bluuebunny/crossref_metadata_2025_split huggingface dataset:
EFFECTS OF CLONIDINE ON CANINE CARDIAC NEUROEFFECTOR STRUCTURES CONTROLLING HEART RATE
Authors: CAVERO I. , ROACH A.G. 
Published: July 2012

In intact dogs anaesthetized with pentobarbitone, clonidine (10 μg/kg, i.v.) produced a sustained decrease in heart rate. This effect was significantly smaller in vagotomized dogs in which the sympathetic drive to the heart was either left intact or experimentally created by continuous electrical stimulation of the decentralized cardioaccelerator nerve. In the latter preparation, the negative chronotropic action of clonidine was reversed by an intravenous injection of phentolamine, whereas in the former experimental situation it was antagonized only by an intravenous plus an intravertebral artery injection of phentolamine.
In dogs with denervated hearts the tachycardia produced by electrical stimulation of the cardioaccelerator nerve was accompanied by a rise in noradrenaline overflowing into the coronary sinus plasma. Clonidine inhibited both these effects and phentolamine restored them to pre‐clonidine levels.
Clonidine decreased heart rate in dogs with an intact parasympathetically innervated heart and decentralized stellate ganglia. When the low basal heart rate of this preparation was elevated by electrical stimulation of the cardioaccelerator nerve, clonidine had a negative chronotropic effect, the degree of which was similar to that observed in intact dogs.
Clonidine neither modified baseline heart rates of dogs with denervated hearts nor the levels of heart rate which in this preparation were reduced by a sustained electrical stimulation of the right vagus or increased by intravenous infusions of either isoprenaline or noradrenaline.
These findings indicate that in the intact dog, bradycardia induced by clonidine resulted both from a reduction of sympathetic drive and from a concomitant increase in parasympathetic tone. The latter action did not occur at the level of cardiac neuroeffector structures since it was observed only in the presence of centrally connected vagal pathways. The inhibition of cardiac sympathetic tone was of both peripheral and central origin. Clonidine, in fact, diminished the quantity of noradrenaline overflowing into the coronary sinus plasma in cardiac denervated dogs with a tachycardia elicited by electrical stimulation of the decentralized cardioaccelerator nerve. This peripheral effect was probably due to an activation of α‐adrenoceptors located on sympathetic nerve terminals since it was antagonized by phentolamine. However, in vagotomized dogs (intact sympathetic pathways) intravenous phentolamine failed to antagonize the heart rate effects of clonidine which were abolished by a subsequent injection of phentolamine into the vertebral artery. Thus, the clonidine‐induced inhibition of both the peripheral and central sympathetic drive to the heart would appear to be mediated via α‐adrenoceptors.
β‐ADRENOCEPTOR ANTAGONISTS: STUDIES ON BEHAVIOUR (DELAYED DIFFERENTIATION) IN THE MONKEY (Macaca mulatta)
Authors: NICHOLSON A.N. , WRIGHT CATHERINE M. 
Published: July 2012

Activity of six β‐adrenoceptor antagonists was studied on behavioural activity (delayed differentiation) in the monkey (Macaca mulatta). The drugs, three relatively lipophilic antagonists (propranolol, oxprenolol and metoprolol), and three relatively hydrophilic antagonists (acebutolol, atenolol and sotalol), were given by intraperitoneal injection (5 to 30 mg/kg).
With atenolol (25 to 30 mg/kg), total response time was increased, but there was no effect on the number of correct responses. With acebutolol (25 to 30 mg/kg), the number of correct responses was reduced, but there was no effect on total response time. With metoprolol (25 to 30 mg/kg), there was an increase in total response time and a decrease in the number of correct responses, and correct responses were decreased 4 h after injection over the whole dose range (5 to 30 mg/kg).
Some animals failed to respond or complete the task with 30 mg/kg oxprenolol, 25 mg/kg sotalol and 20 mg/kg propranolol. With 25 mg/kg oxprenolol, the total response time was increased and the number of correct responses was decreased. With 5–20 mg/kg sotalol, total response time was increased, but there was no effect on the number of correct responses. With 15 mg/kg of (±)‐propranolol and its isomers, there were increases in total response time and decreases in correct responses.
The studies suggest that lipophilic antagonists, such as propranolol, oxprenolol and metoprolol, are likely to have, at least, effects on the central nervous system, while hydrophilic antagonists may modify the peripheral nervous system. In the dose‐ranges studied, propranolol had the greatest, and atenolol and acebutolol had the least effects. Atenolol and acebutolol may prove to be particularly useful in man when disturbances of the nervous system are to be avoided.
ELECTROPHYSIOLOGICAL EFFECTS OF IMPRAMINE ON BOVINE VENTRICULAR MUSCLE AND PURKINJE FIBRES
Authors: RODRIGUEZ SERGIA , TAMARGO JUAN 
Published: July 2012

The effect of imipramine in concentrations between 0.01 μm and 50 μm has been studied on bovine Purkinje fibres and ventricular muscle transmembrane potentials.
In electrically stimulated fibres, imipramine had no effect on the resting membrane potential, but decreased the action potential amplitude, overshoot and maximum rate of depolarization (Vmax).
In Purkinje fibres, imipramine also decreased the conduction velocity and shifted the membrane responsiveness and recovery time curves downward and to the right.
In both Purkinje fibres and ventricular muscle, imipramine decreased the amplitude of phase 2 and prolonged phase 3. In Purkinje fibres, imipramine did not alter the action potential duration (APD) but prolonged the effective refractory period (ERP). In ventricular muscle, at concentrations higher than 1 μm imipramine shortened both the APD and the ERP and made the ERP long as compared to APD.
Imipramine decreased the slope of phase 4 diastolic depolarization in spontaneously beating Purkinje fibres.
These properties of imipramine are quite similar to those of quinidine or procainamide (class 1 antiarrhythmics). The mechanisms responsible for the cardiac effect of imipramine are discussed.
INFLUENCE OF TRACHEAL CONTRACTION ON RELAXANT EFFECTS in vitro OF THEOPHYLLINE AND ISOPRENALINE
Authors: KARLSSON J.‐A. , PERSSON C.G.A. 
Published: July 2012

Relaxation by (−)‐isoprenaline (Iso) and theophylline (Theo) was measured in guinea‐pig isolated trachea, in the presence or absence of carbachol
With basal tone or with carbachol at a concentration of 5.4 × 10−7M, causing 70% maximal contraction, Iso and Theo relaxed the trachea to the same extent
With carbachol concentrations of 5.4×10−6M and 5.4×10−5M (96% and 100% maximal contractions) Iso caused no more than 63% and 34%, respectively, of the maximum relaxation to Theo
When calculated at 25% of the maximum Theo relaxation, the Iso/Theo potency ratio was gradually reduced from 14, 160 when evaluated at basal tone to 1, 560 at the highest carbachol concentration
In combination, at their maximally effective concentrations, Theo and Iso produced no larger a relaxation than did Theo alone
At the two highest concentrations of carbachol, concentration‐response curves to Theo were virtually superimposable whether determined in the absence or the presence of Iso at its maximally effective concentration. 7 It is concluded that Theo causes a greater relaxation of highly contracted tracheal muscle than Iso.
EVIDENCE FOR AN ACTION OF MORPHINE AND THE ENKEPHALINS ON SENSORY NERVE ENDINGS IN THE MOUSE PERITONEUM
Authors: BENTLEY G.A. , NEWTON S.H. , STARR JENNIFER 
Published: July 2012

A modification of the abdominal constriction test in mice has been developed, and used to study the antinociceptive effects of morphine and several related drugs. In most experiments, acetic acid (0.6% i.p.) was used as the nociceptive stimulus, and in a few cases, acetylcholine (3.2mg/kgi.p.) was used. When the abdominal constriction response had reached a maximum, the drugs under test were given intraperitoneally, and their ability to decrease the number of abdominal constrictions was determined, beginning immediately after its administration. The aim of this study was to investigate the possibility that morphine and its congeners may produce an antinociceptive effect by an action within the peritoneum.
It was found that morphine was an extremely potent antinociceptive agent in this modified test, with an ID50 of 5.4 × 10−9 mol/kg (1.54 μg/kg). Codeine and pentazocine were about 40 times less active and oxymorphine was about twice as potent as morphine. Met‐ and Leu‐enkephalin were also potent but their action diminished very rapidly with time. Ketocyclazocine was the most potent substance tested, and had an ID50 value of 1.26 × 1010 mol/kg (0.036 μg/kg). All the drugs tested produced their maximal effect within 1 or 2 min of administration.
Pretreatment of the mice with naloxone caused a dose‐dependent shift to the right of the dose‐response curve to morphine. The pAx plot was linear over part of the range, with a slope of − 1.02 and the ‘apparent pA2’ value was 6.14. Naloxone was much less effective in antagonizing Met‐enkephalin, and caused a slight potentiation of ketocyclazocine and pentazocine and of cocaine, which was used for comparison.
Pretreatment of mice with morphine, 3 h earlier, caused a marked tolerance to a subsequent dose of morphine, and a potentiation of the antagonist potency of naloxone. However, there was little cross‐tolerance between morphine and Leu‐enkephalin.
It is concluded that morphine and its congeners can produce an antinociceptive effect by an action within the mouse peritoneum, presumably by interacting with one or more types of opioid receptors which may be situated on sensory nerve endings.
A STUDY ON THE INTERACTION OF CROTAPOTIN WITH CROTOXIN PHOSPHOLIPASE A2, NOTEXIN AND OTHER PRESYNAPTIC NEUROTOXINS
Authors: CHANG C.C. , SU M.J. 
Published: July 2012

Crotapotin, the acidic subunit of crotoxin, greatly potentiated the presynaptic effect of isolated basic phospholipase A (PLA) of crotoxin in both mouse diaphragm and chick biventer cervicis muscles whereas the myotoxic effect was not affected significantly.
In contrast to crotoxin PLA, the presynaptic effects of notexin and notechis‐5, self‐active single chain toxins, were antagonized by crotapotin while actions of β‐bungarotoxin were not affected.
By assaying PLA activity, crotoxin PLA was found to be unstable in physiological salt solution, especially when in contact with muscle, due to massive non‐specific binding to and destruction by the muscle.
The decline of crotoxin PLA was greatly reduced by the presence of crotapotin but not by another acidic protein, volvatoxin A2, or heparin.
Notechis‐5 was found to be stable even when in the presence of muscles.
[3H]‐acetylated crotoxin PLA, which retained about 40% of its original enzyme and presynaptic blocking activities, also bound rapidly to the mouse diaphragm on incubation and this binding was greatly hindered by the simultaneous addition of crotapotin.
The prevention of binding of crotoxin PLA by crotapotin occurred mostly at those sites where the binding was easily dissociable on washing. No antagonism of binding occurred at the firmly binding site.
The binding of [3H]‐acetylated crotapotin was much less than that of crotoxin PLA, and interestingly, the binding was increased by the latter, suggesting that crotapotin may be first bound to the diaphragm together with crotoxin PLA.
No specific binding at the endplate zone was found either for crotoxin PLA or for crotapotin.
It is concluded that crotapotin potentiates the presynaptic effect of crotoxin PLA by curtailing its non‐specific affinity with muscles, minimizing its dispersal and destruction en route to the nerve terminal, but not by acting as an affinity probe for the nerve terminal.
β‐ADRENOCEPTOR AGONISTS ENHANCE 5‐HYDROXYTRYPTAMINE‐MEDIATED BEHAVIOURAL RESPONSES
Authors: COWEN P.J. , GRAHAME‐SMITH D.G. , GREEN A.R. , HEAL D.J. 
Published: July 2012

The β‐adrenoceptor agonists, salbutamol, terbutaline and clenbuterol, were investigated for their effect on 5‐hydroxytryptamine‐mediated (5‐HT) hyperactivity.
The lipophilic β‐adrenoceptor agonist, clenbuterol (5 mg/kg) enhanced the behaviours induced by quipazine (25 mg/kg), including headweaving, forepaw treading and hind‐limb abduction and thus increased automated activity recording. Clenbuterol (5 mg/kg) also enhanced the hyperactivity syndrome produced by the 5‐HT agonist, 5‐methoxy N,N‐dimethyltryptamine (2 mg/kg) and the combination of tranylcypromine (10 mg/kg) and L‐tryptophan (50 mg/kg). Salbutamol and terbutaline potentiated quipazine‐induced hyperactivity only when given at the higher dose of 20 mg/kg.
The effect of clenbuterol in enhancing quipazine hyperactivity was blocked by the centrally acting β1‐adrenoceptor antagonist, metoprolol (5 mg/kg), but not by the β2‐adrenoceptor antagonist, butoxamine (5 mg/kg) or the peripherally acting β1‐adrenoceptor antagonist, atenolol (5 mg/kg).
Clenbuterol (5 mg/kg) did not enhance the circling responses produced by methamphetamine (0.5 mg/kg) in unilateral nigrostriatal‐lesioned rats.
The results suggest that β‐adrenoceptor agonists in common with some established antidepressant treatments produce enhancement of 5‐HT‐mediated behavioural responses.
PROTEASE INHIBITOR HOMOLOGUES FROM MAMBA VENOMS: FACILITATION OF ACETYLCHOLINE RELEASE AND INTERACTIONS WITH PREJUNCTIONAL BLOCKING TOXINS
Authors: HARVEY A.L. , KARLSSON E. 
Published: July 2012

Five polypeptides, which were isolated from elapid snake venoms and which are structurally related to protease inhibitors, were tested for action on isolated biventer cervicis nerve‐muscle preparations of the chick.
Dendrotoxin from the Eastern green mamba (Dendroaspis angusticeps) and toxins K and I from the black mamba (Dendroaspis polylepis polylepis) increased responses to indirect stimulation without affecting responses to exogenous acetylcholine, carbachol or KCl.
The two other protease inhibitor homologues, HHV‐II from Ringhals cobra (Hemachatus haemachatus) and NNV‐II from Cape cobra (Naja nivea) did not increase responses to nerve stimulation. Trypsin inhibitor from bovine pancreas also had no facilitatory effects on neuromuscular transmission.
The facilitatory toxins from mamba venoms interacted with the prejunctional blocking toxins, β‐bungarotoxin, crotoxin and notexin, but not with taipoxin. The blocking effects of β‐bungarotoxin were reduced by pretreatment with the mamba toxins, whereas the blocking actions of crotoxin and notexin were enhanced.
The results indicate that protease inhibitor homologues from mamba venoms form a new class of neurotoxin, which acts to increase the release of acetylcholine in response to motor nerve stimulation.
From the interaction studies it is concluded that the facilitatory toxins bind to motor nerve terminals at sites related to those occupied by the prejunctional blocking toxins. However, differences in interactions with individual toxins suggest that there must be several related binding sites on the nerve terminals.
Heat loss reaction to capsaicin through a peripheral site of action
Authors: Donnerer Josef , Lembeck Fred 
Published: July 2012

The intravenous injection of 15 fig capsaicin produced an increase in the temperature of tail skin and paw pad and a fall in the colon temperature in conscious rats. These reactions reflect increased heat dissipation.
The increase in skin temperature induced by intravenous capsaicin was absent when the function of small diameter primary afferent neurones was impaired by treatment of the rats with capsaicin as neonates. Thus it appears that intravenous capsaicin triggered the thermoregulatory response predominantly by stimulation of peripheral heat receptors.
By means of local application of capsaicin to the nerves of the hind leg and by their chronic denervation, by treatment with phenoxybenzamine and guanethidine, evidence was obtained that reflex withdrawal of sympathetic vasoconstrictor tone mediates the heat loss reaction to intravenous capsaicin.
Effects of cocaine and desipramine on the neurally evoked overflow of endogenous noradrenaline from the rat heart
Authors: Dart A.M. , Dietz R. , Kübier W. , Schömig A. , Strasser R. 
Published: July 2012

Stimulation of postganglionic cardiac sympathetic nerves produced a stimulation frequency‐dependent overflow of endogenous noradrenaline from the otherwise isolated rat heart.
Such nerve stimulation also produced increases in heart rate. There was significant correlation between heart rate increases and corresponding noradrenaline concentrations in the coronary venous effluent.
Cocaine (3 × 10−5 M) caused a significant reduction in both the noradrenaline overflow and the heart rate increase, produced by nerve stimulation for 1 min at 4 Hz.
Desipramine (10−6M) caused a significant increase in the noradrenaline overflow produced by stimulation for 1 min (4 Hz) with a mean increase of approximately 60%. There was no significant effect on the heart rate increase produced by such stimulation.
The opposite effects of cocaine (3 × 10−5M) and desipramine (10−6M) on noradrenaline overflow are attributed to differences in the local anaesthetic properties of these agents.
Extracellular chloride replacement by isethionate induces abnormal spontaneous release of transmitter at the frog neuromuscular junction
Authors: Ashford M.L.J. , Wann K.T. 
Published: July 2012

Replacement of chloride by isethionate in Ringer solution bathing frog skeletal muscle fibres induces, after a delay of about 30 min, marked mechanical activity which was blocked by tubocurarine. This effect is reversed by washing out the isethionate.
Miniature end plate potentials (m.e.p.ps) and giant potentials (potentials >2 × modal value) were recorded intracellularly in normal Ringer and isethionate Ringer solution.
The frequency of m.e.p.ps was unaltered by isethionate. The proportion of giant potentials increased from 3% in normal Ringer to 24.5% in isethionate Ringer after 90 min. This effect is usually reversible if the exposure to isethionate does not exceed 2 h.
The giant potentials were large enough to initiate trains of action potentials and still occurred in the presence of tetrodotoxin or Ca2+‐free Ringer. Isethionate produced no change in the τD of miniature endplate currents.
Chloride replacement by propionate produced no change in the proportion of giant potentials.
It is suggested that the isethionate anion can induce giant potentials and the possible mechanism of action is discussed.
Different α‐adrenoceptors modulate the release of 5‐hydroxytryptamine and noradrenaline in rat cortex
Authors: Ennis Christine 
Published: July 2012

The potassium‐evoked release of [3H] ‐noradrenaline from slices of rat occipital cortex and the potassium‐evoked release of [3H]‐5‐hydroxytryptamine from slices of rat frontal cortex were measured using a superfusion system.
The rank order of potency for a number of α‐adrenoceptor agonists was different for the two neuronal systems, Clonidine and azepexole being the most potent inhibitors of noradrenaline release and methoxamine and phenylephrine being the most potent against 5‐hydroxytryptamine release.
The rank order of potency for a series of α‐adrenoceptor antagonists in reversing the inhibition of noradrenaline release produced by Clonidine was: phentolamine > rauwolscine = yohimbine = corynanthine >> WB4101, whereas against methoxamine‐inhibition of 5‐hydroxytryptamine release the rank order of potency was: WB4101 > phentolamine > corynanthine > yohimbine > rauwolscine.
The results suggest that the α‐adrenoceptors which modulate potassium‐evoked 5‐hydroxytryptamine release are not identical with the α2‐adrenoceptors located on noradrenergic nerve terminals and may more closely resemble α1‐than α2‐adrenoceptors.
The effects of 2‐nicotinamidoethyl nitrate on smooth muscle cells of the dog mesenteric artery and trachea
Authors: Inoue Toshiro , Ito Yushi , Takeda Kazuo 
Published: July 2012

The effects of 2‐nicotinamidoethyl nitrate (nicorandil; 2‐NN), a synthesized coronary vasodilator, on smooth muscle cells of dog mesenteric artery or trachea were investigated using microelectrode, double sucrose gap and isometric tension recording methods.
Nicorandil hyperpolarized the smooth muscle membrane of the mesenteric artery (5 × 10−6m) and the trachea (5 × 10−5 m).
In both these smooth muscle cells, the nicorandil‐induced hyperpolarization remained constant in various concentrations of [Cl−1]o, but changed with various concentrations of [K+]o. This hyperpolarization was partly inhibited following pretreatment with tetraethylammonium (TEA > 1 mm) and was completely inhibited following pretreatment with procaine (1 mm or 5 mm), indicating that the nicorandyl‐induced hyperpolarization is due to increase in the K‐conductance, in both these membranes.
Following pretreatment with TEA (5 mm), outward current pulses evoked an action potential in tracheal smooth muscle cells. Nicorandil inhibited the generation of action potential due to the hyperpolarization of the membrane but not due to inhibition of the spike generating mechanism.
Nicorandil (10−6m) inhibited the contracture evoked by excess [K]o, in both tissues. The contracture evoked by noradrenaline or repetitive field stimulation with short duration (50 μs) pulses was also inhibited in the mesenteric artery, while a higher dose of nicorandil (10−5m) was required to inhibit the contracture evoked by acetylcholine or repetitive field stimulation in the trachea.
Excitatory junction potentials (e.j.ps) evoked by field stimulation in the mesenteric artery due to the release of noradrenaline, or in the trachea due to release of acetylcholine, were suppressed by 10−5 m or 5 × 10−5 m nicorandil, respectively. The reduction in the amplitude of e.j.p. was mainly due to the hyperpolarization of the membrane with increase in the membrane conductance.
In the mesenteric artery, following pretreatment with TEA (1 mm) an action potential was generated on the e.j.p. Nicorandil suppressed the generation of the action potential by reduction in the amplitude of the e.j.p., below the threshold required for generation of the action potential.
These results indicate that nicorandil hyperpolarizes the membrane by increasing K‐conductance and inhibits the generation of contraction, in both tissues. Higher concentrations of nicorandil are required to suppress the mechanical response in the trachea than in the mesenteric artery. Depression of the mechanical responses in both tissues is partly due to suppression of Ca‐mobilization inside the muscle cells and partly to hyperpolarization of the membrane.