bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.
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.