bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acetal phosphatidic acids: novel platelet aggregating agents
Authors: Brammer J. Preston , Maguire M. Helen , Walaszek E.J. , Wiley R.A. 
Published: July 2012

Palmitaldehyde, olealdehyde and linolealdehyde acetal phosphatidic acids induced rapid shape change and dose‐dependent biphasic aggregation of human platelets in platelet‐rich plasma; aggregation was reversible at low doses and irreversible at high doses of the acetal phosphatidic acids. The palmitaldehyde congener elicited monophasic dose‐dependent aggregation of sheep platelets in platelet‐rich plasma.
The threshold concentration for palmitaldehyde acetal phosphatidic acid (PGAP)‐induced platelet aggregation was 2.5–5 μM for human platelets and 0.25–0.5 μM for sheep platelets. PGAP was 4–5 times as potent versus human platelets as the olealdehyde and linolealdehyde acetal phosphatidic acids, which were equipotent.
PGAP‐induced irreversible aggregation of [14C]‐5‐hydroxytryptamine ([14C]‐5‐HT)‐labelled human platelets in platelet‐rich plasma was accompanied by release of 44.0 ± 2.4% (s.e.) of the platelet [14C]‐5‐HT; reversible aggregation was not associated with release. In contrast, PGAP‐induced release of [14C]‐5‐HT‐labelled sheep platelets was dose‐dependent.
The adenosine diphosphate (ADP) antagonist, 2‐methylthio‐AMP, and the cyclo‐oxygenase inhibitor, aspirin, abolished PGAP‐induced second phase aggregation and release in human platelets but did not affect the first, reversible, phase of aggregation. Both the first and second phases of PGAP‐induced aggregation were abolished by chlorpromazine, by the phospholipase A2 inhibitor, mepacrine, and by nmolar concentrations of prostaglandin E1 (PGE1); these agents abolished the second, but not the first phase of ADP‐induced aggregation.
The related phospholipids, lecithin, lysolecithin and phosphatidic acid, at < 100 μM, neither induced aggregation of human platelets in platelet‐rich plasma, nor modified PGAP‐induced aggregation; 1‐palmityl lysophosphatidic acid elicited aggregation of human platelets at a threshold concentration of 100 μM.
It is concluded that the acetal phosphatidic acids induce platelet aggregation per se by direct action at the platelet membrane, and that the acetal function is of primary importance in their potent platelet‐stimulating activity. Moreover, as the acetal phosphatidic acids are the major components of the smooth muscle‐contracting acidic phospholipid tissue extract ‘Darmstoff’ (Vogt, 1949), their potent platelet‐aggregating properties may be of physiological or pathological significance.
Gold‐containing drugs and the control of proteolytic enzymes
Authors: Rohozková D. , Steven F.S. 
Published: July 2012

NaAuCl4 and aurothioglucose inhibited trypsin in free solution without the need of a carrier molecule.
NaAuCl4, aurothioglucose, aurothiomalate, auranofin and chloro(triethyl phosphine) gold all inhibited the trypsin‐like neutral protease on the surface of Ehrlich ascites tumour cell membranes equally well.
Crude cathepsin preparations were activated by low concentrations of dithiothreitol and also by aurothioglucose, due to the displacement of an inhibitor.
Thiol‐activated cathepsins were inhibited by each of the gold derivatives. The gold could be withdrawn from the enzyme by incremental additions of thiols such as reduced glutathione and cysteine with regeneration of enzymic activity.
Lineweaver‐Burk plots of kinetic data indicated that gold acted as a non‐competitive inhibitor of cathepsins.
A naturally occurring inhibitor of cathepsins was extracted from cartilage. The mechanism of inhibition was again shown to be a thiol‐disulphide exchange, the disulphide being provided by the inhibitor and the thiol being provided by the enzyme.
The role of gold in the attempted control of proteolysis in rheumatoid arthritis is briefly discussed in terms of reversible exchange reactions involving gold thiols, disulphides and cartilage inhibitors of proteolytic enzymes.
Sedative effects of PK 9084 and PK 8165, alone and in combination with chlordiazepoxide
Authors: File Sandra E. 
Published: July 2012

The sedative effects in rats of two phenylquinolines, PK 9084 and PK 8165 (5–50 mg/kg), were examined in a holeboard: both when given alone and when given in conjunction with chlordiazepoxide (5 mg/kg).
Both phenylquinolines produced significant dose‐related decreases in locomotor activity and rearing, with an ED50 about twice that for chlordiazepoxide.
When the phenylquinolines were combined with chlordiazepoxide the degree of sedation was equal to that seen with either drug given alone, whichever produced the greater sedation; the sedative effects of the two drugs were never additive.
PK 9084 (10 and 50 mg kg) significantly reduced rectal temperature, as did chlordiazepoxide (5 mg/kg), but there was no addition nor interaction of their effects.
Both phenylquinolines also reduced exploratory head‐dipping, as did chlordiazepoxide, but in combination they antagonized each other's effects.
The classification of the phenylquinolines as non‐sedative anxiolytics, acting as agonists at the benzodiazepine receptors needs revision.
Characteristics of conditioned taste aversion produced by nicotine in rats
Authors: Kumar R. , Pratt J. A. , Stolerman I.P. 
Published: July 2012

Nicotine produced conditioned taste aversions in rats which were directly related to the dose of nicotine and to the number of conditioning trials.
The tobacco alkaloid (−)‐nicotine was four to five times as potent as its stereoisomer, (+)‐nicotine.
Mecamylamine but not hexamethonium blocked the development of taste aversions produced by nicotine.
Mecamylamine did not block the development of taste aversions produced by apomorphine.
Prolonged treatment with mecamylamine prior to conditioning did not produce supersensitivity to nicotine.
Release of acetylcholine at the motor endplate of the rat — evidence against a muscarinic acetylcholine autoreceptor
Authors: Häggblad J. , Heilbronn E. 
Published: July 2012

The effect of some drugs on the release of endogenous acetylcholine from the phrenic nerve‐hemidiaphragm preparation of the rat was measured. Muscarinic ligands had no effect. 8‐Br‐cyclic GMP, a penetrating analogue of cyclic guanosine 3′,5′‐monophosphate (cyclic GMP) was also without effect. 8‐Br‐cyclic AMP somewhat enhanced the basal release while the potassium‐induced release remained unaltered.
In supersensitivity experiments, no specific binding of ligand [3H]‐quinuclidinylbenzilate ([3H]‐QNB) was found in homogenates of the diaphragm, either before or after atropine treatment, while concomitant binding studies in the CNS demonstrated the expected increase in muscarinic binding sites after atropine.
Our conclusion is that muscarinic acetylcholine receptors are probably absent from the presynaptic motor endplate area of the rat. Certain preliminary results suggest that a presynaptic nicotinic mechanism might be involved in the release of acetylcholine.
The β‐adrenoceptor of pig coronary arteries: determination of β1 and β2 subtypes by radioligand binding
Authors: Schwartz Jean , Velly Jeanne 
Published: July 2012

β‐Adrenoceptors of pig coronary arteries were investigated by the use of a new ligand, 125iodocyanopindolol (ICYP) in binding studies.
Inhibition of ICYP binding by betaxolol (a selective β1‐antagonist), zinterol (a selective β2‐agonist) and ICI 118551 (a selective β2‐blocking drug) resulted in non‐linear Scatchard plots, suggesting that both β‐adrenoceptor subtypes are present in pig coronary arteries.
Computer analysis of the data gave a β1:β2‐adrenoceptor ratio of approximately 65:35.
Effects of α‐adrenoceptor antagonists on clonidine‐induced inhibition of insulin secretion by isolated pancreatic islets
Authors: Langer Joachim , Panten Uwe , Zielmann Siegfried 
Published: July 2012

The effects of clonidine, yohimbine, corynanthine and prazosin on glucose‐induced insulin secretion by incubated or perifused mouse pancreatic islets were investigated.
Clonidine (0.1 μm) inhibited glucose‐induced insulin secretion alone and in the presence of yohimbine (0.1 μm), corynanthine (10 μm) or prazosin (1 μm).
In higher concentrations, yohimbine (1–10 μm) antagonized the inhibitory effect of clonidine (0.1 μm) upon glucose‐induced insulin secretion by incubated islets and by perifused islets.
The results support the view that adrenergic inhibition of insulin secretion is mediated by α2‐adrenoceptors on pancreatic β‐cells.
In vivo, noradrenaline is a substrate for rat brain monoamine oxidase A and B
Authors: Youdim M.B.H. 
Published: July 2012

In vivo clorgyline (5 mg/kg) and (‐)‐deprenyl (5 mg/kg) selectively inhibit monoamine oxidase (MAO) type A and B activities in rat brain hypothalamus and caudate nucleus using 5‐hydroxytryptamine (5‐HT), noradrenaline (NA), and β‐phenylethylamine (PEA) as substrates.
Clorgyline induces a significant increase in NA concentrations of hypothalamus and caudate nucleus; however (‐)‐deprenyl is without effect.
The combination of clorgyline and (‐)‐deprenyl at the above doses completely inhibits both forms of MAO, resulting in an even greater increase in NA levels in both brain areas than observed with clorgyline. The non‐selective inhibitor tranylcypromine (5 mg/kg) produced a similar effect.
Rats pretreated with the selective or the non‐selective inhibitors but given l‐DOPA (50 mg/kg) have a similar pattern of brain NA, but its concentrations are higher in both brain regions.
The results indicate that although in vitro NA may be an exclusive substrate for MAO type A, in vivo, when this enzyme form is selectively inhibited, NA at high concentrations can be a substrate for MAO type B.
Rapid degradation of [3H]‐substance P in guinea‐pig ileum and rat vas deferens in vitro
Authors: Watson Stephen P. 
Published: July 2012

The degradation of [3H]‐substance P was monitored in guinea‐pig ileum and rat vas deferens. Substantial and rapid metabolism occurred in both tissues within the time course of the pharmacological responses; for example, after 1 min more than 50% of the extracted tritium from both tissues was present in the form of metabolites.
[3H]‐inulin was used to estimate the rate of equilibration of the extracellular space of guinea‐pig ileum longitudinal muscle and rat vas deferens with the bath fluid; half‐lives of 30 s and 5 min respectively were observed.
These two factors combine to give different concentrations of substance P in the biophase of the tissues. The peak concentration of substance P reached in the guinea‐pig ileum longitudinal muscle was approximately five times higher than in the rat vas deferens.
An analogue of substance P, [3H]‐DiMe‐C7, was found to be stable in both tissues.
These results are discussed in the light of the suggested existence of multiple receptors for substance P, based on agonist potency differences.
The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate
Authors: Anis N.A. , Berry S.C. , Burton N.R. , Lodge D. 
Published: July 2012

The interaction of two dissociative anaesthetics, ketamine and phencyclidine, with the responses of spinal neurones to the electrophoretic administration of amino acids and acetylcholine was studied in decerebrate or pentobarbitone‐anaesthetized cats and rats.
Both ketamine and phencyclidine selectively blocked excitation by N‐methyl‐aspartate (NMA) with little effect on excitation by quisqualate and kainate.
Ketamine reduced responses to L‐aspartate somewhat more than those of l‐glutamate; the sensitivity of responses to these two putative transmitters was between that to NMA on one hand and that to quisqualate or kainate on the other.
On Renshaw cells, ketamine and phencyclidine reduced responses to acetylcholine less than those to NMA but more than those to quisqualate or kainate. Dorsal root‐evoked synaptic excitation of Renshaw cells was reduced to a greater extent than that following ventral root excitation.
Intravenous ketamine, 2.5–20 mg/kg, and phencyclidine, 0.2–0.5 mg/kg, also selectively blocked excitation of neurones by NMA.
Ketamine showed no consistent or selective effect on inhibition of spinal neurones by electrophoretically administered glycine or γ‐aminobutyricacid (GABA).
The results suggest that reduction of synaptic excitation mediated via NMA receptors contributes to the anaesthetic/analgesic properties of these two dissociative anaesthetics.
Glucocorticoid protection against PAF‐acether toxicity in mice
Authors: Myers Adam , Ramey Estelle , Ramwell Peter 
Published: July 2012

Intravenous platelet activating factor (PAF‐acether, 10 to 25 μg/kg body weight) produced dose‐dependent mortality in both male and female mice.
Pretreatment with indomethacin (50 mg/kg), verapamil (40 mg/kg) or nifedipine (4 mg/kg) failed to inhibit the lethal effect of 20 μg/kg PAF‐acether. This suggests that neither arachidonate cyclo‐oxygenase products nor availability of extracellular Ca2+ mediate the toxic action.
In contrast, pretreatment with 100 mg/kg cortisone acetate (s.c.) daily for four days exerted a highly protective effect, i.e. 100% and 93% survival in males and females, compared to 13% and 7% respectively, in untreated animals.
PAF‐acether‐induced death may be a useful model for the in vivo evaluation of pharmacological agents in anaphylactic shock.
Endothelium‐dependent relaxation induced by angiotensin II and histamine in isolated arteries of dog
Authors: Toda Noboru 
Published: July 2012

In helical strips of dog renal and mesenteric arteries pre‐contracted with prostaglandin F2α (PGF2α), endothelium‐dependent relaxations were investigated. Removal of the endothelium was shown histologically by staining with silver nitrate and functionally by testing the inability of acetylcholine to induce arterial relaxations.
When the endothelium was removed, relaxation of renal arteries to angiotensin (Ang) II was markedly suppressed, whereas relaxations induced by PGI2 or isoprenaline were attenuated only slightly. Removal of the endothelium attenuated the relaxant response of mesenteric arteries to histamine but did not significantly alter the response to PGI2.
Treatment with indomethacin caused an additional attenuation of the relaxant response to histamine or a reversal of the Ang II‐induced relaxation to a contraction in the arterial strips, from which the endothelium had been removed.
Relaxation of renal arteries induced by Ang II and of mesenteric arteries induced by histamine is postulated to result from PGI2 released from the arterial wall. Therefore, it appears that the endothelium is a major site but not the only site responsible for drug‐induced release of PGI2.
Contractions of rat uterine smooth muscle induced by acetylcholine and angiotensin II in Ca2+‐free medium
Authors: Lalanne C. , Mironneau C. , Mironneau J. , Savineau J.P. 
Published: July 2012

The effects of acetylcholine (ACh, 10−4m) and angiotensin II (Ang II, 10−6 M) have been studied on the mechanical and electrical activities of rat myometrial strips perfused in Ca2+‐free EGTA‐containing solutions.
Both ACh and Ang II produced transient contractions, the amplitude of which can be taken as a measurement of the amount of Ca2+ present in a drug‐sensitive Ca2+ store. The degree of filling of this store depended on the external Ca2+ concentration, and on the presence of contractile responses during the Ca2+ loading period. The existence of two pathways (either direct or transcytoplasmic) is suggested for Ca2+ uptake into the internal Ca2+ store.
The rate of filling of the Ca2+ store in 2.1 mm‐Ca2+‐containing solution was faster (time to half‐maximal response, t1/2 = 29 ± 2.2s, n = 4) than the rate of depletion in Ca2+‐free solution (t1/2 = 3 ± 0.3 min, n = 3). The gradual depletion of this store was much slower at 18°C than at 35°C, and in the presence of vanadate which is known to inhibit Ca2+‐ATPases.
Methoxyverapamil (D600, 10−6‐10−5m) had no appreciable effect on the direct Ca2+ uptake or on the release of Ca2+ from the store by ACh and Ang II. Mn2+ (10−3m) completely inhibited the direct pathway to the internal Ca2+ store and also reduced the release of Ca2+.
ACh and Ang II induced repetitive depolarizations close to zero potential which did not parallel the transient contractions as a function of the time of perfusion in Ca2+‐free solution. Applications of 2 mm EGTA, 135 mm K+ or Ca2+ antagonists which suppressed or reduced the drug‐induced depolarizations did not affect appreciably the drug‐induced contractions.
These results suggest that myometrial cells have an intracellular Ca2+ store sensitive to different stimulus substances. This store is not affected by depolarization of the plasma membrane and is certainly different from that described in voltage‐clamp experiments.
Evidence that the positive inotropic effects of the alkylxanthines are not due to adenosine receptor blockade
Authors: Collis M.G. , Keddie J.R. , Torr S.R. 
Published: July 2012

We investigated the possibility that the positive inotropic effects of the alkylxanthines are due to adenosine receptor blockade.
The potency of 8‐phenyltheophylline, theophylline and enprofylline as adenosine antagonists was assessed in vitro, using the guinea‐pig isolated atrium, and in vivo, using the anaesthetized dog.
The order of potency of the alkylxanthines as antagonists of the negative inotropic response to 2‐chloroadenosine in vitro, and of the hypotensive response to adenosine in vivo was 8‐phenyltheophylline > theophylline > enprofylline.
The order of potency of the alkylxanthines as positive inotropic and chronotropic agents in the anaesthetized dog was enprofylline > theophylline > 8‐phenyltheophylline.
The results of this study indicate that the inotropic effects of the alkylxanthines in the anaesthetized dog are not due to adenosine receptor blockade.
Nicorandil attenuates myocardial acidosis during coronary occlusion in dogs
Authors: Abiko Y. , Nishimura T. , Sakai K. 
Published: July 2012

In dogs anaesthetized with pentobarbitone, the left anterior descending coronary artery (LAD) was partially occluded. Before and 30 min after partial occlusion, the myocardial pH was 7.52–7.54 and 6.89–6.91, respectively.
Nicorandil (50 μg kg−1, i.v.) increased the pH that had been reduced by partial occlusion and this effect lasted at least 60 min. Thus nicorandil attenuates ischaemic myocardial acidosis.
Tissue response selectivity of calcium antagonists is not due to heterogeneity of [3H]‐nitrendipine binding sites
Authors: Bristow Michael R. , Ginsburg Robert , Laser Jeffrey A. , McAuley Bruce J. , Minobe Wayne 
Published: July 2012

[3H]‐nitrendipine binding data and isolated tissue response for five calcium antagonists were evaluated in rabbit myocardium and aorta.
The [3H]‐nitrendipine binding site was qualitatively identical in myocardium and aorta, as the [3H]‐nitrendipine KD, KIs for nicardipine and nifedipine and interactions with verapamil, D600‐and diltiazem were not different in aortic and cardiac membranes prepared by similar means.
In contrast, the inhibition of the Ca2+‐induced contractile response in right ventricular myocardium and aortic ring segments indicated a > 10,000 fold selectivity of nicardipine for antagonism of vascular responses. This resulted in a different order of potency for calcium antagonist interaction with the [3H]‐nitrendipine binding site in cardiac membranes (nicardipine > nifedipine > D600 > verapamil > diltiazem) as compared to antagonism of myocardial tissue response (D600 > verapamil > nifedipine > nicardipine > diltiazem). In heart the difference between the potency of nicardipine in binding experiments and tissue response approached 4 orders of magnitude.
We conclude that tissue response selectivity of calcium antagonists is not explained by heterogeneity of [3H]‐nitrendipine binding sites.
Relaxation of cat tracheobronchial and pulmonary arterial smooth muscle by vasoactive intestinal peptide: lack of influence by peptidase inhibitors
Authors: Altiere Ralph J. , Diamond Louis 
Published: July 2012

Vasoactive intestinal peptide (VIP) caused concentration‐dependent relaxation in precontracted segments of trachea, hilar bronchus, intrapulmonary bronchus and intrapulmonary artery (IPA) isolated from cat lungs.
VIP‐induced relaxation responses were abolished by preincubation of tissues with the proteolytic enzyme, α‐chymotrypsin (2 units ml−1). At the concentration employed, α‐chymotrypsin treatment did not adversely affect tissue viability as isoprenaline and bethanechol continued to relax airways and IPA, respectively.
Aprotinin prevented enzymatic degradation of VIP by α‐chymotrypsin as demonstrated by the ability of VIP to relax tissues incubated with both the peptidase inhibitor and α‐chymotrypsin.
A spectrum of peptidase inhibitors, including aprotinin, leupeptin, bestatin, bacitracin, β‐phenylpropionic acid and captopril, individually or in combination, did not augment the relaxant effects of VIP in isolated pulmonary tissues.
These results suggest that local enzymatic degradation may not be a primary route for inactivation of VIP in cat isolated airways and IPA. If VIP acts as a neurotransmitter in these tissues, a mechanism other than enzymatic proteolysis may be responsible for terminating its action.
An investigation into the characteristics of reperfusion‐induced arrhythmias in the anaesthetized rat and their susceptibility to antiarrhythmic agents
Authors: Kane K. A. , Parratt J.R. , Williams F.M. 
Published: July 2012

Reperfusion‐induced arrhythmias were elicited in the pentobarbitone‐anaesthetized rat by occlusion of the left main coronary artery and subsequent release.
These arrhythmias were rapid in onset, occurring within 20 s after release of the ligature, and were of short duration (1–2 min). Their severity was dependent upon the duration of the preceding occlusion. A 5 or 15 min occlusion period produced the most severe arrhythmias on release, the incidence of ventricular fibrillation being 56 and 50% respectively.
Evidence that reperfusion had occurred was provided by fluorescein dye distribution and intramyocardial temperature studies.
The severity of reperfusion arrhythmias and mortality was unaffected by bilateral vagotomy, β‐adrenoceptor blockade by atenolol (2 mg kg−1 i.v.) or a combination of the two.
The incidence of reperfusion‐induced ventricular fibrillation was significantly reduced by Org 6001 (which blocks the fast inward sodium current), melperone (which acutely prolongs the cardiac action potential duration) and bepridil (which blocks both fast and slow inward currents). It was unaffected by nitroglycerine and the calcium antagonists verapamil, prenylamine and nifedipine.
We have shown that reperfusion‐induced cardiac arrhythmias can be consistently elicited in the anaesthetized rat and that they are particularly susceptible to drugs that can block the fast inward sodium current.