bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of soman on the electrical properties and excitability of bullfrog sympathetic ganglion neurones
Authors: Heppner Thomas J. , Fiekers Jerome F. 
Published: July 2012

The effects of soman (0.1–10 μm), an irreversible inhibitor of acetylcholinesterase (AChE), were examined on the electrical properties of ganglion neurones of the paravertebral sympathetic chain of the bullfrog, Rana catesbeiana.
Soman (10 μm) depolarized 29 of 35 (83%) ganglion neurones studied by 6.4 ± 0.65 mV within 10 min of application and reduced the cell input resistance in 9 of 11 neurones examined (82%) to 55 ± 5.3% of control.
Soman (10 μm) significantly reduced the maximum amplitude and the maximum rate of rise of the action potential and the duration, but not the amplitude, of the after‐hyperpolarization (AHP) following the action potential elicited by either direct or antidromic stimulation. The maximum rate of fall and the duration of the action potential were not significantly affected by soman. These actions of soman were independent of the agent‐induced depolarization. When examined by a single microelectrode voltage clamp, soman reduced the amplitude and the time constant of the current underlying the slow AHP, IAHs.
Soman (1–10 μm) produced an increase in neuronal excitability which was evidenced as either an increase in the number of action potentials or a decrease in the interspike interval in response to constant‐current depolarizing pulses. The soman‐induced increase in excitability occurred independently of both the agent‐induced depolarization and the decrease in input resistance, was reversible with washing, was not caused by an inhibition of the M‐current and was also recorded in dissociated sympathetic ganglion neurones.
The effects of soman on the membrane potential, input resistance and the duration of the AHP but not cell excitability were blocked by pretreatment with atropine (10 μm). Pretreatment with dihydro‐β‐erythroidine (DHβE) (10μm) was ineffective in blocking or reversing the effects of soman. These results suggest that the direct actions of soman on the electrical properties of these neurones are mediated by activation of muscarinic receptors.
Barbiturates inhibit ATP‐K+ channels and voltage‐activated currents in CRI‐G1 insulin‐secreting cells
Authors: Kozlowski R.Z. , Ashford M.L.J. 
Published: July 2012

Patch‐clamp recording techniques were used to examine the effects of barbiturates upon the ATP‐K+ channel, and voltage‐activated channels present in the plasma membrane of CRI‐G1 insulin‐secreting cells.
Thiopentone inhibited ATP‐K+ channel activity when applied to cell‐attached patches or the intracellular or extracellular surface of cell‐free patches. Secobarbitone and pentobarbitone were also effective inhibitors of ATP‐K+ channels in cell‐free patches, whereas phenobarbitone was ineffective.
The diabetogenic agent, alloxan, which is structurally related to the barbiturates also produced an inhibition of ATP‐K+ channel activity in outside‐out patches.
Whole‐cell ATP‐K+ currents were used to quantify the effects of the barbiturates: concentration‐inhibition curves for thiopentone, secobarbitone and pentobarbitone resulted in IC50 values of 62, 250 and 360 μm respectively. Phenobarbitone at a concentration of 1 mm was virtually ineffective.
Calculation of the apparent membrane concentrations for these drugs indicate that for a given degree of ATP‐K+ channel inhibition a similar concentration of each barbiturate is present in the membrane. This suggests that hydrophobicity plays a primary role in their mechanism of action. The pH‐dependence and additive nature of barbiturate block also indicates a membrane site of action.
Thiopentone, (100 μm) was also found to inhibit differentially voltage‐activated whole‐cell currents. The relative potency of thiopentone at this concentration was 0.64, 0.38 and 0.12 for inhibiting Ca2+, K+ and Na+ currents respectively when compared with its ability to inhibit the ATP‐K+ channel.
Effect of acute and subchronic nicotine treatment on cortical efflux of [3H]‐d‐aspartate and endogenous GABA in freely moving guinea‐pigs
Authors: Beani Lorenzo , Tanganelli Sergio , Antonelli Tiziana , Ferraro Luca , Morari Michele , Spalluto Piero , Nordberg Agneta , Bianchi Clementina 
Published: July 2012

The [3H]‐d‐aspartate preloading of the parietal cortex of freely moving guinea‐pigs equipped with epidural cups makes it possible to investigate drug effects on the efflux of this radiolabel, assumed as a marker of the glutamatergic structures underlying the cup. In the same model, the efflux of [3H]‐γ‐aminobutyric acid ([3H]‐GABA) and endogenous GABA can be measured.
Nicotine, 0.9–3.6 mg kg−1, s.c., or 3–5 μg, i.c.v., increased the efflux of [3H]‐d‐aspartate but reduced that of GABA.
These effects were mediated through mecamylamine‐sensitive receptors but the ganglionic blocking agent was devoid of any primary activity.
The inhibition of GABA efflux induced by nicotine 3.6 mg kg−1, s.c., was abolished by methysergide 2 mg kg−1, i.p. and was reduced by naloxone 3 mg kg−1 i.p. pretreatment, suggesting the involvement of tryptaminergic and opioid systems. In contrast, muscarinic and catecholamine antagonists were ineffective.
Chronic treatment with nicotine (3.6 mg kg−1, twice daily for 16 days) reduced the facilitatory effect of [3H]‐d‐aspartate and abolished the inhibition of endogenous GABA efflux.
A slight increase in the number of nicotinic binding sites (by use of [3H]‐nicotine as ligand) was found in the neocortex of chronically treated guinea‐pigs.
The higher degree of tolerance to chronic nicotine treatment shown by GABA as compared with [3H]‐d‐aspartate efflux suggests that adaptative changes of the inhibitory neuronal pools prevail. This may contribute to the reinforcing and addictive properties of nicotine.
Nitric oxide synthase in cultured endocardial cells of the pig
Authors: Schulz R. , Smith J.A. , Lewis M.J. , Moncada S. 
Published: July 2012

Endocardial cells release factors which regulate myocardial contractility and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels. One of these factors is indistinguishable from endothelium‐derived relaxing factor (EDRF).
The effluent from pig heart endocardial cells cultured on microcarrier beads caused the relaxation of a pig coronary artery ring denuded of endothelium. This relaxation was enhanced by a combination of superoxide dismutase and catalase and was attenuated by haemoglobin, which binds nitric oxide (NO), and by inhibitors of NO synthase, NG‐monomethyl‐l‐arginine (l‐NMM A) or NG‐nitro‐l‐arginine.
A Ca2+‐, l‐arginine‐ and NADPH‐dependent enzyme activity which generated NO was detected by a specific spectrophotometric assay in cytosol prepared from endocardial cells. The formation of NO was inhibited in a concentration‐dependent manner by l‐NMMA (but not d‐NMMA) and this could be partially reversed upon addition of excess l‐arginine.
Like endothelial cells from the blood vessels, the endocardial cells possess the ability to synthesize NO, which may act to regulate myocardial contractility.
Inhibition of the release of endothelium‐derived relaxing factor in vitro and in vivo by dipeptides containing NG‐nitro‐l‐arginine
Authors: Thiemermann Christoph , Mustafa Marina , Mester P. Achim , Mitchell Jane A. , Hecker Markus , Vane John R. 
Published: July 2012

We have shown that dipeptides containing NG‐nitro‐l‐arginine (NO2Arg) inhibit the biosynthesis of endothelium‐derived relaxing factor (EDRF) in vitro and in vivo.
In anaesthetized rats, intravenous administration at 1–30 mg kg−1 of the methyl ester of NO2Arg, NO2‐Arg‐l‐phenylalanine (NO2Arg‐Phe), l‐alanyl‐NO2Arg (Ala‐NO2Arg) or NO2Arg‐l‐arginine (NO2Arg‐Arg) produced dose‐related increases in mean arterial blood pressure (MABP) which were unaffected by d‐arginine (d‐Arg; 20 mg kg−1 min−1 for 15 min), but prevented by co‐infusions of l‐arginine (l‐Arg; 20 mg kg−1 min−1 for 15 min) or by their parent dipeptides.
NO2Arg methyl ester, NO2Arg‐Phe methyl ester or Ala‐NO2Arg methyl ester (10 mg kg−1, i.v.) also inhibited the reduction in MABP caused by the endothelium‐dependent vasodilator, acetylcholine (30 μg kg−1 min−1 for 3 min), but not those induced by glyceryl trinitrate (20 μg kg−1 min−1 for 3 min) or iloprost (6 μg kg−1 min−1 for 3 min) which act directly on the vascular smooth muscle.
Moreover, NO2Arg methyl ester, NO2Arg‐Phe methyl ester or NO2Arg‐Arg methyl ester (100 μm) inhibited the acetylcholine‐induced relaxation of rabbit aortic strips, and NO2Arg‐Phe methyl ester (30 μm) blocked the stimulated (bradykinin, 30 pmol) release of EDRF from bovine aortic endothelial cells grown on microcarrier beads.
In endothelial cells grown in l‐Arg‐deficient medium, l‐Arg‐containing dipeptides such as l‐Arg‐l‐Phe, l‐Ala‐l‐Arg or l‐Arg‐l‐Arg increased both the basal and stimulated release of EDRF. Moreover, the l‐Arg containing dipeptides, but not their NO2Arg analogues, were rapidly cleaved by these cells.
Thus, dipeptides containing NO2Arg can directly interfere with the biosynthesis of EDRF in vitro and in vivo. Moreover, the potentiation of EDRF release from endothelial cells deprived of l‐Arg by dipeptides containing l‐Arg suggests that such peptides may serve as an additional or alternative substrate for the biosynthesis of EDRF.
Regional coronary haemodynamic effects of two inhibitors of nitric oxide synthesis in anaesthetized, open‐chest dogs
Authors: Richard Vincent , Berdeaux Alain , la Rochelle Christophe Drieu , Giudicelli Jean‐François 
Published: July 2012

The role of endothelial nitric oxide synthesis from l‐arginine in the regulation of coronary vascular tone and myocardial tissue perfusion was evaluated in anaesthetized, open‐chest dogs. Coronary blood flow was measured with an electromagnetic flow probe placed around the left circumflex coronary artery. Coronary vascular resistance was calculated from mean arterial blood pressure and mean coronary blood flow, whereas regional myocardial tissue flow was determined by use of the radioactive microspheres technique.
NG‐monomethyl l‐arginine (l‐NMMA) and NG‐nitro‐l‐arginine methyl ester (l‐NAME), administered directly into the left circumflex artery, induced a small increase in arterial blood pressure and an increase in coronary vascular resistance. However, myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural), was unaffected by l‐NMMA or l‐NAME.
Acetylcholine, administered intracoronarily, induced an increase in left circumflex coronary blood flow and a decrease in coronary vascular resistance, without affecting systemic haemodynamics. This coronary vasodilator effect of acetylcholine was markedly inhibited by l‐NMMA and l‐NAME, the latter being a more potent antagonist than the former.
These results indicate that the endothelial l‐arginine pathway is largely responsible for the coronary vasodilator effect of acetylcholine. However, although basal release of nitric oxide from l‐arginine apparently contributes to the regulation of resting coronary vascular tone, blockade of this pathway does not affect myocardial tissue perfusion, possibly because of compensatory mechanisms occurring at the level of small arterioles and/or capillaries.
The role of the l‐arginine‐nitric oxide pathway in relaxation of the opossum lower oesophageal sphincter
Authors: Tøttrup A. , Knudsen M.A. , Gregersen H. 
Published: July 2012

The role of the l‐arginine‐nitric oxide pathway in lower oesophageal sphincter (LOS) relaxation and oesophageal peristalsis was investigated.
Twenty four adult opossums were anaesthetized and the right vagus nerve was isolated in the neck and sectioned. Electrical stimulation, applied to the peripheral end of the nerve, resulted in a frequency‐dependent relaxation of the LOS, and peristaltic and non‐peristaltic contractions in the oesophageal body.
Nω‐nitro‐l‐arginine (l‐NNA, 10−8–10−5mol kg−1), an inhibitor of the l‐arginine‐nitric oxide pathway, inhibited LOS relaxation in a dose‐dependent manner, but did not affect resting LOS pressure. At the highest dose of l‐NNA no relaxation of the LOS was elicited in response to vagal stimulation. The effect of l‐NNA, (10−5mol kg−1) was fully reversed by infusion of 10−4mol kg−1 l‐arginine. Peristaltic velocity and amplitude of contractions in the oesophageal body were unaffected by l‐NNA.
Infusion of sodium nitroprusside reduced LOS pressure to zero, and the drug was equally potent in control animals (–log ED50: 8.1 ± 0.2 mol kg−1) and in animals pretreated with l‐NNA (–log ED50: 8.2 ± 0.3 mol kg−1). This suggests that the effect of l‐NNA was not directly on guanylate cyclase.
A significant elevation of blood pressure was recorded after administration of l‐NNA (10−5mol kg−1).
It is suggested that the l‐arginine‐nitric oxide pathway plays an important functional role for relaxation of the LOS, but not for oesophageal peristalsis. Whether the active substance is nitric oxide or a related nitroso‐compound remains to be settled.
Ca2+ion sequestration by guinea‐pig tracheal cartilage: its influence on trachealis reactivity to KCl
Authors: Gupta Paul , Markham Anthony , Morgan Rae M. 
Published: July 2012

The contractile response of guinea‐pig isolated trachealis to KCl has been studied in the presence and absence of cartilage.
Dissection of cartilage from the trachealis resulted in both a rightward displacement of the concentration‐response curve to KCl (EC50 value: intact strip, 26.9 ± 3.7 mm n = 5; dissected strip, 38.7 ± 2.6 mm n = 5; P < 0.05), and a reduction in the contractile response to KCl (30 mm) observed in a nominally Ca2+‐free medium.
Removal of cartilage from the trachealis did not alter the responsiveness of the tissue to CaCl2 (2.5 mm) when added to K+depolarized tissues.
Muscle‐denuded cartilage rings were prepared by surgical removal of the trachealis muscle. Autoradiographic studies, and a direct comparison of Ca2+(2.5 mm) uptake with that of sorbitol (2.5 mm) showed that cartilage per se had a high capacity to accumulate Ca2+ions by a process which was resistant to iodoacetate (100 μm), diflunisal (100 μm) and boiling.
The uptake of 45Ca into isolated cartilage was unaltered by the addition of orthovanadate (500 μm), verapamil (10 μm), diltiazem (10 μm) or Bay K 8644 (10 μm), but was significantly reduced (P < 0.05) in the presence of LaCl3 (1–10 mm).
We conclude, like previous studies, that cartilage may supply a pool of Ca2+ions to airway smooth muscle during the generation of tension in a noninally Ca2+‐free medium, and that LaCl3 may provide an experimental tool to elucidate further the role of non‐muscle Ca2+‐depots in smooth muscle contraction.
Substance P modulates the time course of nicotinic but not muscarinic catecholamine secretion from perfused adrenal glands of rat
Authors: Zhou Xin‐Fu , Marley Philip D. , Livett Bruce G. 
Published: July 2012

Substance P (SP) and acetylcholine (ACh) are contained within the splanchnic nerve terminals in the adrenal gland and can be released in response to stress. In the rat, the release of ACh brings about secretion of catecholamines (CA) by acting on nicotinic and muscarinic receptors on the adrenal chromaffin cells.
In the present study, we have used a rat isolated adrenal gland preparation to investigate the effects of SP, perfused at different concentrations, on CA secretion evoked by 10−5m nicotine and 10−4m muscarine.
In the first 10 min stimulation period (S1), in the absence of SP, nicotine (10−5m) evoked substantial and equal secretion of noradrenaline (NA) and adrenaline (Ad). In a second 10 min stimulation period (S2), carried out 18 min after S1, the nicotinic response was desensitized. In contrast, the muscarinic response, which preferentially evoked Ad secretion in S1 (Ad/NA: 8.7/1), was well maintained in S2.
SP present in S1 had no effect on desensitization of the subsequent nicotinic response in S2.
At low concentrations (10−7–10−10m), SP changed the time course of nicotine‐induced CA secretion during S1 by enhancing CA secretion in the first 4 min and inhibiting CA secretion thereafter. The maximal effect occurred at 10−9m SP.
At a higher concentration (10−5m), SP inhibited total nicotinic CA secretion throughout S1 and produced a biphasic secretion of CA (depressed in the presence of SP and enhanced after wash out of SP). Pre‐exposure of adrenal glands to SP (10−9to 10−5m) for 10 min produced marked inhibition of the nicotine‐induced CA secretion.
In contrast to the effect of SP on the nicotinic response, SP from 10−9to 10−5m had no effect on muscarinic CA secretion.
This difference in sensitivity of the nicotinic and muscarinic responses to SP points to a diversity of mechanisms available for control of adrenal catecholamine secretion. In addition to the ability of SP to increase or decrease the total amount of adrenal CA secretion, dependent on the concentration of SP, the present study shows that SP can change the time‐course of nicotinic CA secretion. These results with the rat adrenal gland perfused in vitro suggests both a quantitative and temporal role for SP as a novel modulator of adrenal CA secretion.
The effects of neuropeptide Y on myocardial contractility and coronary blood flow
Authors: Awad Sonia J. , Einstein Rosemarie , Potter Erica K. , Richardson Desmond P. 
Published: July 2012

This study was designed to assess the effects of exogenous neuropeptide Y (NPY) on cardiac contractility and coronary blood flow (CBF) in anaesthetized dogs and to evaluate the effect of NPY on the responses to sympathetic and parasympathetic stimulation and to inotropic agents.
Bolus doses of NPY (500 μg), administered via the femoral vein, increased mean arterial pressure. The pressor effect was associated with reductions in heart rate, CBF and cardiac contractility.
The effects of NPY (500 μg) on contractility and CBF were compared with that of vasopressin (VP) (1 unit). For similar reductions in CBF, NPY and VP had similar negative inotropic effects. Thus, it is likely that the negative inotropic response to NPY is not due to a direct effect of NPY on the heart muscle but is largely due to coronary vasoconstriction.
In the presence of NPY (500 μg, i.v.), there was an inhibition of the positive inotropic response to stimulation of the left cardiac sympathetic nerve (2 or 5 Hz, 0.05 ms). NPY also inhibited the negative inotropic response and chronotropic response to vagal stimulation (2, 3 or 5 Hz, 0.05 ms).
Dose‐response curves were obtained for the inotropic, chronotropic and pressor responses to cumulative infusions of noradrenaline (n = 6) and dobutamine (n = 6). NPY had no effect on these dose‐response curves.
The effect of NPY on the responses to salbutamol and impromidine was assessed. NPY did not alter the positive inotropic, chronotropic or depressor responses to these agonists.
Our results indicate that NPY has direct, postsynaptic vasoconstrictor activity and the reduction in myocardial contractility and heart rate are due to a combination of coronary vasoconstriction, baroreceptor reflex activation and presynaptic inhibition of transmitter release from sympathetic nerves. The well‐documented inhibitory effect of NPY on the chronotropic response to parasympathetic stimulation was confirmed and similar inhibition of the inotropic response to both sympathetic and parasympathetic stimulation was demonstrated. Since there was no modulation of the inotropic effects of exogenous α‐ and β‐ adrenoceptor or H2‐receptor agonists, it is concluded that the effects of NPY on myocardial contractility are exerted presynaptically.
Effects of lemakalim on changes in Ca2+concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery
Authors: Ito Shinichi , Kajikuri Junko , Itoh Takeo , Kuriyama Hirosi 
Published: July 2012

Effects of (−)‐cromakalim (lemakalim) on tension and Ca2+mobilization induced by noradrenaline (NA) were investigated by measuring intracellular Ca2+concentration ([Ca2+]i), isometric tension and production of inositol‐1,4,5‐trisphosphate (IP3) in smooth muscle strips of the rabbit mesenteric artery.
In thin smooth muscle strips, 10 μm NA produced a large phasic, followed by a small tonic increase in [Ca2+]i, which correlated well with the evoked phasic and tonic contractions, respectively. Lemakalim (0.1–10 μm) lowered the resting [Ca2+]i without a decrease in the resting tension, and also inhibited the increased [Ca2+]i and tension induced by 10 μm NA, all in a concentration‐dependent manner. Glibenclamide (1 μm) inhibited these actions of lemakalim.
In Ca2+‐free solution containing 2 mm EGTA, NA (10 μm) transiently increased [Ca2+]i, tension and synthesis of IP3. Lemakalim (over 0.01 μm) inhibited these actions of NA in Ca2+‐free solution containing 5.9 mm K+, but not in Ca2+‐free solution containing 128 mm K+. These actions of lemakalim were prevented by glibenclamide (1 μm). Lemakalim (1 μm) did not modify the increases in [Ca2+]i and tension induced by 10 mm caffeine.
In β‐escin‐skinned strips, 10 μm NA increased [Ca2+]i in Ca2+‐free solution containing 50 μm EGTA, 3 μm guanosine triphosphate (GTP) and 2 μm Fura 2 after the storage sites were loaded by application of 0.3 μm Ca2+for 2 min, suggesting that Ca2+is released from intracellular storage sites following activation of the α‐adrenoceptor. Lemakalim (1 μm) did not inhibit the Ca2+release from storage sites induced by NA.
We conclude that lemakalim inhibits NA‐induced Ca2+release due to inhibition of NA‐induced IP3 production in a manner dependent on the membrane potential and causes inhibition of the phasic contraction induced by NA.
Mechanism of action of platelet activating factor in the pulmonary circulation: an investigation using a novel isotopic system in rabbit isolated lung
Authors: Seale J.P. , Nourshargh S. , Hellewell P.G. , Williams T.J. 
Published: July 2012

Rabbit isolated lungs were perfused via the pulmonary artery with Tyrode solution containing 4.5% Ficoll and 0.1% bovine serum albumin at a constant rate of 20 ml min−1. Lung perfusate was drawn for alternating 5 min periods from two reservoirs, one containing 125I‐albumin and the other unlabelled albumin to wash out the intravascular label. Microvascular 125I‐albumin leakage was determined from the count remaining at the end of the washout phase with an external gamma scintillation probe. In addition, perfusion pressure was monitored continuously. Each experiment comprised 6 cycles over a total period of 60 min.
Infusion of platelet activating factor (PAF, 3 nmol min−1 for 10 min) resulted in microvascular 125I‐albumin leakage, whereas lyso‐PAF was without effect. During PAF infusions there was also an increase in perfusion pressure. Both the permeability and pressor effects of PAF were inhibited by the PAF antagonist L‐652731.
Infusion of the thromboxane analogue U‐46619 (0.6 nmol min−1 for 10 min) caused an increase in perfusion pressure but protein accumulation was not significantly different from that observed with control infusions.
Bolus injections of PAF (1 nmol) caused increases in perfusion pressure which were reduced by indomethacin, dazmegrel and BW 755C. Bolus injections of PAF, repeated at 30 min intervals caused reproducible pressor responses; however, repeated injections at 60 min intervals resulted in augmented responses. This augmentation did not occur in the presence of indomethacin.
Retrograde perfusion of PAF via the pulmonary vein induced increased perfusion pressure and microvascular 125I‐albumin leakage. The observed increase in leakage when compared with forward perfusion suggests that PAF produces predominantly arteriolar constriction i.e. proximal to the site of leakage during forward perfusion.
These results indicate that PAF is a vasoconstrictor in the rabbit pulmonary circulation and augmented responses occur with repeated injections at 60 min intervals. Cyclo‐oxygenase inhibition abolished this vascular hyperresponsiveness induced by PAF. PAF also caused protein accumulation in the lungs. Both these actions of PAF appear to be receptor‐mediated because they were inhibited by PAF antagonists. Another pulmonary vasoconstrictor, U‐46619 did not cause protein accumulation suggesting that the extravasation of protein with PAF is not merely secondary to changes in vascular tone.