bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphine‐neural interactions on canine intestinal absorption and blood flow
Authors: Mailman David
Published: July 2012

Intestinal Na and H2O fluxes and blood flow were determined in extrinsically denervated or innervated ileum of fed dogs during intra‐arterial (0.2, 2, 20 μg min−1) or intraluminal (4, 40, 400 μg ml−1) morphine sulphate infusion.

3H2O and 22Na were used to determine unidirectional fluxes and 3H2O clearances were used to determine total segmental and absorptive site blood flow.

Net Na and H2O absorption decreased with time in innervated gut segments but were unchanged in denervated segments.

Intra‐arterial morphine prevented the decrease in net Na and H2O absorption in innervated segments due to increases in unidirectional absorptive fluxes. Intra‐arterial morphine did not affect absorption in denervated segments.

Intraluminal morphine increased net Na and H2O absorption from both innervated and denervated ileal segments due to increases in the unidirectional absorptive fluxes.

Absorptive site blood flow was linearly related to unidirectional absorptive Na fluxes in each group although not with the same slopes. The increment in absorptive site blood flow vs. absorptive Na flux was greatest with luminal morphine, intermediate with intra‐arterial morphine and in denervated segments without morphine and least in innervated segments.

It was concluded that intra‐arterial morphine inhibits an antiabsorptive effect of extrinsic nerves and that intraluminal morphine promotes an absorptive effect which could be direct or mediated through intrinsic nerves.
Characterization of the α‐adrenoceptors in the female rabbit urethra
Authors: Andersson Karl‐Erik , Larsson Bengt , Sjögren Christer
Published: July 2012

A radioligand binding technique was used to evaluate the proportions of α1‐ and α2‐adrenoceptors in crude membrane preparations obtained from the female rabbit bladder base and urethra. In addition, urethral rings were studied in vitro in an attempt to determine if α1‐ and/or α2‐adrenoceptors are located postjunctionally in the urethral smooth muscle.

Studies of the inhibition of [3H]‐dihydroergocryptine binding by the selective α1‐adrenoceptor antagonist prazosin or the selective α2‐adrenoceptor antagonist rauwolscine revealed the α‐adrenoceptor population to consist of approximately 25% α1‐adrenoceptors and 75% α2‐adrenoceptors. These proportions were confirmed in saturation studies with [3H]‐prazosin and [3H]‐rauwolscine. The sum of α1‐ and α2‐adrenoceptors labelled by these selective α1‐ and α2‐adrenoceptor antagonists was about equal to the number labelled by the non‐selective α‐adrenoceptor antagonist [3H]‐dihydroergocryptine.

Noradrenaline, as well as the selective α1‐adrenoceptor agonist phenylephrine and the selective α2‐adrenoceptor agonist clonidine, induced contractions of urethral ring preparations. Prazosin blocked contractions induced by phenylephrine to a greater extent than contractions induced by clonidine. The opposite was true for the inhibitory effect of rauwolscine.

In addition to showing that both α1‐ and α2‐adrenoceptor binding sites exist in membrane preparations of the rabbit bladder base and urethra, the results reveal the presence of both adrenoceptor subtypes postjunctionally in the rabbit urethra; and both mediate contraction of the smooth muscle.
The action of dantrolene sodium on individual fast and slow motor units of the rat anaesthetized with urethane
Authors: Leslie G.C. , Part N.J.
Published: July 2012

Rats, anaesthetized with urethane, were injected intravenously with dantrolene sodium in a vehicle of 5% mannitol taken to pH 10 with NaOH.

The muscle relaxant action of dantrolene sodium was measured from the contractions of individual motor units of the extensor digitorum longus (EDL), soleus (SOL) and segmental tail (ST) muscles. Data were also collected from their parent whole muscle preparations.

The depressant action of dantrolene sodium on the percentage‐normalized amplitude of contraction of the individual motor units was greater than its effect on the whole muscle twitch amplitude, in all three muscles.

The twitch amplitude of fast contracting motor units was significantly more reduced (P < 0.001) by dantrolene sodium than was that of slow contracting motor units.

Dantrolene sodium reduced the contraction time of all motor units. The effect of the drug on half‐relaxation time varied within and between groups of motor units studied.

The drug was confirmed to have a greater depressant action on the twitch contraction than on the fused tetanus of whole muscle. This was true also for single motor units.

With tetanic stimulation the effect of dantrolene sodium was also dependent upon the motor unit type, fast or slow. A maximum depression of contractile tension occurred at a stimulation frequency of 64 Hz for fast EDL motor units whereas the maximum depression for ST slow units, the slowest units tested, was at a stimulation frequency of 14 Hz.
Release of endogenous 5‐hydroxytryptamine from the myenteric plexus of the guinea‐pig isolated small intestine
Authors: Holzer P. , Skofitsch G.
Published: July 2012

The presence of 5‐hydroxytryptamine (5‐HT) and its metabolite 5‐hydroxyindoleacetic acid (5‐HIAA) in, and the release of these substances from, the myenteric plexus‐longitudinal muscle (MPLM) layer of the guinea‐pig isolated small intestine were investigated. 5‐HT and 5‐HIAA were measured by high performance liquid chromatography and electrochemical detection.

Freshly prepared MPLM contained measurable amounts of 5‐HT and 5‐HIAA. For the release experiments, the MPLM was incubated in a medium containing the 5‐HT uptake inhibitor fluoxetine and the monoamine oxidase inhibitor nialamide; this led to a decrease in the 5‐HIAA content of the MPLM whereas the 5‐HT content remained unchanged.

There was a spontaneous release of 5‐HT and 5‐HIAA from the MPLM. The release of 5‐HT was so small that it was just detectable; it seemed equivalent to about 0.8% of the tissue stores released per min.

Depolarization of the tissue by increasing the [K+] or by exposing it to veratridine enhanced the release of 5‐HT in a Ca2+‐dependent manner whereas the release of 5‐HIAA was not increased. Tetrodotoxin inhibited the veratridine‐evoked release of 5‐HT but did not affect the K+‐evoked release of 5‐HT.

The presence of 5‐HT in myenteric neurones and the characteristics of the release of 5‐HT from these neurones strongly support the hypothesis that 5‐HT is an enteric neurotransmitter.
Adrenergic transmission in the dog mesenteric vein and its modulation by α‐adrenoceptor antagonists
Authors: Suzuki H.
Published: July 2012

Adrenergic transmission was investigated in the dog mesenteric vein by recording electrical responses of single smooth muscle cells to perivascular nerve stimulation.

Perivascular nerve stimulation generated an excitatory junction potential (e.j.p.) and a slow depolarization of the membrane. The amplitude of the e.j.p. was increased by increasing the stimulus intensity, and at high intensity, a spike potential was generated.

Repetitive stimulation of the nerves showed facilitation of e.j.ps and enhanced the amplitude of slow depolarization. A linear relationship was observed between the amplitude of the e.j.p. and of slow depolarization.

The slow depolarization was inhibited by application of yohimbine or phentolamine, but not by prazosin. The amplitude of e.j.p. was increased by prazosin and was decreased by yohimbine. Both e.j.p. and slow depolarization were inhibited by guanethidine or tetrodotoxin.

Exogenously applied noradrenaline depolarized the muscle membrane and, in high concentrations (> 10−7 m), generated slow waves. These effects of noradrenaline were blocked by yohimbine. High concentrations of prazosin (> 10−6m) showed weak inhibitory effects on the noradrenaline actions.

The amplitude of e.j.p. was decreased by exogenously applied noradrenaline in a dose‐dependent manner. The inhibitory effect of noradrenaline on the e.j.p. was suppressed by yohimbine, but not by prazosin or phentolamine.

Phentolamine, but not prazosin, enhanced the facilitation process of e.j.ps. This effect was not suppressed by exogenously applied noradrenaline.

Application of neostigmine but not of atropine, reduced the e.j.p. amplitude without affecting the slow depolarization.

It was concluded that, in the dog mesenteric vein, perivascular nerve stimulation produced three types of electrical responses of the smooth muscle membrane, i.e., e.j.p., slow depolarization and spike potential. The slow depolarization was generated by activation of α2‐adrenoceptors. Exogenously applied noradrenaline reduced the e.j.p. amplitude through activation of prejunctional α2‐adrenoceptors, but the reduction may not involve α‐autoinhibitory mechanisms.
The interaction between hexamethonium and tubocurarine on the rat neuromuscular junction
Authors: Rang H.P. , Rylett R. Jane
Published: July 2012

The ability of hexamethonium (C6) to reverse the neuromuscular blocking action of tubocurarine (Tc) has been reinvestigated at the voltage clamped endplate of the omohyoid muscle of rat. The possibility that a weak anticholinesterase action of C6 could contribute to the paradoxical potentiation of the peak amplitude of the endplate response has been examined.

C6 (50–200 μm) caused an increase in the amplitude of nerve‐evoked endplate currents (e.p.cs) recorded in the presence of 0.6 μm Tc. The effect decreased with hyperpolarization of the muscle fibre. Irreversible inhibition of acetylcholinesterase resulted in a loss of the anti‐curare effect of C6.

C6 did not cause an increase in e.p.c. amplitude when acetylcholine (ACh) receptors were blocked irreversibly by α‐bungaratoxin. When transmission was blocked by increased Mg2+ concentration, C6 (50–400 μm) reduced the amplitude of e.p.cs without appreciably affecting their time course.

C6 caused a decrease in the amplitude of miniature endplate currents (m.e.p.cs) the effect being slightly increased when the fibre was hyperpolarized. An e‐fold increase in the effectiveness of C6 occurred with approximately 58 mV hyperpolarization. High concentrations (> 400 μm) affected the time course of m.e.p.cs in a manner suggestive of open channel block, but this was not evident at 200 μm, the concentration that was most effective in reversing Tc block.

When tested against responses to short ionophoretic pulses of agonists, C6 was less effective against ACh ((EC50 ca. 300 μm) than against carbachol (CCh) (EC50 100 μm). When cholinesterase was irreversibly inhibited, C6 blocked responses to both agonists equally (EC50 ca. 100 μm).

The effectiveness of C6 in blocking the action of CCh was reduced 10 fold in the presence of 0.6 μm Tc, implying that the two antagonists compete for the same binding site.

C6 (50–200 μm) in the presence of Tc (0.6 μm) increased the response to ionophoretically applied ACh but not that to CCh.

C6 was equipotent in blocking m.e.p.cs and responses to ionophoretically applied ACh whereas Tc was more potent against the exogenously applied agonist.

C6 was a weak inhibitor of acetylcholinesterase activity in rat muscle homogenates (EC50 1.5 mm).

The results are discussed in terms of the kinetic hypothesis advanced by Ginsborg & Stephenson (1974) to account for the Tc reversal phenomenon. It is concluded that this theory can explain most of the effect on e.p.cs, but that the weak anticholinesterase action of C6 is also a factor, particularly in the reversal of Tc block of ionophoretic responses.
Tolbutamide as a model drug for the study of enzyme induction and enzyme inhibition in the rat
Authors: Back D.J. , Sutcliffe F. , Tjia J.F.
Published: July 2012

The effects of various drugs on the pharmacokinetics of tolbutamide have been examined in the rat.

Phenobarbitone pretreatment caused a significant decrease in half life and area under the curve (AUC) and a significant increase in clearance and volume of distribution (Vd).

Acute administration of primaquine significantly increased half life and AUC and decreased clearance. In contrast, the related animoquinolone chloroquine, was without effect.

Acute administration of cimetidine produced similar changes to primaquine but of lesser magnitude.

Formation of the major metabolite hydroxytolbutamide, was markedly enhanced by phenobarbitone and reduced by primaquine and cimetidine.

We conclude that due to its single pathway of metabolism, tolbutamide is a good substrate to use when examining pharmacokinetic interactions involving hepatic enzyme induction and inhibition.
Comparative studies of the effects of some antimuscarinic agents on gastric damage and pupillary reflex in the rat
Authors: Daniotti S. , Del Soldato P.
Published: July 2012

The effects of some antimuscarinic compounds on oxotremorine‐induced gastric damage, the pupil size and the pupillary light reflex have been studied in the rat. Unlike atropine, propantheline and methylscopolamine, pirenzepine is effective in preventing gastric erosions at doses much lower than those that affect pupillary reflex.
The effect of acetylsalicylic acid on renal function in the Pekin duck
Authors: Gray D. A. , Langrieger N. , Reschmaier J. , Simon E.
Published: July 2012

The acute effects of intravenously administered lysine‐acetylsalicylic acid (ASA) on renal function in the Pekin duck have been studied with special reference to possible interactions with the antidiuretic hormone, arginine vasotocin (AVT), in the control of renal water and solute output.

ASA produces an immediate increase in urine flow rate which is dose‐related in the range 25 to 100 mg kg−1 and is associated with a slight reduction in urine osmolality, but an overall increase in renal osmolal excretion affecting Na+, CI− and K+ to approximately equal extents.

The effects, which are similar in both saltwater and freshwater adapted ducks infused with hyposmotic saline or glucose solution, can also be produced by similar doses of sodium salicylate (SA).

The mechanism of action is probably not related to inhibition of prostaglandin synthetases.

There is no change in the glomerular filtration rate or peripheral blood pressure following the ASA injection.

There is no change in the circulating level of AVT; however, preliminary studies do not exclude the possibility of a partial antagonism of salicylate to AVT at the renal level.
Effects of phosphorothioate analogues of ATP, ADP and AMP on guinea‐pig taenia coli and urinary bladder
Authors: Burnstock G. , Cusack N.J. , Meldrum L. A.
Published: July 2012

Phosphorothioate analogues of ATP, ADP and AMP were tested on the guinea‐pig taenia coli and urinary bladder.

The Rp diastereoisomers of the phosphorothioate analogues, ATP‐α‐S and ADP‐α‐S were respectively 7 and 3 times more effective than the Sp diastereoisomers in causing relaxation of the taenia coli. No stereoselectivity was observed for the diastereoisomers of ATP‐β‐S.

In guinea‐pig bladder, no stereoselectivity was observed for any of the phosphorothioate analogues.

These results show that P2‐purinoceptors mediating inhibitory responses in the guinea‐pig taenia coli show marked stereoselectivity, while P2‐purinoceptors mediating excitatory responses in the guinea‐pig bladder show little stereoselectivity.
Alteration of monocrotaline pyrrole‐induced cardiopulmonary effects in rats by hydralazine, dexamethasone or sulphinpyrazone
Authors: Hilliker Katherine S. , Roth Robert A.
Published: July 2012

The effects of intraperitoneal hydralazine, dexamethasone, or sulphinpyrazone on the toxicity of monocrotaline pyrrole (MCTP) were examined in rats 14 days after injection of MCTP (5 mg kg−1, i.v.).

MCTP alone caused increases in lung weight, and of both lactate dehydrogenase activity and protein concentration in bronchopulmonary lavage fluid. Right ventricular hypertrophy also occurred.

Hydralazine (3 mg kg−1, daily), a vasodilator and platelet prostaglandin synthesis inhibitor, reduced the degree of right ventricular hypertrophy and the elevation in the concentration of protein in lavage fluid.

Dexamethasone (27 μg kg−1, daily), an anti‐inflammatory agent and inhibitor of phospholipase, also reduced the right ventricular hypertrophy and the increased protein concentration in lavage fluid caused by MCTP.

Sulphinpyrazone (100 mg kg−1, twice daily), an inhibitor of platelet prostaglandin biosynthesis, prevented right ventricular hypertrophy in the MCTP treated rats without affecting any of the indices of lung injury.

These results provide further support for the hypothesis that platelets and vasoconstrictor agents play a role in the development of MCTP‐induced pulmonary hypertension.
A hypothesis to explain the presynaptic effects of adrenoceptor antagonists
Authors: Kalsner Stanley , Quillan Mark
Published: July 2012

The hypothesis of negative feedback regulation of transmitter release was examined in a range of tissues obtained from three species.

Tissues were transmurally stimulated with 100 pulses at 2 Hz with pulse durations from 50 μs to 5,000 μs, and the efflux of [3H]‐noradrenaline determined.

The stimulation‐induced efflux of tritium increased with increasing pulse duration, but yohimbine, a prototypal α2‐antagonist had an effect which was consistently contrary to expectations for a negative feedback system. Enhancement of efflux by the antagonist, supposedly correlated directly with the extent of ongoing auto‐inhibition, became smaller rather than larger as the stimulation‐induced efflux rose with increases in pulse duration, with all other parameters of stimulation maintained constant. Similar findings were obtained in rat spleen with the haloalkylamine antagonist, phenoxybenzamine.

It is concluded that the presynaptic effects of adrenoceptor antagonists do not involve a negative feedback function nor do they relate, in any detectable way, to the extracellular concentration of transmitter.

The effects on stimulation‐induced tritium efflux of yohimbine, phenoxybenzamine and enlargment of the pulse duration, in a variety of tissues, support the previously described hypothesis of a common action to enhance efflux. The antagonists increased efflux to approximately the same value between 50 and 1,000 μs pulse durations and that value was equivalent to that obtained in each given tissue with pulses of 1,000–2,000 μs in the absence of the antagonist.

Tetraethylammonium, an inhibitor of stimulation‐induced potassium efflux from nerves had an effect on transmitter efflux in rat spleen essentially like that of the adrenoceptor antagonists. These findings provide further support for an alternative to the hypothesis of negative feedback. Yohimbine and other presynaptic antagonists may prolong the period of potassium efflux from nerve varicosities, and by this means prolong depolarization and the associated period of transmitter release, rather than act by disrupting an ongoing system sensing and responding to fluctuations in extracellular transmitter levels.
Endothelial mediated inhibition of contraction and increase in cyclic GMP levels evoked by the α‐adrenoceptor agonist B‐HT 920 in rat isolated aorta
Authors: Miller R.C. , Mony M. , Schini V. , Schoeffter P. , Stoclet J.C.
Published: July 2012

In the presence of endothelium maximal contractions of rat aorta preparations evoked by B‐HT 920 were about 10% of those evoked in the absence of endothelium.

6‐Allyl‐2‐amino‐5,6,7,8‐tetrahydro‐4H‐thiazolo‐(4,5‐d)azepin dihydrochloride (B‐HT 920, 0.1 μM to 0.1 mM) induced concentration‐dependent contractions of rat aorta in the absence of endothelium. Maximal contractions were comparable in magnitude to those induced by noradrenaline.

In the presence of endothelium but not in its absence B‐HT 920 (0.1 mM) stimulated an increase in tissue cyclic GMP levels of about 2 fold. Levels of cyclic AMP were unaffected. Removal of endothelium reduced basal tissue levels of cyclic GMP.

The guanylate cyclase inhibitor methylene blue (0.5 JIM) potentiated B‐HT 920‐induced contractions in the presence of endothelium and inhibited increases in cyclic GMP.

In the presence of endothelium 5,8,11,14‐eicosatetraynoic acid (ETYA; 0.1 mM), an inhibitor of both lipoxygenase and cyclo‐oxygenase systems, inhibited the B‐HT 920‐induced increase in cyclic GMP but did not potentiate B‐HT 920‐induced contractions. ETYA also antagonized B‐HT 920‐induced contractions in the absence of endothelium.

It is concluded that endothelium continuously releases a product or products which influence the smooth muscle. Inhibition of B‐HT 920‐induced contractions in the presence of endothelium is associated with increased tissue levels of cyclic GMP.
Adenosine potentiates immunological histamine release from rat mast cells by a novel cyclic AMP‐independent cell‐surface action
Authors: Churchi Martin K. , Hughes Philip J.
Published: July 2012

Adenosine enhanced histamine release and prolonged the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) response in purified rat peritoneal mast cells following immunological challenge. The effect on the cyclic AMP response, which was blocked by 8‐phenyltheophylline, probably results from an interaction with A2‐purinoceptors. Enhancement of histamine release showed different characteristics. It was not inhibited by dipyridamole or hexobendine, thereby indicating an action at the cell surface. However, the relative potencies of adenosine analogues and nucleotides, together with the observation that this effect was not antagonized by 8‐phenyltheophylline or theophylline, suggest that it is not mediated by a previously recognised purinoceptor. Thus, enhancement of histamine release may represent a novel cell surface action of adenosine which is independent of its effects on adenylate cyclase.
Reduction of urinary excretion of PGE2 and 6 keto PGF1α by tiaprofenic acid
Authors: Lote C. J. , McVicar A.J. , Thewles A.
Published: July 2012

Tiaprofenic acid (Surgam, Cassenne) was administered intravenously to saline‐diuretic conscious rats, at doses of 2, 10 and 25 mg kg−1 body weight.

Tiaprofenic acid significantly reduced urinary prostaglandin E2 (PGE2) and 6 keto PGF1α excretion, at all three doses employed. The extent of the reduction was similar for both PGE2 and 6 keto PGF1α output; hence no evidence of ‘selectivity’ (i.e. sparing of PGI2 synthesis) was observed.

Tiaprofenic acid was also administered to rats receiving an infusion of 5% dextrose. The dose employed (0.5 or 1 mg kg−1 body weight) was submaximal and elicited reductions in PGE2 output to values still more than 60% of the control period values. In this group of animals, the percentage change in 6 keto PGF1α excretion was again not significantly different from that of PGE2.

The maximal extent of reduction in urinary PGE2 excretion with tiaprofenic acid (25 mg kg−1 body weight) was not significantly different from that elicited by indomethacin (10 mg kg−1 body weight), although the time course of the reduction was different.
New models for the evaluation of opioid effects in the guinea‐pig ileum
Authors: Donnerer Josef , Lembeck Fred
Published: July 2012

The pharmacology of morphine and opioid peptides was studied in the guinea‐pig ileum by examining their inhibitory effects on propulsive peristaltic activity and on the cooling‐induced longitudinal contraction.

In these experiments, dose‐response curves were recorded. The rank order of potency in inhibiting peristalsis was found to be: dermorphin> FK 33–824 > dynorphin‐(1–17)> dynorphin‐(1–13)> δ‐receptor‐peptide > morphine > [Leu] enkephalin, whereas the rank order in inhibiting cooling‐induced contractions was found to be: dynorphin‐(1–13) ⋍ FK 33–824 ⋍ dermorphin> δ‐receptor peptide > morphine. Naloxone antagonized the maximally effective dose of each of the opioid agents.

In view of the differences between the abilities of these opioids to inhibit propulsive peristaltic activity, these models seem to be valuable for the examination of inhibitory opioid effects in the gut.
Effect of tetracaine and glibenclamide on 45Ca2+ handling by isolated pancreatic islets
Authors: Norlund Lena , Sehlin Janove
Published: July 2012

The 45Ca2+ uptake in β‐cell‐rich ob/ob‐islets was measured using the La3+ wash technique.

Tetracaine (1 mM) markedly enhanced the 45Ca2+ net uptake (120 min) in the presence of 3 mM glucose, and at 7 and 20 mM glucose there were clear tendencies to dose‐dependent increases with 0.1 to 1 mM tetracaine. Glibenclamide 1 μM to 0.2 mM, stimulated the 45Ca2+ net uptake in the presence of 3 mM glucose and 0.1 mM to 0.2 mM glibenclamide potentiated the uptake in the presence of 7 mM glucose. When the drugs were added for only a 10 min incubation period, glibenclamide, 1 μM to 0.2 mM, but not tetracaine (10 μM to 1 mM) increased the short‐term uptake of 45Ca2+. After preincubation with either of the drugs, neither tetracaine (10 μM to 1 mM) nor glibenclamide (10 nM to 0.2 mM) had any effect on the short‐term 45Ca2+ uptake.

In islets incubated with 45Ca2+ and tetracaine and washed without La3+ the apparent net uptake of 45Ca2+ was reduced by 0.5 to 1 mM tetracaine both at 3 and 20 mM glucose.

Tetracaine (0.5 mM) stimulated the 45Ca2+ efflux in the presence of 3 mM glucose.

The results show that both drugs affected the Ca2+ handling. It is suggested that glibenclamide mainly increases Ca2+ influx by voltage‐dependent pathways, whereas tetracaine, at certain concentrations, mobilizes Ca2+ from intracellular stores in the islet cells.
Mechanisms underlying electrical and mechanical responses of the bovine retractor penis to inhibitory nerve stimulation and to an inhibitory extract
Authors: Byrne N.G. , Muir T. C.
Published: July 2012

The response of the bovine retractor penis (BRP) to stimulation of non‐adrenergic, non‐cholinergic (NANC) inhibitory nerves and to an inhibitory extract prepared from this muscle have been studied using intracellular microelectrode, sucrose gap and conventional mechanical recording techniques.

Both inhibitory nerve stimulation and inhibitory extract hyperpolarized the membrane potential and relaxed spontaneous or guanethidine (3 × 10−5 M)‐induced tone. These effects were accompanied by an increase in membrane resistance.

Following membrane potential displacement from an average value of − 53 ± 7 mV (n = 184; Byrne & Muir, 1984) inhibitory potentials to nerve stimulation were abolished at approximately − 30 mV; there was no evidence of reversal. Displacement by inward hyperpolarizing current over the range − 45 to − 60 mV increased the inhibitory response to nerve stimulation and to inhibitory extract; at more negative potential values (above approximately − 60 mV) the inhibitory potential decreased and was abolished (approximately − 103 mV). There was no evidence of reversal.

Removal of [K+]o reversibly reduced hyperpolarization to nerve stimulation and inhibitory extract. No enhancement was observed. Increasing the [K+]o to 20 mM reduced the inhibitory potential to nerve stimulation but this was restored by passive membrane hyperpolarization. Inhibitory potentials were obtained at membrane potential values exceeding that of the estimated EK(‐ 49 mV).

[Cl−]o‐free or [Cl−]o‐deficient solutions reduced and abolished (after some 20–25 min) the hyperpolarization produced by inhibitory nerve stimulation or inhibitory extract. The inhibitory potential amplitude following nerve stimulation was not restored by passive displacement of the membrane potential from − 26 to − 104 mV approximately. Ouabain (1−5 × 10−5 M) reduced then (45–60 min later) abolished the inhibitory potential to nerve stimulation. The effects of this drug on the extract were not investigated.

It is concluded that the inhibitory response to nerve stimulation and extract in the BRP may involve several ionic species. However, unlike that in gastrointestinal muscles the NANC response in the BRP is accompanied by an increased membrane resistance and does not primarily involve K+.

The underlying mechanisms for the inhibitory response to both NANC nerve stimulation and inhibitory extract appear to be similar, compatible with the view that the latter may contain the inhibitory transmitter released from these nerves in this tissue.
Effects of caffeine on hippocampal pyramidal cells in vitro
Authors: Greene R.W. , Haas H.L. , Hermann A.
Published: July 2012

The effects of caffeine on the electrophysiological properties of CA1 pyramidal neurones were investigated in the rat hippocampal slice preparation in vitro.

A concentration‐dependent increase in both the extracellularly recorded excitatory postsynaptic potential (e.p.s.p.) and the population spike resulting from stimulation of the stratum radiatum could be evoked by caffeine with a threshold concentration of 10 μM.

Intracellular recordings demonstrate a caffeine‐evoked decrease in resting membrane potential, an increase in input resistance, a reduction of the long afterhyperpolarization (a.h.p.) and a decrease in accommodation.

The interaction between caffeine and adenosine was investigated on the extracellularly recorded e.p.s.p. The maximal response evoked by caffeine was increased in the presence of adenosine and the adenosine concentration‐response curve was shifted to the right in a parallel fashion in the presence of caffeine.

It is suggested that the effects of caffeine on hippocampal neurones may be mediated by a decrease of one or more potassium conductance(s), and that adenosine and caffeine may compete for the same electrophysiologically active receptor site on these cells.
Failure of SKF 38393‐A to relieve parkinsonian symptoms induced by 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine in the marmoset
Authors: Close S.P. , Marriott A.S. , Pay Sharon
Published: July 2012

Chronic administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) induced parkinsonian symptoms, predominantly bradykinesia and tremor, in marmosets. These symptoms were reduced by L‐DOPA plus benserazide but the putative D1‐preceptor agonist SKF 38393‐A did not affect tremor and increased the bradykinesia. Neither treatment affected behaviour in normal marmosets. It is suggested that D1‐receptor agonists are unlikely to be effective in the treatment of Parkinson's disease.
The effects of the combined administration of β‐adrenoceptor antagonists and non‐steroidal anti‐inflammatory drugs on ligation‐induced arrhythmias in rats
Authors: Fagbemi O.
Published: July 2012

Pretreatment of anaesthetized rats with intravenously administered β‐adrenoceptor antagonists or non‐steroidal anti‐inflammatory drugs (NSAIDs) reduced the incidence and severity of ventricular arrhythmia which resulted from acute coronary artery ligation.

The β‐adrenoceptor antagonists preferentially suppressed the immediate (Phase 1A) arrhythmia while the NSAIDs suppressed the delayed (Phase IB) arrhythmias.

Combined administration of β‐adrenoceptor antagonists and the NSAIDs produced a more pronounced antiarrhythmic effect than either of the drugs alone.
Comparison of effects of a new dihydropyridine, Bay K 8644, and nifedipine on spontaneous mechanical activity in rat portal vein
Authors: Mikkelsen Erich
Published: July 2012

In isolated portal veins from rats, Bay K 8644 (methyl‐1, 4‐dihydro‐2, 6‐dimethyl‐3‐nitro‐4 (2‐trifluoromethyl‐phenyl) pyridine‐5‐carboxylate) increased the spontaneous mechanical activity in low but not in high concentrations.

The Bay K 8644‐induced increase in spontaneous mechanical activity was abolished in Ca‐free medium and restored by readdition of Ca.

Nifedipine abolished the augmenting effect of Bay K 8644 on the spontaneous mechanical activity; this effect of nifedipine could be eliminated by further increasing the concentration of Bay K 8644.

The results are consistant with the conclusion that in rat portal vein, Bay K 8644 increases the entry of extracellular Ca by a mechanism antagonistic to that of nifedipine and in high concentration has a Ca‐entry blocking effect.
Pharmacological modulation of responses of guinea‐pig airways contracted with antigen and calcium ionophore A23187
Authors: Burka John F.
Published: July 2012

Ovalbumin (OA) and calcium ionophore A23187 were used to induce contractions of sensitized guinea‐pig tracheal and lung parenchymal preparations in the presence and absence of indomethacin. This model was used to examine the properties of a series of compounds reported to inhibit 5‐lipoxygenase or to antagonize lipoxygenase products at the receptor level.

FPL55712 and piriprost appeared to act as pharmacological antagonists because they rapidly reduced tracheal tone established by OA.

The prolonged phase (i.e. > 10 min post‐challenge) of airways contractions induced by OA is assumed to be lipoxygenase‐dependent and was inhibited by nordihydroguaiaretic acid (NDGA), FPL55712, nafazatrom and benoxaprofen, in order of potency. Piriprost had similar inhibitory effects on the trachea, but not on lung parenchyma. The inhibitory effects of NDGA and FPL55712 were reduced, and those of nafazatrom increased by indomethacin. Indomethacin decreased the inhibitory effect of piriprost on the trachea, but facilitated inhibition by this agent on the parenchyma. A roughly similar pattern was seen on A23187‐induced contractions, but FPL55712 did not modify these contractions and benoxaprofen enhanced the response of the trachea.

BW755C enhanced the overall contractile response of OA‐ and A23187‐induced tracheal contractions (but not parenchymal contractions) in a bell‐shaped manner, an effect not seen in the presence of indomethacin. This indicated that BW755C could be acting as a cyclo‐oxygenase inhibitor.

The results suggested that, although inhibitors of the lipoxygenase pathway were partially effective in inhibiting the contractions of the airways induced by OA or A23187, other mediators in addition to those of the lipoxygenase pathway contribute to these contractions.
Adenosine‐induced coronary release of prostacyclin at normal and low pH in isolated heart of rabbit
Authors: Ciabattoni Giovanni , Wennmalm Åke
Published: July 2012

Rabbit hearts were perfused by the Langendorff method with drug‐free perfusion medium or with a medium containing adenosine (10−7 M‐ 10−4M) and the coronary and transmyocardial efflux rates of 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) were measured. Perfusion was performed both at pH 7.4 and 6.9.

In other experiments the hearts were pre‐labelled with [14C]‐arachidonic acid and the coronary efflux of radioactivity and of labelled lipids and 6‐keto‐PGF1α were determined.

The basal coronary flow was elevated by almost 70% during tissue acidosis, in comparison to control. Adenosine induced a dose‐dependent increase in the coronary flow, amounting to about 75% at normal pH and a drug concentration of 10−5 M. The adenosine‐induced increase in coronary flow was not facilitated by low pH.

The base coronary efflux of 6‐keto‐PGF1α from the hearts was 2.5‐3.6 ng min−1. Adenosine (10−6–10−5M) significantly facilitated this efflux, up to 6.5 ng min−1. The efflux of 6‐keto‐PGF1α was not changed by perfusion with acidic medium, either in the basal state or during perfusion with adenosine.

The basal interstitial efflux of 6‐keto‐PGF1α was 4.5‐5.5 ng 3 min−1. This efflux was not affected by perfusion of the heart with adenosine‐containing medium. In hearts pre‐labelled with [14C]‐arachidonic acid, adenosine (10 μM) induced a specific liberation of labelled lipid‐extractable substances, including 6‐keto‐PGF1α.

From these data we conclude that adenosine stimulates the liberation of 6‐keto‐PGF1α from the rabbit heart by increasing precursor availability and subsequent formation of prostacyclin in the coronary vessels. Furthermore, the increase in coronary flow induced by tissue acidosis is not related to an augmented formation of prostacyclin.
Effects of selective channel blocking agents on contractions and action potentials in K+‐depolarized guinea‐pig atria
Authors: Brown J. , Marshall R. J. , Winslow E.
Published: July 2012

Contractions and transmembrane action potentials were induced by 1 μM isoprenaline in K+‐depolarized guinea‐pig left atria driven at 0.5 Hz.

The stability of these responses was significantly increased by doubling the extracellular glucose concentration to 22 mM.

Action potential overshoot increased by 28 mV per ten fold increase in extracellular calcium concentration suggesting that the inward current in this preparation is carried by Ca2+.

In depolarized driven preparations, nanomolar concentrations of nifedipine and nisoldipine reduced contractility, maximum rate of depolarization (dV/dt max) and action potential height, whereas the fast channel blocking agents tetrodotoxin and mexiletine (in micromolar concentrations) produced little change. Nifedipine also rendered spontaneously beating depolarized right atrial preparations quiescent.

In concentrations which reduced dV/dt of normal action potentials, the sodium channel blocking agents quinidine and Org 6001 reduced the amplitude of contractions and reduced the maximum rate of phase 0 depolarization (dV/dt) of action potentials in depolarized tissue. These actions were reversed by Ca2+ and suggest calcium antagonistic activity. However action potential height was not reduced. Like bepridil, both drugs also reduced the frequency of spontaneous contractions in depolarized right atrial preparations.

Unlike Org 6001, quinidine failed to produce a shift in calcium log dose‐response curves in driven depolarized preparations and induced positive inotropy in the presence of functional sodium channels.

Bepridil inhibited contractions in depolarized atria in the absence of a reduction in dV/dt suggesting that any calcium antagonistic action in atrial tissue is mainly located at an intracellular site.

In conclusion, action potentials elicited by isoprenaline in potassium‐depolarized atria bathed in high glucose appear to be Ca2+ mediated. In concentrations which inhibit the inward Na+ current, both quinidine and Org 6001 exhibit calcium channel blocking properties.
Comparison of the cardiovascular effects of meptazinol and naloxone following haemorrhagic shock in rats and cats
Authors: Chance E. , Paciorek P.M. , Todd M.H. , Waterfall J.F.
Published: July 2012

The cardiovascular effects of the opioid mixed agonist‐antagonist, meptazinol, and the opioid antagonist, naloxone, have been evaluated in conscious rats, anaesthetized rats and anaesthetized cats following the induction of haemorrhagic shock.

The mean arterial pressure of conscious rats decreased by 17–29 mmHg following a haemorrhage of 20% of blood volume. Meptazinol (17 mg kg−1, i.m.) administered after haemorrhage evoked a rapid and sustained increase in mean arterial pressure to pre‐haemorrhage levels. Naloxone (10 mg kg−1, i.v.) also increased mean arterial pressure to a level significantly higher than post‐haemorrhage values.

Neither haemorrhage nor subsequent drug treatments evoked significant changes in the heart rates of conscious rats.

In anaesthetized rats, 20% haemorrhage evoked decreases in mean arterial pressure, heart rate and cardiac output. Blood flow to the heart, skin, skeletal muscle, kidneys, spleen and liver (arterial) was decreased. Meptazinol and naloxone increased blood pressure and total peripheral resistance, but did not significantly alter heart rate or cardiac output. Hepatic arterial flow decreased further in both drug and vehicle treated groups. In addition meptazinol slightly reduced skeletal muscle flow.

In anaesthetized cats 40% haemorrhage decreased mean arterial pressure by 46 ± 3 mmHg. An intravenous infusion of either meptazinol or naloxone (cumulative 2 mg kg−1, i.v.) partially restored blood pressure.

In experimental animal models of haemorrhagic shock, meptazinol has a similar cardiovascular profile to naloxone. The established analgesic activity of meptazinol may confer an advantage in some shock states.
A role for inositol 1,4,5‐trisphosphate in the initiation of agonist‐induced contractions of dog tracheal smooth muscle
Authors: Hashimoto Toshihiko , Hirata Masato , Ito Yushi
Published: July 2012

To elucidate the role of inositol 1,4,5‐trisphosphate (Ins‐P3) in the initiation of agonist‐induced contraction of the smooth muscle cells of the dog trachea, we investigated the effects of acetylcholine (ACh) on the concentrations of Ins‐P3, phosphatidylinositol‐4,5‐bisphosphate (PI‐P2) or phosphatidic acid (PA). The effects of Ins‐P3 on the Ca2+ stored in the smooth muscle cells were also studied in saponin‐permeabilized smooth muscle cells.

A half maximal or maximal Ca2+ accumulation into the cells was observed in the dispersed single, smooth muscle cells treated by saponin, in free Ca2+ concentrations of 4.6 × 10−7 or 5 × 10−5 M, respectively. The ATP‐dependent Ca2+ accumulation was maximal at 0.63 nmol/105 cells.

Effects of Ins‐P3 on stored Ca2+ were observed at a free Ca2+ concentration of 3.7 × 10−7 M, which induces about half maximal ATP‐dependent Ca2+‐accumulation. Ins‐P3 released the Ca2+ accumulated by ATP, in a dose‐dependent manner. About 40% of the total Ca2+ was released following application of 3 μM Ins‐P3.

The release of stored Ca2+ induced by application of Ins‐P3 was followed by its re‐uptake into the smooth muscle cells. Thus, the stored Ca2+ was repeatedly released with repetitive applications of Ins‐P3.

Application of ACh (10−5 M) to the dog trachea stimulated the production of Ins‐P3 in the soluble fraction and 10 s after this application, the relative amount of Ins‐P3 was 290% of the control value.

Concomitantly, ACh (10−5 M) either reduced or increased the contents of phosphatidyl inositol 4,5‐biphosphate (PI‐P2) or phosphatidic acid (PA) in the lipid fraction of the smooth muscle cells to 60% or to 350% of the control value, respectively, thereby indicating that ACh stimulates the phosphodiesteric hydrolysis of PI‐P2.

5‐Hydroxytryptamine (5‐HT; 10−5 M) also reduced or increased the contents of PI‐P2 or PA to 80 or to 200% of the control values, respectively. However, neither histamine (10−5 M), in the presence or absence of cimetidine (10−5 M), nor prostaglandin F2α (PGF2α 10−7 M) showed any effect on the contents of PI‐P2 or PA in the lipid fraction of the smooth muscle cells.

These results indicate that in muscle cells of the dog trachea, Ins‐P3 may play the role of intracellular second messenger in the initiation of ACh or 5‐HT‐induced contraction, but not in the case of histamine or PGF2α‐induced contraction.
The effects of metoprolol and dazmegrel, alone and in combination, on arrhythmias induced by coronary artery occlusion in conscious rats
Authors: Leprán Istvan , Parratt James R. , Szekeres Laszlo , Wainwright Cherry L.
Published: July 2012

The effects of metoprolol and the thromboxane synthetase inhibitor dazmegrel, alone and in combination, were examined in a model of coronary artery occlusion in conscious rats.

In a dose (2 mg kg−1), intravenously, that resulted in a marked bradycardia (of 50–80 beats min−1) metoprolol did not influence the incidence or severity of the ventricular arrhythmias that occur in the first 20 min following occlusion, nor did it improve survival (assessed at both 20 min and 16 h). In a dose (5 mg kg−1), intravenously, that in another conscious rat model involving tissue hypoperfusion inhibited thromboxane production, dazmegrel also did not modify ischaemic arrhythmias or survival.

In contrast, metoprolol and dazmegrel (2 mg kg−1 and 5 mg kg−1 i.v.) when given together prior to coronary artery occlusion, produced a significant reduction in mortality both at 20 min and 16 h (e.g. from 60–75% in the control, metoprolol alone and dazmegrel alone groups and only 25% in the combined‐treatment group). This was due to a decrease in the incidence of terminal ventricular fibrillation.

The results suggest that a combination of a β‐adrenoceptor blocking drug with a drug that inhibits thromboxane synthesis may offer more protection against ischaemia‐induced ventricular fibrillation than either drug used alone. They suggest a role for both catecholamines and thromboxane in the genesis of ischaemia‐induced ventricular fibrillation.
Electrophysiological effects of propafenone in untreated and propafenone‐pretreated guinea‐pig atrial and ventricular muscle fibres
Authors: Delgado C. , Tamargo J. , Tejerina T.
Published: July 2012

The electrophysiological effects of propafenone (10−7 to 10−4 M) were studied on guinea‐pig isolated atrial and ventricular muscle fibres obtained from untreated animals and animals pretreated with propafenone, 3 and 10 mg kg−1, for 28 days.

In untreated atria propafenone produced a dose‐dependent decrease in the rate and maximum following frequency, prolonged the sinus node recovery time and reduced the maximum chronotropic responses to isoprenaline.

In untreated atrial and ventricular muscle fibres propafenone depressed action potential amplitude and Vmax, reduced the resting membrane potential and prolonged the action potential duration (APD) and the effective refractory period, lengthening the effective refractory period relative to APD.

Propafenone depressed the amplitude and Vmax and shortened the duration of the slow action potentials induced by isoprenaline and caffeine in K‐depolarized papillary muscles.

Pretreatment with propafenone reduced atrial rate, but did not modify the action potential characteristics compared to the values obtained in untreated atria. Further addition of propafenone produced similar but more marked changes in untreated atria.

In ventricular muscle fibres pretreated with 3 mg kg−1, action potential characteristics before and after further addition of propafenone were similar to those obtained in untreated fibres. However, muscles pretreated with 10 mg kg−1 exhibited a significant prolongation of the APD compared to that in untreated muscles or those pretreated with 3 mg kg−1; further addition of propafenone shortened the APD even when this parameter was of similar value to those observed in the other two series of experiments.

It is concluded that even though the effects of propafenone are similar to those of quinidine (class I antiarrhythmic), it also exhibited class II and class IV actions. In pretreated animals a prolongation of the APD (class III action) could also be involved in the antiarrhythmic effects of the drug.
Electrophysiological mechanisms for the antiarrhythmic action of mexiletine on digitalis‐, reperfusion‐ and reoxygenation‐induced arrhythmias
Authors: Amerini Sandra , Carbonin Pierugo , Cerbai Elisabetta , Giotti Alberto , Mugelli Alessandro , Pahor Marco
Published: July 2012

The antiarrhythmic potency of mexiletine was evaluated on three groups of guinea‐pig isolated hearts. Arrhythmias were induced (a) with digitalis intoxication, (b) with hypoxia followed by reoxygenation and (c) with ischaemia followed by reperfusion.

Mexiletine 10 μM was found to be very effective against all three types of arrhythmias in all three groups.

The electrophysiological effects of mexiletine were then studied on sheep cardiac Purkinje fibres manifesting oscillatory afterpotentials and triggered automaticity induced by barium or strophanthidin.

Mexiletine 10 μM consistently decreased the amplitude of oscillatory afterpotentials and blocked subsequent triggered activity in sheep Purkinje fibres.

In contrast, mexiletine 10 μM had no significant effect on in normal, barium‐ and strophanthidin‐treated preparations.

The results are discussed in relation to the mechanisms of antiarrhythmic action of mexiletine.