bluuebunny/crossref_metadata_2025_split huggingface dataset:
The inhibitory adenosine receptor at the neuromuscular junction and hippocampus of the rat: antagonism by 1,3,8‐substituted xanthines
Authors: Sebastião A.M. , Stone T.W. , Ribeiro J.A. 
Published: July 2012

The ability of 1,3,8‐substituted xanthines to antagonize the inhibitory effects of adenosine receptor agonists on the amplitude of nerve‐evoked twitches of the rat phrenic‐diaphragm and on the amplitude of orthodromically‐evoked population spikes, recorded from the CA1 pyramidal cells of rat hippocampal slices, was investigated.
1,3‐Dipropyl‐8‐cyclopenthylxanthine (DPCPX), 1,3‐dipropyl‐8‐(carboxymethyloxyphenyl)xanthine (XCC), 1,3‐dipropyl‐8‐(4‐((2‐aminoethyl)amino)carbonylmethyloxyphenyl)xanthine (XAC), 1,3‐dipropyl‐8‐(2‐amino‐4‐chlorophenyl)xanthine (PACPX), 8‐phenyltheophylline (8‐PT), 1,3‐diethyl‐8‐phenylxanthine (DPX) and PD 115,199, in concentrations virtually devoid of effect on neuromuscular transmission, shifted to the right in a near parallel manner the log concentration‐response curve for the inhibitory effect of 2‐chloroadenosine (CADO) on nerve‐evoked twitches of the phrenic‐diaphragm. Linear Schild plots with slopes near to unity were obtained for all the xanthines.
The order of potency of the xanthines as antagonists of the effect of CADO in the phrenic‐diaphragm was DPCPX (Ki = 0.54 nm) > XCC (Ki = 10 nm), XAC (Ki = 11 nm), PACPX (Ki = 13 nm) > DPX (Ki = 22 nm), 8‐PT (Ki = 25 nm) > PD 115,199 (Ki = 57 nm). The potency of DPCPX in antagonizing the inhibitory effects of R‐N6‐phenylisopropyladenosine (R‐PIA) and 5′‐N‐ethylcarboxamide adenosine (NECA) on nerve‐evoked twitch responses was not statistically different from its potency in antagonizing the inhibitory effect on CADO.
In the hippocampal slices, DPCPX, XCC and XAC, used in concentrations virtually devoid of effect on population spike amplitude, shifted to the right in a near parallel manner the log concentration‐response curve for the inhibitory effect of CADO on the amplitude of the population spikes. The Schild plots were linear with slopes near unity.
The potencies of DPCPX (Ki = 0.45 nm) and XAC (Ki = 11 nm) in antagonizing the inhibitory adenosine receptor at the hippocampus were similar to their potencies for antagonism of the inhibitory adenosine receptor at the phrenic‐diaphragm. XCC was only slightly more potent (Ki = 5.4 nm) as an antagonist of the adenosine receptor in the hippocampus than in the phrenic‐diaphragm.
The results suggest that the inhibitory adenosine receptors in the phrenic‐diaphragm and in the hippocampus of the rat are similar, and that according to the antagonist potencies, these receptors belong to the A1‐adenosine receptor subtype.
The effects of novel vasodilator long chain acyl carnitine esters in the isolated perfused heart of the rat
Authors: Criddle D.N. , Dewar G.H. , Wathey W.B. , Woodward B. 
Published: July 2012

The effects of palmitoyl carnitine (PC) and novel derivatives were examined on the isolated Langendorff perfused heart of the rat.
Bolus injections of PC (1–300 nmol) produced coronary constriction accompanied by a cumulative irreversible depression of contractility.
Prior storage of PC in chloroform containing 2% ethanol in heat‐sealed ampoules resulted in production of the ethyl ester of the compound (PCE). This compound was isolated and also synthesized (P1E). In contrast to PC, both PCE and P1E exhibited potent vasodilator activity.
Increasing the fatty acid chain length from palmitoyl to stearoyl resulted in a significant reduction in coronary dilator activity of the ester compound, whereas different ester groups did not affect the vasodilator action appreciably. Complete removal of the fatty acid chain abolished all vascular effects at the doses used.
The vasodilatation produced by these acyl carnitine esters was comparable to that produced by several known vasodilator drugs including verapamil, cromakalim, amyl nitrate and iloprost; however, the duration of the vasodilator response was more prolonged with the carnitate derivatives.
Relationships between tumour necrosis factor, eicosanoids and platelet‐activating factor as mediators of endotoxin‐induced shock in mice
Authors: Myers Adam K. , Robey James W. , Price Ray M. 
Published: July 2012

The toxicity of intravenous recombinant human tumour necrosis factor (rhTNF), a TNF fragment (TNF114–130), endotoxin and combinations of rhTNF or TNF114–130 were tested in mice. Neither rhTNF nor TNF114–130 was lethal alone, but when combined with a non‐lethal dose of endotoxin, rhTNF provoked dose‐dependent mortality, as did higher doses of endotoxin alone.
Both the toxicity and the vasopermeability changes induced by endotoxin alone were blocked by the platelet‐activating factor (PAF) antagonist BN52021, indomethacin or the dual cyclo‐oxygenase/lipoxygenase inhibitor BW755C.
The lethality of the combined low dose endotoxin/rhTNF challenge was unaffected by pretreatment with BN52021, indomethacin or BW755C, or by treatment at 6h intervals with BN52021 or BW755C.
The results of these studies suggest that TNF, a putative, early mediator of septic or endotoxin shock, cannot by itself mimic all of the effects of bacterial endotoxin in the model used in this study. Apparently, TNF works synergistically with other mediators whose release is stimulated by endotoxin.
The results also suggest that the mechanism of shock production by the rhTNF/endotoxin combination in mice is not dependent on the early stimulation of eicosanoid or PAF synthesis by rhTNF.
Central inhibition by γ‐aminobutyric acid and muscimol of the release of vasopressin and oxytocin by an osmotic stimulus in the rat
Authors: Bisset G.W. , Chowdrey H.S. , Fairhall K.M. , Gunn L.K. 
Published: July 2012

In water‐loaded rats under ethanol anaesthesia, the injection of 2–4 μl 1.54 m NaCl solution (hypertonic saline: HS) into a lateral cerebral ventricle (i.c.v.) produced an antidiuretic and a pressor response, together with increased urinary excretion of vasopressin and ‘oxytocin‐like radioimmunoreactivity’ (OLRI). In lactating rats HS also produced a milk‐ejection response which was shown to be due to the release of oxytocin.
The injection of 20–40 μg γ‐aminobutyric acid (GABA) or 40–80 ng muscimol i.c.v. 2 min before HS inhibited the antidiuretic, pressor and milk‐ejection responses and reduced the urinary excretion of vasopressin and OLRI.
The pressor response to HS was abolished by a ganglion blocking agent but it was not reduced by a vasopressin antagonist. After the antagonist, the antidiuretic response to HS was abolished and the pressor response was accompanied by a diuresis both of which were blocked by muscimol.
The threshold dose of HS for an antidiuretic response was 4–8 times higher on injection into the cisterna magna (i.cist.) than when injected i.c.v. GABA, i.v. or i.cist, did not inhibit the response to HS i.c.v.
The results confirm other evidence that, in the rat, in contrast some other species, an osmotic stimulus causes release of both vasopressin and oxytocin. This release is blocked by GABA and muscimol. These drugs and HS act at a site reached not from the subarachnoid space but from the cerebral ventricles, probably the hypothalamus. The pressor response to HS under the experimental conditions used is due entirely to central sympathetic stimulation and this effect, as well as the release of vasopressin and oxytocin, is blocked by muscimol.
Inhibitory action of α‐human atrial natriuretic peptide on noradrenaline‐induced synthesis of myo‐inositol 1,4,5‐trisphosphate in the smooth muscle cells of rabbit aorta
Authors: Kajikuri Junko , Kuriyama Hirosi 
Published: July 2012

Interactions between the synthesis of myo‐inositol 1,4,5‐trisphosphate (IP3) and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) in the smooth muscle cells of the rabbit aorta were investigated.
In the presence or absence of vascular endothelium, noradrenaline (NA; 5 μm) consistently reduced the amount of phosphatidylinositol 4,5‐bisphosphate (PI‐P2) and increased both phosphatidic acid (PA) and IP3.
In the presence or absence of endothelium, acetylcholine (ACh; 100 μm but not 5 μm) slightly increased the amount of IP3, but exposure to ACh (100 μm) 4 min after application of NA did not modify NA‐induced synthesis of IP3.
ACh (100 μm) markedly enhanced the synthesis of cyclic GMP in the presence of endothelium but not in the endothelium‐denuded tissues.
Prazosin (5 μm) but not dibutyryl cyclic GMP (db‐cyclic GMP; 100 μm) blocked the hydrolysis of PI‐P2 induced by 5 μm NA. Synthesis of IP3 induced by NA, as estimated with [3H]‐inositol was not modified by application of 100 μm db‐cyclic AMP or db‐cyclic GMP.
α‐Human atrial natriuretic peptide (α‐hANP; 0.1 μm) increased cyclic GMP in the presence or absence of endothelium. α‐hANP (0.1 μm) consistently inhibited the hydrolysis of PI‐P2 induced by 5 μm NA.
The results indicate that synthesis of IP3 is inhibited neither by the synthesis of cyclic GMP in the cytosol nor by cyclic GMP itself. However, synthesis of IP3 through hydrolysis of PI‐P2 may be inhibited by an interaction between some steps in the IP3 synthetic process and by the activation of the α‐hANP‐guanylate cyclase process at the sarcolemma.
The influence of thyroid states upon responses of the rat aorta to catecholamines
Authors: Gunasekera Ranjan D. , Kuriyama Hirosi 
Published: July 2012

Mechanical responses to various stimulants and the distribution of adrenoceptor subtypes were investigated in smooth muscle cells of the rat aorta in eu‐ (control), hyper‐ and hypo‐thyroid states.
Concentration‐response relationships for K showed that the KCl EC50 value was slightly higher (28.4 mm K) in hypothyroid than in euthyroid and hyperthyroid states (22.5 mm and 22.8 mm K, respectively). The order of maximum amplitudes of KCl contraction was control > hypothyroid > hyperthyroid.
The EC50 values for the noradrenaline (NA)‐induced contraction for eu‐, hypo‐ and hyper‐thyroid states were 7.4, 12.5 and 5.5 nm, respectively. The density of α1‐adrenoceptors was increased to 1.4 times the control in the hypothyroid state and reduced to 0.26 times the control in the hyperthyroid state.
The EC50 values for the phenylephrine‐induced contraction in eu‐, hypo‐ and hyper‐thyroid states were 43.4, 247 and 41.5 nm, respectively, and those for clonidine 104, 1360 and 56.5 nm, respectively. The IC50 values for prazosin against 0.1 μm NA‐induced contractions in eu‐, hypo‐ and hyper‐thyroid states were 5.8, 3.5 and 0.7 nm, respectively, and those for yohimbine 8.9, 5.4 and 4.1 μm, respectively.
The IC50 values for isoprenaline against phenylephrine‐induced contractions were 63 nm and 2.4 μm in hyper‐ and eu‐thyroid states, respectively, and the corresponding IC25 values for eu‐ and hypo‐thyroid states were 72 and 423 nm, respectively. The density of β‐adrenoceptors was increased to 3.91 times the control in the hyperthyroid and reduced to 0.68 times the control in the hypothyroid states. The amount of adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) synthesized by isoprenaline increased in parallel with the density of β‐adrenoceptors in the three thyroid states.
NA consistently increased the amount of inositol 1,4,5‐trisphosphate (IP3) within 30 s in the three thyroid states. In the hypothyroid state, the amount of IP3 was slightly increased and in the hyperthyroid condition, it occurred to a lesser extent than in the euthyroid state.
The results indicate that in hypothyroidism, the density of α1‐adrenoceptors is increased and that of β‐adrenoceptors reduced in vascular beds. The latter but not the former is accompanied by corresponding mechanical responses. In hyperthyroidism, the density of α1‐adrenoceptors is decreased and β‐adrenoceptors increased with parallel changes in mechanical responses.
The effect of diltiazem on the coronary haemodynamic and cardiac functional effects produced by intracoronary administration of endothelin‐1 in the anaesthetized dog
Authors: Nichols Andrew J. , Koster Paul F. , Ohlstein Eliot H. 
Published: July 2012

We have studied the effect of the calcium channel antagonist, diltiazem, on the coronary haemodynamic and cardiac functional responses produced by intracoronary (i.c.) administration of endothelin‐1 (ET‐1) in anaesthetized dogs.
ET‐1, 1, 3 and 10 ng kg−1 i.c., produced dose‐delated increases in coronary blood flow with no cardiac functional or systemic haemodynamic changes. ET‐1, 30, 100 and 300 ng kg−1 i.c., produced dose‐related reductions in coronary artery blood flow. The reduction in coronary blood flow was accompanied by dose‐related falls in cardiac output, mean arterial pressure, +dP/dt and –dP/dt and increases in left ventricular end‐diastolic pressure. However, there was no reflex tachycardia in response to the fall in blood pressure and at 300 ngkg−1, ET‐1 produced a 22% reduction in heart rate.
Following a series of abnormal ECG changes, four out of five dogs died of ventricular fibrillation at 13 ± 2 min after 300 ng kg−1 ET‐1.
The administration of diltiazem (15 μg kg−1 min−1, i.v.) reduced mean arterial pressure by 10% and heart rate by 15%, and increased coronary blood flow by 39%. Diltiazem did not have any significant effect on the coronary dilator response to low doses of ET‐1. Although there was a general trend for diltiazem to inhibit the coronary vasoconstrictor responses to ET‐1, diltiazem significantly attenuated only the reduction in coronary blood flow produced by 100 ng kg−1 ET‐1 by 60% but not the response to 30 or 300 ng kg−1 ET‐1. Two out of five diltiazem‐treated dogs died of ventricular fibrillation with a mean time to death of 20 min following treatment with ET‐1 (300 kg−1).
ET‐1 is a very potent coronary vasodilator. At slightly higher doses ET‐1 is also a coronary vasoconstrictor. ET‐1 also appears to have direct cardiotoxicity independent of myocardial ischaemia. The vasoconstrictor activity and direct cardiotoxicity are only weakly inhibited by diltiazem.
Regulation of gastric mucosal integrity by endogenous nitric oxide: interactions with prostanoids and sensory neuropeptides in the rat
Authors: Whittle B.J.R. , Lopez‐Belmonte J. , Moncada S. 
Published: July 2012

The interactions between nitric oxide (NO), prostacyclin and sensory neuropeptides in the maintenance of gastric mucosal integrity have been investigated in the anaesthetized rat.
Administration of either NG‐monomethyl‐l‐arginine (l‐NMMA) to inhibit endothelium‐derived NO formation, indomethacin to inhibit prostanoid biosynthesis or chronic capsaicin pretreatment to deplete sensory neuropeptides, did not induce acute mucosal injury.
In capsaicin‐pretreated rats, however, l‐NMMA (12.5–100 mg kg−1 i.v.) dose‐dependently induced acute mucosal damage, characterized as vasocongestion and haemorrhagic necrosis. The enatiomer d‐NMMA (100 mg kg−1 i.v.) did not induce any detectable mucosal damage.
This mucosal injury induced by l‐NMMA was inhibited by concurrent administration of l‐arginine (300 mg kg‐1 i.v.).
In indomethacin (5 mg kg−1 i.v.)‐pretreated rats, l‐NMMA also induced mucosal damage. Furthermore, following indomethacin administration in capsaicin‐pretreated rats, l‐NMMA induced widespread, severe haemorrhagic necrotic damage.
These findings suggest a role for endogenous NO formed from l‐arginine, acting in concert with prostacyclin and sensory neuropeptides, in the modulation of gastric mucosal integrity.
Suramin antagonizes responses to P2‐purinoceptor agonists and purinergic nerve stimulation in the guinea‐pig urinary bladder and taenia coli
Authors: Hoyle Charles H.V. , Knight Gillian E. , Burnstock Geoffrey 
Published: July 2012

Suramin, an inhibitor of several types of ATPase, was investigated for its ability to antagonize responses mediated via P2X‐purinoceptors in the guinea‐pig urinary bladder and P2Y‐purinoceptors in the guinea‐pig taenia coli.
In isolated strips of bladder detrusor muscle, suramin (100 μm‐1 mm) caused a non‐competitive antagonism of responses to α,β‐methylene ATP with an estimated pA2 of approximately 4.7, and inhibited responses to stimulation of the intramural purinergic nerves, with a similar pA2 value. At a concentration of 10 μm, suramin had little effect, but at a concentration of 1 μm, suramin potentiated responses to α,β‐methylene ATP, and potentiated responses to electrical stimulation of intramural purinergic nerves.
In isolated strips of taenia coli, in which a standard tone had been induced by carbachol (100 nm), suramin at 100 μm and 1 mm significantly antagonized relaxant responses to ATP (at an EC50 concentration) with an estimated pA2 of 5.0 ± 0.82 and relaxant responses to electrical stimulation of the intramural non‐adrenergic, non‐cholinergic inhibitory nerves, either single pulses or trains of 8 Hz for 10 s, with estimated pA2 values of 4.9 ± 0.93 and 4.6 ± 1.01, respectively. Suramin had no significant effect at 1 or 10 μm.
Suramin, at any of the concentrations tested, did not affect contractile responses to histamine (10 μm) or carbachol (10 μm) in the bladder detrusor preparations. In the taenia coli, suramin did not affect either the relaxant responses to noradrenaline (at an EC50 concentration) or the contractile responses to carbachol (100 nm).
Thus, suramin at concentrations above 10 μm blocked actions mediated via P2X‐ and P2Y‐purinoceptors in the guinea‐pig urinary bladder and taenia coli respectively. Potentiation of purinoceptor‐mediated activity was seen only at a low concentration of suramin (1 μm) and only in the urinary bladder (P2X‐purinoceptor). For its antagonistic activity suramin did not discriminate between P2X‐ and P2Y‐purinoceptors, but it was selective for P2‐purinoceptor‐mediated activity rather than that mediated via cholinoceptors, adrenoceptors or histamine receptors.
Antigen challenge induces pulmonary airway eosinophil accumulation and airway hyperreactivity in sensitized guinea‐pigs: the effect of anti‐asthma drugs
Authors: Sanjar S. , Aoki S. , Kristersson A. , Smith D. , Morley J. 
Published: July 2012

Guinea‐pigs were sensitized with 3 injections of ovalbumin (OA) (1 or 10 μg per animal) using Al(OH)3and pertussis vaccine as adjuvants at two week intervals.Sensitized guinea‐pigs were challenged with an aerosol of OA (0.1%) over a one hour period and both airway reactivity and cellular content of bronchoalveolar lavage (BAL) fluid were assessed at intervals for up to 7 days.Guinea‐pigs sensitized with 1 μg of ovalbumin responded to an aerosol of OA with increased pulmonary airway eosinophilia, which was evident 1 day after challenge and was present for up to 7 days. Airway hyperreactivity was not detectable in these animals.Guinea‐pigs sensitized with 10 μg of ovalbumin responded to an aerosol of OA with increased pulmonary airway neutrophilia and eosinophilia and with increased airway reactivity which was maximal between 8 and 24 h after exposure to OA.Depletion of circulating platelets or neutrophils, by use of selective antisera, did not alter either the magnitude of eosinophilia or the intensity of airway reactivity in sensitized guinea‐pigs (10 μg) exposed to an aerosol of OA.Pretreatment of sensitized guinea‐pigs (10 μg) for 6 days with AH 21–132, aminophylline, dexamethasone or ketotifen inhibited pulmonary airway eosinophilia, but did not diminish airway hyperreactivity. Neither eosinophil accumulation nor development of airway hyperreactivity was influenced by treatment with mepyramine or salbutamol over a 6 day period before OA inhalation.Although eosinophilia may occur in association with increased airway reactivity in this animal model, there is no evidence of a causal relationship.
Potassium channel blockers and the effects of cromakalim on the smooth muscle of the guinea‐pig bladder
Authors: Fujii K. , Foster C.D. , Brading A.F. , Parekh A.B. 
Published: July 2012

The K+ channel blocking drugs tetraethylammonium Cl (TEA), procaine, 4‐aminopyridine (4AP) and quinidine all produced concentration‐dependent contractions of strips of smooth muscle from the guinea‐pig urinary bladder. Apamin and glibenclamide caused little increase in the mechanical activity, and tolbutamide inhibited it.
TEA, procaine, 4AP, quinidine and apamin all increased the frequencies of spontaneous action potentials recorded with microelectrodes. TEA, quinidine and procaine all caused prolongation of the falling phase of the spike, and procaine and apamin completely abolished the after‐hyperpolarization.
TEA and procaine increased K+ efflux from the tissue, an effect blocked by nifedipine. TEA and apamin increased, whereas quinidine, procaine and 4AP decreased K+ uptake.
Cromakalim caused a concentration‐dependent hyperpolarization of the membrane, abolished spike activity, increased K+ fluxes and relaxed the smooth muscle. The relaxant effect of cromakalim was unaffected by apamin, and in its presence the effects of cromakalim on membrane potential and K+ fluxes were unchanged. Procaine abolished all the effects of cromakalim, and TEA at high concentrations reduced but did not abolish these effects. Quinidine reduced the effects of cromakalim on tension and membrane potential, but its actions were surmounted by higher concentrations of cromakalim. The effects of 4AP on tension and membrane properties were transitory, but it had some effects on the actions of cromakalim. Glibenclamide and tolbutamide reversed the relaxant effects of submaximal cromakalim concentrations, tolbutamide only transiently.
It is concluded that the channels opened by cromakalim are not those involved in generating the spike after‐hyperpolarization. They have properties similar to the delayed rectifier K+ channels responsible for spike repolarization, and also are similar to the ATP‐dependent K channels in vascular smooth muscle.