bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Ca2+‐antagonist and binding properties of the phenylalkylamine, anipamil
Authors: Dillon J.S. , Nayler W.G. 
Published: July 2012

Isolated, Langendorff‐perfused rat hearts, isolated membranes, and pharmacological and receptor binding techniques were used to study the properties of the newly developed verapamil derivative, anipamil.
When added acutely to isolated, spontaneously beating or electrically paced hearts, anipamil (0.01‐0.15 μm) exerted a dose‐dependent negative inotropic effect which developed slowly and persisted after 60 min washout.
When added acutely (0.05‐0.1 μm) to isolated hearts, or when given intravenously (2 mg kg−1 body weight 1 h before the animals were killed), anipamil displaced the dose‐response curves for the positive inotropic effect of (0.10‐3.mm) Ca2+ and (10–50 nm) Bay K 8644 to the right.
When added to freshly isolated cardiac membranes, 0.1 μm anipamil increased the dissociation constant (KD) of the phenylalkylamine (—)‐[3H]‐desmethoxyverapamil ((—)‐[3H]‐D888) from 1.22 ± 0.2 to 2.91 ± 0.46 nm, without any significant change in density (Bmax; control: 163 ± 17; anipamil: 117 ± 20fmol mg−1 protein). Bound (—)‐[3H]‐D888 was displaceable by (—)‐D888 (Ki, 1.7 ± 0.4 nm) > (—)‐D600 (Ki 12 ± 0.5 nm) > verapamil (Ki 55 ± 11 nm) > (+)‐D600 (Ki 108 ± 12.2) > anipamil (Ki 471 ± 52 nm).
In cardiac membranes isolated from rats pretreated with anipamil (2 mg kg−1 i.v.) 1 h before they were killed, the KD of (—)‐[3H]‐D888 binding was increased (P < 0.05) from 1.59 ± 0.18 to 3.28 ± 0.65 nm with no significant change in density, compared to the placebo‐treated (control) rats.
These results establish that anipamil interacts in a competitive manner with the phenylalkylamine binding sites in cardiac membranes, and that it resembles other Ca2+ antagonists in displacing the dose‐reponse curve for the positive inotropic effect of Ca2+ to the right. The results also show that although anipamil binds tightly to the cardiac membranes, it binds to the (—)‐[3H]‐D888 recognition sites less potently than (—)‐D888, (—)‐D600 or verapamil.
Electrophysiological effects of melperone on isolated rabbit heart muscles
Authors: Ikeguchi Shigeru , Hashimoto Satoshi , Horie Minoru , Kadoya Makoto , Konishi Tomotsugu , Kawai Chuichi 
Published: July 2012

Electrophysiological effects of melperone on isolated atrial and ventricular muscle preparations of the rabbit were studied by a conventional microelectrode technique.
Melperone (3.3 μm) prolonged the action potential duration and effective refractory period of the atrial preparations without affecting the maximum rate of depolarization (). These effects of melperone on action potential duration and effective refractory period were inhibited by a low potassium perfusate (2.7 mm).
A high concentration of melperone (16.6 μm) decreased of atrial preparations. In ventricular muscles, melperone at either concentration decreased , although the increase in action potential duration was greater than in the atrium.
Depression of of ventricular muscles by melperone was found to be augmented by an increase of stimulation frequency and drug concentration.
The rate of onset of rate‐dependent block of in ventricle was increased with drug concentration and frequency of stimulation. However, the time constant of recovery from rate‐dependent block was almost constant. The kinetics of rate‐dependent block of by melperone were approximately similar to those of quinidine and disopyramide. Consequently it is concluded that melperone possesses class la antiarrhythmic activity as well as class 3 activity.
Investigations into the origin of the high pressure neurological syndrome: the interaction between pressure, strychnine and 1,2‐propandiols in the mouse
Authors: Bowser‐Riley F. , Daniels S. , Smith E.B. 
Published: July 2012

The effects of a variety of structural isomers of the centrally acting muscle relaxant mephenesin on the high pressure neurological syndrome have been investigated. Threshold pressures for the onset of the behavioural signs, tremors and convulsions, were established. The effects of these compounds on the response to pressure were also compared with their ability to antagonize the convulsive action of strychnine.
The dose‐response relationships for strychnine and picrotoxin were investigated at fixed pressures. Additionally, the dose‐response relationship of strychnine, in the presence of mephenesin, at pressure was investigated.
All the isomers of mephenesin protected against the effects of both pressure and strychnine. The relative potency was found to be identical with respect to both. Mephenesin was clearly the most effective; it raised the threshold pressure for tremors by 2.5 times, that for convulsions elicited by pressure by 1.5 and the ED50 for strychnine convulsions by 1.6 times. Strychnine was found to be strictly additive with pressure whereas picrotoxin exhibited gross deviations from additivity. Mephenesin ameliorated the combined effects of pressure and strychnine equally.
The marked dependence on structure of the anticonvulsant activity of the mephenesin isomers can be interpreted as evidence that pressure acts not by some general perturbation of the membranes of excitable cells but rather via some specific interaction. The finding that strychnine and pressure are strictly additive supports the idea of specificity and also indicates that they may share a common mechanism in the production of convulsions. By analogy with the established mechanism of action of strychnine, it is suggested that the hyperexcitability associated with pressure might arise from an action on glycine‐mediated inhibitory processes.
Evidence that the population of postjunctional‐adrenoceptors mediating contraction of smooth muscle in the rabbit isolated ear vein is predominantly α2
Authors: Daly C.J. , McGrath J.C. , Wilson V.G. 
Published: July 2012

Noradrenaline (NA), phenylephrine and UK‐14304 elicited concentration‐dependent contractions of the rabbit isolated ear vein of similar maximal magnitude. The rank order of potency, UK‐14304 > noradrenaline > phenylephrine, is consistent with that of an effect mediated through an α2‐subtype.
The potent and highly selective α1‐adrenoceptor antagonists prazosin and YM‐12617, at concentrations as high as 1 μm, produced less than a 4 fold rightward displacement of the NA concentration‐response curve.
The selective α2‐adrenoceptor antagonists rauwolscine, Wy‐26703 and CH‐38083 antagonized responses to noradrenaline in a competitive manner. For all three antagonists, the pA2 values were consistent with an effect at α2‐adrenoceptors. However, 0.1 μm YM‐12617 increased the potency of rauwolscine 2 fold indicating the presence of a small population of postjunctional α1‐adrenoceptors.
The relative antagonist potency of the yohimbine diastereoisomers rauwolscine and corynanthine against noradrenaline (rauwolscine 30 fold > corynanthine) is also consistent with an effect at α2‐adrenoceptors.
Contractions elicited by noradrenaline in the rabbit isolated ear vein appear to be mediated predominantly by postjunctional α2‐adrenoceptors.
Neuroanatomical sites of action of 5‐HT3 receptor agonist and antagonists for alteration of aversive behaviour in the mouse
Authors: Costall B. , Kelly M.E. , Naylor R.J. , Onaivi E.S. , Tyers M.B. 
Published: July 2012

The cerebral topography of the action of diazepam and the action of the 5‐hydroxytryptamine 5‐HT3 receptor antagonists GR38032F and ICS 205–930 in attenuating an aversive response was studied in the mouse.
Mice which had been cannulated to allow drug injection into the dorsal and median raphe nuclei, the amygdala, nucleus accumbens or caudate‐putamen were placed in a two compartment black (dimly illuminated) and white (brightly illuminated) test box. Measurements were made of the time spent, rearing and line crossings in the two sections and the latency of initial movement from the white to the black area.
The injection of diazepam (0.1–10 ng), GR38032F (0.01–1.0 ng) and ICS 205–930 (1.0–10 ng) into the dorsal raphe nucleus and amygdala, and the injection of diazepam (0.1–10 ng) into the median raphe nucleus, reduced an aversive response to the brightly illuminated white area, delaying the initial movement into the black section and increasing the time spent, rearings and line crossings in the white area. Concomitantly such activities were decreased in the black section.
The injection of the 5‐HT3 agonist 2‐methyl‐5‐hydroxytryptamine (0.1–10 ng) into the dorsal raphe nucleus and amygdala caused the opposite response, decreasing the time taken to move into the black section and increasing the time spent, rearings and line crossings in the black section, decreasing such activities in the white area.
The 5‐HT3 agonist and antagonists showed little or no effect following injection into the median raphe nucleus and there were no changes in exploratory behaviour following their injection, or injection of diazepam, into the nucleus accumbens or caudate‐putamen.
It is concluded that in the mouse the cerebral topography of action of GR38032F and ICS 205–930 in attenuating an aversive response follows that of diazepam in the dorsal raphe nucleus and amygdala but that diazepam may have additional effects mediated via the median raphe nucleus.
The effect of propranolol on the hyperaemic response of the hepatic artery to portal venous occlusion in the dog
Authors: Alexander B. , Blumgart L.H. , Mathie R.T. 
Published: July 2012

It has been reported that activation of β‐adrenoceptors may be responsible for the hyperaemic response of the hepatic artery to portal venous blood flow reduction.
The effect of β‐adrenoceptor blockade on the hepatic arterial response to portal vein occlusion was investigated in 6 anaesthetized dogs. A side‐to‐side portacaval shunt was established to prevent loss of venous return and arterial blood pressure during periods of portal occlusion. Measurements of hepatic arterial and portal venous blood flows were made by use of electromagnetic flow probes.
Intravenous propranolol injection, at a dose sufficient to block the vasodilator effect of low doses of exogenous adrenaline, did not alter the magnitude of the hyperaemic response of the hepatic artery. Propranolol also produced no change in baseline portal venous pressure.
It is concluded that hepatic β‐adrenoceptors are unlikely to be involved in the arterial response to portal occlusion. The absence of any reduction in basal portal venous pressure by propranolol is of interest in view of the current application of the drug in the treatment of patients with portal hypertension.
A specific inhibitor of nitric oxide formation from l‐arginine attenuates endothelium‐dependent relaxation
Authors: Rees Daryl D. , Palmer Richard M.J. , Hodson Harold F. , Moncada Salvador 
Published: July 2012

The role of l‐arginine in the basal and stimulated generation of nitric oxide (NO) for endothelium‐dependent relaxation was studied by use of NG‐monomethyl l‐arginine (l‐NMMA), a specific inhibitor of this pathway.
l‐Arginine (10–100 μm), but not d‐arginine (100 μm), induced small but significant endothelium‐dependent relaxations of rings of rabbit aorta. In contrast, l‐NMMA (1–300 μm) produced small, endothelium‐dependent contractions, while its enantiomer NG‐monomethyl‐d‐arginine (d‐NMMA; 100 μ) had no effect.
l‐NMMA (1–300 μm) inhibited endothelium‐dependent relaxations induced by acetylcholine (ACh), the calcium ionophore A23187, substance P or l‐arginine without affecting the endothelium‐independent relaxations induced by glyceryl trinitrate or sodium nitroprusside.
The inhibition of endothelium‐dependent relaxation by l‐NMMA (30 μm) was reversed by l‐arginine (3–300 μm) but not by d‐arginine (300 μm) or a number of close analogues (100 μm).
The release of NO induced by ACh from perfused segments of rabbit aorta was also inhibited by l‐NMMA (3–300 μm), but not by d‐NMMA (100 μm) and this effect of l‐NMMA was reversed by l‐arginine (3–300 μm).
These results support the proposal that l‐arginine is the physiological precursor for the basal and stimulated generation of NO for endothelium‐dependent relaxation.
Adenosine enhancement of adrenergic neuroeffector transmission in guinea‐pig pulmonary artery
Authors: Wiklund N. Peter , Cederqvist Bo , Gustafsson Lars E. 
Published: July 2012

Adenosine and its derivatives N6‐[(R)−1‐methyl‐2‐phenylethyl]adenosine (R‐PIA) or 5′‐N‐ethylcarboxamideadenosine (NECA) enhanced nerve‐induced contractile responses and augmented the basal smooth muscle tone in transmurally stimulated isolated strips of the guinea‐pig pulmonary artery.
Adenosine, R‐PIA and NECA enhanced contractile responses induced by noradrenaline, whereas N6‐[(S)−1‐methyl‐2‐phenylethyl]‐adenosine (S‐PIA) was virtually inactive.
Adenosine, R‐PIA and NECA inhibited the nerve stimulation evoked release of [3H]‐noradrenaline. However, the total release of [3H]‐noradrenaline during the periods of NECA application was increased.
The nucleoside effects were blocked by the adenosine receptor antagonist 8‐p‐sulphophenyltheophylline.
8‐p‐Sulphophenyltheophylline inhibited nerve‐induced contractions and lowered basal muscle tone in preparations not having received any exogenous purines.
It is suggested that the observed stimulatory effects on muscle tone and on contractile responses to transmural nerve stimulation are mainly due to action at postjunctional stimulatory A1 adenosine receptors. In addition, actions at prejunctional inhibitory A1 and stimulatory A2 adenosine receptors are evident in this preparation.
Time course and extent of α1‐adrenoceptor density changes in rat heart after β‐adrenoceptor blockade
Authors: Steinkraus Volker , Nose Monika , Scholz Hasso , Thormählen Katrin 
Published: July 2012

It has been suggested that impaired β‐adrenoceptor stimulation is a condition under which the functional role of cardiac α1‐adrenoceptors is enhanced. We therefore investigated the extent and time course of changes in α1‐adrenoceptor characteristics after chronic treatment with the β‐adrenoceptor blocker propranolol in rat heart. For comparison β‐adrenoceptors were also studied. The mechanism of the changes in adrenoceptor density was investigated with cycloheximide, an inhibitor of protein synthesis. The functional significance of an increased α1‐adrenoceptor density was tested by measuring isometric force of contraction in the presence of phenylephrine or isoprenaline in right ventricular papillary muscles.
Rats were treated with propranolol (9.9 mg kg−1 daily) or 0.9% NaCl, applied with osmotic minipumps for 1, 2, 3 or 7 days. Propranolol treatment resulted in a maximally 28% increase of α1‐adrenoceptor density after 3 days (NaCl 95.9 ± 3.5 vs. propranolol 123.0 ± 1.6 fmol mg−1 protein, n = 6, P < 0.01). This up regulation reached significant levels after 2 days of treatment and was reversible after cessation of treatment within two days. KD‐values were the same for NaCl‐ and propranolol‐treated rats. Changes of Bmax and KD in β‐adrenoceptor binding assays did not reach significant levels.
Cycloheximide (1.5 mg kg−1 i.p. daily for 3 days) inhibited the propranolol‐induced increase in Bmax of α1‐adrenoceptors completely. In addition, cycloheximide also decreased the density of α1‐ and β‐adrenoceptors also under control conditions.
pD2‐values for the positive inotropic effect of phenylephrine and isoprenaline in isolated electrically driven papillary muscle were similar in NaCl‐ and propranolol‐treated rats (phenylephrine: 5.41 ± 0.11 vs. 5.41 ± 0.19, n = 7; isoprenaline: 6.31 ± 0.18 vs. 6.65 ± 0.19, n = 7). The observed increase in α1‐adrenoceptor density in healthy rat heart may therefore not be high enough to enhance the phenylephrine‐induced increase in force of contraction.
In conclusion, time course and effects of cycloheximide indicate that the increase in Bmax of myocardial α1‐adrenoceptors is due to de novo synthesis of receptors. However, at least for the rat heart model, a functional significance of this increase could not be demonstrated.
Ouabain distinguishes between nicotinic and muscarinic receptor‐mediated catecholamine secretions in perfused adrenal glands of cat
Authors: Yamada Yutaka , Nakazato Yoshikazu , Ohga Akira 
Published: July 2012

The effect of ouabain on catecholamine (adrenaline and noradrenaline) secretion induced by agents acting on cholinoceptors was studied in perfused cat adrenal glands. Acetylcholine (ACh) (5 × 10−7 to 10−3m), pilocarpine (10−5 to 10−3m) and nicotine (10−6 to 5 × 10−5m) caused dose‐dependent increases in catecholamine secretion. Both ACh and nicotine released more noradrenaline than adrenaline and the reverse was the case for pilocarpine.
Ouabain (10−5m) enhanced catecholamine secretion induced by ACh (10−5m), pilocarpine (10−3m) and nicotine (3 × 10−6m) during perfusion with Locke solution. The ratio of adrenaline to noradrenaline was not affected by ouabain.
In the absence of extracellular Ca2+, ACh and pilocarpine, but not nicotine, still caused a small increase in catecholamine secretions, which were enhanced by treatment with ouabain (10−5m) plus Ca2+ (2.2 mm) for 25 min. The effect of ouabain was much more significant on noradrenaline secretion than on adrenaline secretion. The enhanced response was blocked by atropine (10−6m) but not by hexamethonium (5 × 10−4m).
Nifedipine (2 × 10−6m) inhibited the responses to pilocarpine and nicotine. The treatment with ouabain (10−5 m) reversed only the response to pilocarpine and resulted in a significant increase in the proportion of noradrenaline released.
It is suggested that ouabain enhances evoked catecholamine secretions by facilitating Ca2+ entry through nicotinic receptor‐linked Ca2+ channels and by increasing the intracellular Ca2+ pool linked to muscarinic receptors.
Effect of a new potent CCK antagonist, lorglumide, on caerulein‐ and bombesin‐induced pancreatic secretion and growth in the rat
Authors: Scarpignato Carmelo , Varga Gábor , Dobronyi István , Papp Miklós 
Published: July 2012

The effect of lorglumide, a new potent cholecystokinin (CCK) antagonist, on pancreatic secretion and growth induced by caerulein and bombesin was studied in the rat.
Pancreatic exocrine secretion was studied both in vitro (isolated and perfused pancreatic segments) and in vivo (anaesthetized animals with cannulation of the common bile duct) whereas the trophic effect was investiged after short‐term (5 days) administration of the peptides and/or lorglumide.
Both caerulein and bombesin stimulated amylase release from in vitro pancreatic segments in a concentration‐dependent manner. Although the efficacy of both peptides was virtually identical, the potency of caerulein was higher than that of bombesin. Lorglumide displaced the concentration‐response curves to caerulein to the right without affecting the maximum response, suggesting a competitive antagonism. The Schild plot analysis of data gave a straight line with a slope not significantly different from unity. The calculated pA2 for lorglumide was 7.31 ± 0.45. The antagonist, however, was completely ineffective when tested against bombesin‐induced amylase release.
In vivo experiments confirmed results from in vitro studies since lorglumide (5 and 10 mg kg−1) significantly reduced pancreatic exocrine secretion induced by caerulein without affecting the response to bombesin.
Administration of either peptide increased the weight of the pancreas, the total pancreatic protein and DNA, trypsin and amylase content. Lorglumide (10 mg kg−1), administered together with caerulein, reduced the peptide‐induced increase in pancreatic weight, protein and enzyme content. On the contrary, when lorglumide was given together with bombesin, all the parameters that were examined were not altered by concomitant administration of the antagonist.
These results have demonstrated the ability of lorglumide to antagonize the effects on the pancreas of a CCK‐analogue, caerulein, and its inability to affect bombesin‐induced pancreatic secretion and growth, suggesting that lorglumide is a potent and selective antagonist of CCK‐receptors in the pancreas.
Electrophysiological and antiarrhythmic effects of UK 52,046–27 during ischaemia and reperfusion in the guinea‐pig heart
Authors: Flores Nicholas A. , Sheridan Desmond J. 
Published: July 2012

We studied the antiarrhythmic and electrophysiological effects of UK 52,046–27 (10−8 m and 5 × 10−8 m), a highly selective α1‐adrenoceptor antagonist, during global ischaemia (flow reduced to 10% of control for 30 min) and reperfusion, in isolated, buffer‐perfused hearts of guinea‐pigs.
The compound had few electrophysiological effects during normal perfusion, although action potential amplitude and were reduced with 10−8 m (by 9% and 22%) and refractory period was increased with 5 × 10−8 m (by 13%) compared to control hearts.
Perfusion with 5 × 10−8 m UK 52,046–27 reduced the incidence of ventricular tachycardia during ischaemia from 67% to 25%, and during reperfusion reduced the incidence of ventricular tachycardia (from 83% to 17%) and ventricular fibrillation (from 67% to 8%).
The compound prolonged significantly action potential duration and refractory period during ischaemia and reperfusion. was reduced to a greater extent during reperfusion in the treated hearts, while greater increases in QRS width and stimulation threshold occurred during ischaemia in the treated group.
These results confirm that blockade of the α1‐adrenoceptor subpopulation during myocardial ischaemia and reperfusion decreases the incidence of arrhythmias and alters cellular electrophysiology during ischaemia and reperfusion.
Capsaicin and nicotine‐sensitive afferent neurones and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis
Authors: Stjärne P. , Lundblad L. , Lundberg J.M. , Änggård A. 
Published: July 2012

Applications of capsaicin, nicotine and methacholine were made locally onto the nasal mucosa in human controls and patients suffering from hyperreactive nasal disorders. Perception of sensation was registered as a sympton score and secretion quantified. The sensory reaction (irritation ‐pain) to capsaicin was similar in the three groups studied, i.e. controls, a group of patients with the diagnosis of vasomotor rhinitis and a group of patients with increased nasal secretion as the main symptom of the hyperreactive disorder. Nicotine induced only a mild itching sensation in the three groups. However, capsaicin and nicotine challenge caused a significantly larger secretory response in the last group than in the unselected vasomotor rhinitis group and in the control group.
Pretreatment with muscarinic receptor antagonists almost completely abolished the secretory response to both capsaicin and nicotine, and blocked methacholine‐induced secretion. Furthermore, pretreatment with a combination of local anaesthetic and vasoconstrictor agent abolished the capsaicin‐induced irritation, as well as the capsaicin‐ and nicotine‐induced secretion on both the ipsilateral and the contralateral side. Therefore, no clearcut contribution seems to be exerted by locally released peptides from sensory neurones as direct trigger substances for the secretory response to capsaicin.
In conclusion, the nasal secretory response, in man, to both capsaicin and nicotine, seems to be mediated via cholinergic parasympathetic reflexes. In patients with hyperreactive non‐allergic disorders of the nasal mucosa with rhinorrhea as the main complaint, the enhanced secretion may be due to a hyperreactive efferent cholinergic mechanism rather than hypersensitive irritant receptors on capsaicin‐ and nicotine‐sensitive sensory neurones. Challenge with irritant agents seems a useful test for the evaluation of both afferent and efferent reflexogenic responses in hyperreactive disorders of the nasal mucosa.