bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of α‐adrenoceptor agonists on cardiac output and its regional distribution in the pithed rat
Authors: Hiley C. Robin , Thomas G. Roger 
Published: July 2012

Cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in pithed rats during pressor responses elicited by either α1‐adrenoceptor agonists (cirazoline, phenylephrine) or α2‐adrenoceptor agonists (xylaxine, B‐HT 933). Two doses were used for each of cirazoline and B‐HT 933 and phenylephrine was investigated in the presence of propranolol (3 mg kg−1). The rats were pithed under halothane anaesthesia.
Cardiac output was increased by xylazine, the higher dose of B‐HT 933 and phenylephrine. Heart rate was increased by phenylephrine and the higher doses of both cirazoline and B‐HT 933. Stroke volume was greater in those groups given xylazine, phenylephrine and the higher dose of B‐HT 933 but was decreased in those animals given the higher dose of cirazoline.
Both α2‐adrenoceptor agonists increased the number of microspheres trapped in the lungs and the proportion of the cardiac output passing through the hepatic artery but decreased that flowing through the spleen and gastrointestinal tract. The higher dose of B‐HT 933 also decreased the fraction of cardiac output flowing to the kidneys but kidney blood flow was maintained as a result of the increased cardiac output. Also, this treatment reduced blood flow in the epididimal fat pads.
Both α1‐adrenoceptor agonists increased the fraction of cardiac output received by the coronary vasculature but the only other effect on distribution common to these agents was an increase in the percentage of the cardiac output passing to the hepatic artery. Cirazoline decreased the proportion of cardiac output distributed to the gastrointestinal tract and spleen but the total fraction of cardiac output passing to the hepatosplanchnic region was maintained as a result of the increase to the hepatic artery.
Cirazoline markedly reduced the proportion of the cardiac output received by the kidneys and absolute flow in these organs was only 1.4% of control after the higher dose of this agonist but flow at the lower dose was maintained by the higher cardiac output.
It is concluded that there is a significant contribution to the pressor responses elicited by α‐agonists resulting from an α‐adrenoceptor‐mediated increase in cardiac output that may result from greater heart rates or stroke volumes. Also, there is a differential distribution of α‐receptor subtypes throughout the vasculature which is especially noticeable in the kidneys.
The action of pentobarbitone on stimulus‐secretion coupling in adrenal chromaffin cells
Authors: Pocock G. , Richards C.D. 
Published: July 2012

The action of pentobarbitone on stimulus‐secretion coupling was studied in bovine isolated adrenal medullary cells.
Pentobarbitone inhibited catecholamine release evoked by 500 μm carbachol with half maximal inhibition (IC50) around 50 μm. It also inhibited catecholamine release induced by depolarization with 77 mm potassium (IC50 100 μm). These effects of pentobarbitone were observed with concentrations that lie within the range encountered during general anaesthesia.
Evoked secretion required the presence of calcium in the extracellular medium and was associated with an influx of Ca2+ through voltage‐sensitive channels. Pentobarbitone inhibited 45Ca influx in response to both carbachol (IC50 50 μm) and K+‐depolarization (IC50 150 μm).
The action of pentobarbitone on the relationship between intracellular free Ca and exocytosis was examined using electropermeabilised cells which were suspended in solutions containing a range of concentrations of ionised calcium between 10−8 and 10−4 M. Catecholamine secretion was measured in the presence of 0, 50, 200 or 500 μm pentobarbitone. The anaesthetic had no effect on the activation of exocytosis by intracellular free calcium.
When catecholamine secretion in response to potassium or carbachol was modulated by varying extracellular calcium or by adding pentobarbitone to the incubation medium, the amount of catecholamine secretion for a given Ca2+ entry was the same.
Pentobarbitone inhibited the secretion and 45Ca uptake induced by carbachol in a non‐competitive manner.
The secretion evoked by nicotinic agonists was associated with an increase in 22Na influx. Pentobarbitone inhibited this influx with an IC50 of 100 μm.
We concluded that: (a) Pentobarbitone inhibits the catecholamine secretion from bovine adrenal chromaffin cells induced by nicotinic agonists by non‐competitive inhibition of the nicotinic receptor. (b) The decrease in Ca influx caused by pentobarbitone accounts fully for the decrease in secretion in response to depolarization with potassium.
PD117302: a selective agonist for the κ‐opioid receptor
Authors: Clark C.R. , Birchmore B. , Sharif N.A. , Hunter J.C. , Hill R.G. , Hughes J. 
Published: July 2012

A new nonpeptide κ‐opioid compound, a cyclohexyl benzeneacetamide derivative (PD117302), has been synthesized and its affinity for the different types of opioid receptor determined. The ability of PD117302 to modify the activity of the electrically‐stimulated guinea‐pig ileum and rabbit vas deferens has also been evaluated.
In binding studies using guinea‐pig brain homogenates, unlabelled PD117302 had a high affinity (Ki = 3.7 nm) at [3H]‐etorphine labelled κ sites and a low affinity at [3H]‐[d‐Ala2, MePhe4, glyol5]‐enkephalin ([3H]‐DAGOL) labelled μ sites (Ki = 408 nm) and [3H]‐SKF 10047 labelled s sites (Ki = 1.8 μm). In bioassay studies, PD117302 was a potent agonist, producing a maximum inhibition of the electrically‐evoked contractions of the guinea‐pig ileum (IC50 = 1.1 nm) and rabbit vas deferens (IC50 = 45 nm) which was naloxone‐reversible.
In guinea‐pig brain, [3H]‐PD117302 bound to a high‐affinity opioid binding site with a KD of 2.7 nm and a Bmax of 3.4 pmol g−1 wet weight. The Bmax was found to be less than 50% of the Bmax values for [3H]‐etorphine and [3H]‐bremazocine suggesting that [3H]‐PD117302 may be a specific ligand for a subtype of κ receptor. [3H]‐PD117302 also bound with micromolar affinity to a non‐opioid binding site.
Kinetic studies found that [3H]‐PD117302‐specific binding to the high affinity site was saturable, reaching equilibrium within 20 min at 4°C, and reversible, with a half‐life of dissociation of 3.9 min.
Several unlabelled compounds with high affinities for the [3H]‐etorphine labelled κ binding site, had comparable affinities when competing for the [3H]‐PD117302‐specific high affinity binding site. In contrast, DAGOL, [d‐Ala2, d‐Leu5] enkephalin (DADLE) and [d‐Pen2, d‐Pen5] enkephalin (DPDPE) had no significant effect on [3H]‐PD117302 binding, suggesting minimal interaction with μ and δ binding sites.
In autoradiography studies [3H]‐PD117302 binding sites were found throughout the brain with the greatest density in the striatum, cerebral cortex (layers V‐VI), substantia nigra, and the molecular layer of the cerebellum. Lowest levels were found in the granular layer of the cerebellum, thalamus and cerebral cortex (layers I‐IV).
Autoregulation of acetylcholine release from vagus nerve terminals through activation of muscarinic receptors in the dog trachea
Authors: Ito Yushi , Yoshitomi Takeshi 
Published: July 2012

The effects of pirenzepine and gallamine on the membrane and contractile properties of smooth muscle cells and on excitatory neuro‐effector transmission in the dog trachea were investigated by means of microelectrode, double sucrose gap and tension recording methods.
Pirenzepine (10−7 m) and gallamine (10−5 m) had no effect on the resting membrane potential or the input resistance of the smooth muscle cells.
Pirenzepine (10−10‐10−9 m) and gallamine (10−7 m) enhanced the amplitude of twitch contractions evoked by field stimulation in the combined presence of indomethacin (10−5 m) and propranolol (10−6 m). At higher concentrations pirenzepine (10−8 m) inhibited the twitch contractions in a dose‐dependent manner. Both pirenzepine and gallamine in doses over 10−7 and 10−5 m, respectively, reduced muscle tone.
Pirenzepine (10−10‐10−9 m) and gallamine (10−7 m) enhanced the amplitude of excitatory junction potentials (e.j.ps) evoked by field stimulation (single or repetitive stimulation). However, a high concentration of pirenzepine (10−8 m) reduced the amplitude of e.j.ps. In parallel with its action on e.j.ps, pirenzepine (over 10−9 m) reduced the response of smooth muscle cells to acetylcholine (ACh), in a dose‐dependent manner. Gallamine (5 × 10−5 m) markedly enhanced the amplitude of e.j.ps but also reduced the response of muscle cells to ACh.
ACh (10−10‐10−9 m) inhibited twitch contractions evoked by field stimulation, with a slight increase of resting tension.
Gallamine enhanced the summation of e.j.ps during repetitive field stimulation at a high frequency (20 Hz), but was without effect on the depression phenomena of e.j.ps observed during double stimulus experiments at different time intervals (5–60 s).
These results indicate that both pirenzepine and gallamine have dual actions on pre‐ and postjunctional muscarinic receptors in dog tracheal tissue. At low concentrations both agents potentiate excitatory neuro‐effector transmission, presumably due to enhancement of release of ACh from vagal nerve terminals through blockade of a negative auto‐regulatory process activated by endogenous ACh. At higher concentrations, these agents inhibit the response of smooth muscle cells to ACh through post‐junctional muscarinic receptors and relaxation of the muscle tissue occurs.
Nisoldipine and perfusion of post‐stenotic myocardium in conscious pigs with different degrees of concentric stenosis
Authors: Duncker Dirk J. , Heiligers Jan P.C. , Saxena Pramod R. , Verdouw Pieter D. 
Published: July 2012

The effects of oral nisoldipine on the perfusion and wall function of a myocardial segment distal to a fixed coronary artery stenosis were studied in 2 groups of conscious pigs with different degrees of stenosis. In group 1 (n = 8) systolic wall thickening (SWT) of the post‐stenotic segment was more than 15% (27 ± 4%); in group 2 (n = 7) SWT was less than 10% (7 ± 1%).
The systemic haemodynamic profiles at baseline and during nisoldipine were similar in both groups. Dose‐titrations of nisoldipine (0.24 + 0.02 mg kg−1 and 0.47 + 0.04 mg kg−1) were performed to obtain increases in heart rate of 25% and 50%, respectively. These increases were accompanied by increases in cardiac output (up to 50%) and left ventricular (LV)dP/dt max (60%), while systemic vascular resistance (35%) and mean arterial blood pressure (10%) were reduced. Left ventricular systolic and end‐diastolic blood pressure and stroke volume were not affected.
In both groups, nisoldipine caused increases in blood flow to the non‐stenotic area which favoured the subepicardium more than the subendocardium. Blood flow to the post‐stenotic area of group 1 was normal at baseline and was only slightly enhanced (preferentially to the subepicardium) by nisoldipine. In the post‐stenotic area of group 2 transmural and subendocardial blood flow were lower at baseline compared to the control area. Nisoldipine did not affect subepicardial blood flow but reduced subendocardial blood flow.
In spite of the reflex‐mediated positive chronotropic actions of nisoldipine, the acute poststenotic systolic wall thickening was not affected by nisoldipine in either group.
We conclude that, under the experimental conditions employed (concentric stenosis, no coronary collaterals and acute drug administration), nisoldipine does not have a useful effect on post‐stenotic myocardial blood flow, particularly in animals with severe stenosis. In view of a possible resetting of the baroreceptors (subsiding of the tachycardia) with chronic treatment and the presence of eccentric stenosis in many patients, additional studies are warranted.
Evidence for co‐transmitter role of neuropeptide Y in the pig spleen
Authors: Lundberg Jan M. , Rudehill Anders , Sollevi Alf , Hamberger Bertil 
Published: July 2012

The possible involvement of neuropeptide Y (NPY) in relation to noradrenaline (NA) and adenosine triphosphate (ATP) mechanisms in the sympathetic nervous control of the vascular tone and capsule contraction in the blood perfused pig spleen was investigated in vivo.
Local injections or infusions of NA, NPY and α‐, β‐methylene ATP (mATP) caused vasoconstriction (perfusion pressure increase) and capsule contraction (increased venous blood flow). ATP only evoked vasodilatation. NPY was about 50 fold more potent than NA as a vasoconstrictor, and the NPY response was more long‐lasting. Reserpine treatment did not change the effects of NPY.
Electrical stimulation of the splenic nerves in control animals caused a frequency‐dependent, guanethidine‐sensitive output of both NPY‐like immunoreactivity (‐LI) and NA, suggesting co‐release. The output of NPY‐LI relative to NA was enhanced at high frequency stimulation. Furthermore, α‐adrenoceptor blockade by phentolamine enhanced both the output of NPY‐LI and NA while inhibition of the neuronal uptake of NA with desipramine reduced the low frequency stimulation‐evoked overflow of NPY‐LI. Preganglionic denervation did not change the output of NPY‐LI or NA.
Reserpine treatment reduced both the splenic content of NA and NPY‐LI. Preganglionic denervation inhibited the reserpine‐induced depletion of the NPY content but not of NA in terminal areas. The stimulation‐evoked NPY overflow was markedly enhanced, especially at low‐frequency stimulation after resperpine, and the plasma levels of NPY‐LI in the venous effluent were then in the nmolar range (i.e. where exogenous NPY induced vasoconstriction). The perfusion‐pressure increase upon stimulation in reserpine‐treated, preganglionically‐denervated animals was highly correlated (r = 0.91) to the NPY overflow. The functional 0.5 Hz responses were reduced after reserpine, while at higher frequencies the functional effects were of similar magnitude to controls but longer‐lasting.
Tyramine induced a release of NA but not of NPY‐LI. Furthermore, the increase in perfusion pressure induced by tyramine was absent after reserpine.
After tachyphylaxis to the vasoconstrictor effects of mATP, the nerve stimulation‐evoked, functional response as well as the NA and NPY‐LI overflow were unchanged. After reserpine treatment, both the perfusion‐pressure increase and NPY‐LI overflow to nerve stimulation were reduced after mATP tachyphylaxis.
In conclusion, release of NPY rather than ATP may explain the long‐lasting, non‐adrenergic, splenic functional responses in reserpinized animals upon sympathetic stimulation. However, NA is most likely the main splenic transmitter when low‐frequency stimulation is used under control conditions.
Effect of palytoxin on the calcium current and the mechanical activity of frog heart muscle
Authors: Sauviat Martin‐Pierre 
Published: July 2012

The effect of palytoxin (PTX) on the Ca current (ICa) and the mechanical activity of frog atrial fibres was studied by use of the double sucrose gap voltage clamp technique.
In normal Ringer solution, PTX transiently increased the electrically‐evoked peak tension which then decreased while a major contracture developed. PTX slowed the time course of the relaxation phase of the evoked tension.
Evidence is presented which suggests that the toxin also increased the entry of Ca and Sr via the Na‐Ca exchange mechanism. It also induced the development of a Ca‐dependent outward current which was inhibited by Sr.
In Na‐free solution, PTX increased ICa and shifted the reversal potential for Ca towards more negative membrane potentials, thus suggesting that the internal Ca concentration had increased. Current‐voltage, tension‐voltage, time to peak‐voltage and inactivation time constant‐membrane potential curves were all shifted towards more negative membrane potentials in the presence of PTX.
These effects of PTX are similar to those caused by the increase in internal Ca concentration induced by Na ionophores by way of voltage‐dependent Ca influx of the Na‐Ca exchange mechanism.
Thapsigargin, a new calcium‐dependent epithelial anion secretagogue
Authors: Brayden D.J. , Hanley M.R. , Thastrup O. , Cuthbert A.W. 
Published: July 2012

Thapsigargin, a sesquiterpene lactone, was shown to cause electrogenic anion secretion in monolayers of human colonic epithelial cells, an effect which was crucially dependent upon calcium and did not involve eicosanoid formation.
To measure the secretory effect calcium needed to be present in the external bathing solution. By means of Fura‐2 fluorescence measurements thapsigargin was shown to raise Cai by around 250 nm when the bathing solution contained calcium. In the nominal absence of external calcium thapsigargin raised Cai by only 60 nm, but from a lower basal value. This was insufficient to cause secretion.
Effects of other calcium‐dependent secretagogues (e.g. lysylbradykinin) were inhibited in the presence of thapsigargin, whereas kinin responses were potentiated if the peptide was added following a stimulus which increases cyclic AMP.
From the data given here and the known behaviour of colonic epithelia it is concluded that thapsigargin increases Cai by a non‐ionophoric mechanism by release from internal stores. Calcium‐stimulated calcium influx then follows resulting in the opening of basolateral K channels, increasing the electrochemical gradient for chloride efflux, or alternatively by activating anion channels in the apical membrane. It is concluded that thapsigargin is a potentially important tool for examining epithelial mechanisms.
Effects of the putative antagonists phaclofen and δ‐aminovaleric acid on GABAB receptor biochemistry
Authors: Robinson T.N. , Cross A.J. , Green A.R. , Toczek J.M. , Boar B.R. 
Published: July 2012

Phaclofen and δ‐aminovaleric acid (δ‐AVA) have been reported to be antagonists at γ‐aminobutyric acidB (GABAB) receptors. Phaclofen, δ‐AVA and related compounds were examined for potency and specificity at GABAB and GABAA receptors in rat cortical membranes labelled with [3H]‐(−)−baclofen and [3H]‐muscimol, respectively. Additionally phaclofen and δ‐AVA were examined in two functional tests of central GABAB activity in rat cortical slices, namely the inhibition of forskolin‐stimulated cyclic AMP accumulation, and the potentiation of isoprenaline‐stimulated cyclic AMP accumulation.
δ‐AVA (IC50 = 11.7 μm) was 20 fold more potent than phaclofen (IC50 = 229 μm) on GABAB receptor binding. All compounds possessing a phosphonic acid group, including phaclofen, which were active at GABAB receptors were inactive at GABAA receptors, while δ‐AVA was equally potent at both receptors. Several compounds exhibited Hill coefficients of less than unity in displacing [3H]‐(−)−baclofen binding.
(−)−Baclofen inhibited forskolin‐stimulated cyclic AMP accumulation (IC50 = 7.9 μm) but this effect was not stereospecific. Phaclofen (1 mm) was inactive against this inhibition but produced a potentiation of the forskolin effect. δ‐AVA (1 mm) failed to antagonize the effect of baclofen; rather it mimicked baclofen.
(−)−Baclofen (10 μm) potentiated isoprenaline‐stimulated cyclic AMP accumulation, an effect antagonized by phaclofen (1 mm). δ‐AVA (1 mm) may be a weak antagonist but also potentiated basal cyclic AMP accumulation.
We conclude that neither δ‐AVA nor phaclofen are potent specific GABAB receptor antagonists.
Pharmacological characterization of 8‐OH‐DPAT‐induced inhibition of rat hippocampal 5‐HT release in vivo as measured by microdialysis
Authors: Sharp Trevor , Bramwell Steven R. , Hjorth Stephan , Grahame‐Smith David G. 
Published: July 2012

We have previously found that the putative 5‐HT1A agonist 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) decreases hippocampal 5‐hydroxytryptamine (5‐HT) release in the anaesthetized rat, as measured by brain microdialysis. The present study attempted to characterize the receptor involved in this response using a range of monoamine receptor antagonists.
The classical 5‐HT receptor antagonists, metergoline (5 mg kg−1 s.c.), methysergide (10 mg kg−1 s.c.) and methiothepin (10 mgkg−1 s.c.) each reduced dialysate levels of 5‐HT which complicated their use as antagonists in these experiments. Nevertheless, pretreatment with metergoline but not methiothepin and methysergide partially reduced the 5‐HT response to a maximally effective dose of 8‐OH‐DPAT (0.25 mg kg−1 s.c.).
The mixed 5‐HT1/β‐adrenoceptor antagonist pindolol (8 mg kg−1 s.c.) was without effect on spontaneous 5‐HT output but attenuated the effect of both maximally (0.25 mg kg−1 s.c.) and submaximally (0.05 mg kg−1 s.c.) effective dose of 8‐OH‐DPAT. In comparison, propranolol (10 mg kg−1 s.c.) did not affect 5‐HT output when injected alone and did not alter the response to 8‐OH‐DPAT (0.25 mg kg−1 s.c.).
The 5‐HT2 receptor antagonist ritanserin (0.2 mg kg−1 s.c.) and the 5‐HT3 receptor antagonist BRL 43694 (0.5 mg kg−1 s.c.) neither altered 5‐HT output alone nor significantly changed the response to 8‐OH‐DPAT (0.25 mg kg−1 s.c.).
The 8‐OH‐DPAT (0.25 mg kg−1 s.c.) response was not affected by pretreatment with either the dopamine D2‐receptor antagonist sulpiride (10 mg kg−1 s.c.) or the α1/α2‐adrenoceptor antagonist phentolamine (10 mg kg−1 s.c.).
We conclude from these data that the decrease of hippocampal 5‐HT output induced by 8‐OH‐DPAT does not involve 5‐HT2, 5‐HT3, adrenoceptors or dopamine D2‐receptors and that activation of a 5‐HT1 class of receptor seems probable. Full classification of the 8‐OH‐DPAT response awaits development of a suitably selective 5‐HT1 receptor antagonist with low intrinsic activity at the somatodendritic 5‐HT autoreceptor.
Evidence for two P2‐purinoceptor subtypes in human small pulmonary arteries
Authors: Liu S.F. , McCormack D.G. , Evans T.W. , Barnes P.J. 
Published: July 2012

P2‐purinoceptors have not been characterized in human pulmonary vessels and we therefore examined the effects of adenosine 5′‐triphosphate (ATP) and its analogues on human isolated small pulmonary arteries (SPA) in vitro.
Contractile responses were induced by all of the analogues, with the rank order of potency α,β‐methylene‐ATP (α,β‐meATP) = β,γ‐methylene‐ATP (β,γ‐meATP) > ATP > 2‐methylthio‐ATP, indicating the presence of vasoconstrictor P2x receptors.
In precontracted SPA, vasodilator responses were produced by all of the analogues. The rank order of potency for the analogues causing vasodilator responses was: 2‐methylthio‐ATP ATP β,γ‐meATP = α,β‐meATP, indicating a vasodilator P2y receptor.
Removal of endothelial cells had no significant effect on either the contractile or relaxant responses to any of the analogues.
After pretreatment of the endothelium‐denuded vessels with α,β‐meATP (to desensitize P2x receptors), the contractile response to β,γ‐meATP (a potent P2x receptor agonist) was abolished.
We conclude that both P2x‐ and P2y‐purinoceptors are present in human SPA and that both receptors reside on the vascular smooth muscle.