro studied by intracellular recording
Authors: Calabresi P. , Lacey M.G. , North R.A. 
Published: July 2012

Intracellular recordings were made from presumed dopamine‐containing neurones in the ventral tegmental area (VTA) in rat brain slices.
Nicotine (10–100 μm) and acetylcholine (ACh) depolarized the neurones. The depolarization caused by ACh was typically biphasic; both components were increased by neostigmine (0.1–10 μm), but only the slower component was blocked by scopolamine (1–10 μm).
The nicotinic action of ACh, studied in the presence of neostigmine and scopolamine, persisted in the presence of tetrodotoxin (1 μm) and cobalt (2–5 mM).
ACh or carbachol (30 μm) caused inward currents in neurones voltage‐clamped near the resting potential. These currents reversed polarity at around −4mV, were blocked by hexamethonium (1–100 μm) in a voltage‐dependent manner, and showed desensitization with prolonged or repeated agonist applications.
Depolarizations caused by ACh and carbachol were reduced in slices pretreated with κ‐bungarotoxin, but were not changed by α‐bungarotoxin.
These responses to ACh and nicotine resemble those previously described on autonomic ganglion cells. The direct action on VTA neurones may contribute to the positive reinforcement associated with nicotine consumption.
Actions of anaesthetics and avermectin on GABAA chloride channels in mammalian dorsal root ganglion neurones
Authors: Robertson Brian 
Published: July 2012

The γ‐aminobutyric acid (GABA)‐mimetic actions of some anaesthetics and the antehelminthic avermectin B1a were examined on freshly isolated mammalian dorsal root ganglion (DRG) neurones by use of suction electrodes and a single electrode voltage clamp.
Pentobarbitone (60 μm‐3 mM), chloralose (600 μm‐1 mM), etomidate (10–100 μm), alphaxalone (10–60 μm) and avermectin (10–60 μm) directly activated chloride channels in GABA‐sensitive DRG neurones. The agonist action was sensitive to block by bicuculline and picrotoxinin.
Steady‐state current‐voltage (I‐V) curves for the anaesthetics were either linear, or rectified in the opposite direction to steady‐state I‐V curves obtained with GABA. Current relaxations in response to voltage jumps were also of the opposite direction. An extra surge of current (‘bounce’) was commonly observed on washout of some of these agonists.
Pentobarbitone was ineffective as an agonist at alkali pH (10.4 and 9.4), but was approximately twice as effective at acid (5.4) than at normal (7.4) pH values.
These results suggest that some anaesthetics and avermectin are capable of ‘blocking’ GABA channels in addition to activating them.
Cardiac electrophysiological actions of captopril: lack of direct antiarrhythmic effects
Authors: Hemsworth Paul D. , Pallandi Regan T. , Campbell Terence J. 
Published: July 2012

Standard microelectrode techniques were used to study the effects of captopril (1, 10 and 100 μm) on action potentials recorded from guinea‐pig ventricular cells and sinoatrial node cells.
Captopril had no effect on the maximum rate of depolarization () of ventricular action potentials in cells exposed to either normal Locke solution or ‘simulated ischaemic’ solution (K+ = 11.2 mM; pH = 6.4; Po2 < 80 mmHg), nor was there any augmentation of the normal small decline in with increasing stimulation rate (range of interstimulus intervals = 2400 ms to 300 ms).
Captopril had no effect on the duration of ventricular action potentials, nor did it alter the shortening seen on exposure to simulated ischaemia.
Captopril did not alter spontaneous sinus cycle length or any recorded parameter of sinus node action potentials.
It is concluded that any antiarrhythmic effects observed during clinical use of captopril are most unlikely to be due to direct actions of the drug on cardiac cell membrane properties.
Accumulation of extracellular calcium at the endplate of mouse diaphragm after ecothiopate in vitro
Authors: Burd P.F. , Ferry C.B. , Smith J.W. 
Published: July 2012

Experiments were carried out to investigate the accumulation from the extracellular medium of 45Ca2+ by the endplate region of skeletal muscle.
Mouse diaphragm muscle was incubated in physiological saline labelled with 45Ca at 37°C for periods of up to 1.5 h.
The muscle was divided into junctional and non‐junctional portions and the Ca from the extracellular fluid accumulated at the endplate determined from the 45Ca content of the portions.
The accumulation of extracellular Ca at the endplate region of muscles incubated in physiological saline alone was nil, but there was accumulation in the presence of the anticholinesterase ecothiopate iodide 0.5 × 10−6 m (ECO). Stimulation of the phrenic nerve at 0.02 Hz caused no further increase in accumulation, but reduced the amount of spontaneous fasciculation. In tetrodotoxin (TTX) 10−6 m, the accumulation was halved, and in 3.5 mM Mg2+ the accumulation was nil. Carbachol 10−4 m resulted in an accumulation of Ca similar to that in ECO.
It is concluded that there was an accumulation of extracellular Ca following excitation of the nerve by stimulation at a low frequency and during the spontaneous fasciculations, and about half of the accumulation of extracellular Ca after ECO in the experiments was due to the postsynaptic action of ACh released non‐quantally from the nerve terminals.
Inotropic response to DPI 201‐106 in the failing human heart
Authors: Böhm Michael , Diet Frank , Kemkes Bernhard , Wankerl Michael , Erdmann Erland 
Published: July 2012

The present study was designed to characterize the positive inotropic response to DPI 201‐106 in isolated papillary muscle strips obtained from heart failure patients undergoing surgery.
The positive inotropic responses to isoprenaline and milrinone and cardiac β‐adrenoceptor density were also determined.
DPI 201‐106 increased the force of contraction in papillary muscle strips from patients with moderate (NYHA II‐III) and severe (NYHA IV) heart failure, in a concentration‐dependent manner. This positive inotropic effect was more pronounced in tissues from NYHA IV patients. Furthermore, these responses were greater than those produced by milrinone or isoprenaline. The positive inotropic effects of isoprenaline and milrinone were reduced in NYHA IV compared to NYHA II‐III. Consistently, there was also a smaller density of β‐adrenoceptors in myocardium from NYHA IV than in NYHA II‐III. The positive inotropic effect of Ca2+ was similar in tissues from both groups of patients.
The positive inotropic effect of DPI 201‐106 was not antagonized by adenosine or carbachol, whereas both compounds reduced the positive inotropic effect of isoprenaline.
DPI 201‐106 did not increase the Ca2+‐sensitivity of chemically skinned ventricular fibres, whereas a significant increase of the Ca2+‐sensitivity was obtained with trifluoperazine.
It is concluded that DPI 201‐106 produces significant positive inotropic effects in tissue excised from the failing human heart. The lack of inhibition by adenosine and carbachol might contribute to its greater effectiveness in NYHA IV than NYHA II‐III and indicates that its mechanism of action is cyclic AMP‐independent. A sensitization of the contractile proteins to Ca2+ does not appear to be important for the positive inotropic action of DPI 201‐106 in the failing human heart.