bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tissue selectivity and spasmogen selectivity of relaxant drugs in airway and pulmonary vascular smooth muscle contracted by PGF2α or endothelin
Authors: O'Donnell Stella R. , Wanstall Janet C. , Kay Christine S. , Zeng Xiang‐ping 
Published: July 2012

The spasmolytic effects of smooth muscle relaxant drugs with different mechanisms of action have been examined on isolated preparations of guinea‐pig trachea and rat pulmonary artery. The preparations were contracted with concentrations of prostaglandin F2α (PGF2α) or endothelin selected to give approximately 80% of the agonist maximum response on each tissue. These concentrations also caused similar levels of tone (% of tissue maximum contraction) on each tissue.
With endothelin as the spasmogen, the potassium channel opening drug, pinacidil, was more potent on trachea (– log IC50 5.49) than on pulmonary artery (4.39), i.e. was airway‐vascular selective, whereas with PGF2α as the spasmogen it was more potent on pulmonary artery (6.01) than on trachea (5.27), i.e. was vascular‐airway selective.
With endothelin as the spasmogen, fenoterol was also airway‐vascular selective (8.35 on trachea; little effect on pulmonary artery), nitroprusside was vascular‐airway selective (7.50 on pulmonary artery; 5.99 on trachea) and forskolin was non‐selective (6.69 on trachea; 6.70 on pulmonary artery). Thus, the airway‐vascular selectivity of the relaxant drugs varied with the drug.
On pulmonary artery, pinacidil, nitroprusside and forskolin were all more potent against PGF2α than against endothelin, i.e. 42, 4 and 7 fold respectively. On trachea, these drugs were equipotent against PGF2α and endothelin.
The results suggest that, in pulmonary artery, but not in trachea, the relative contribution of protein kinase C activation and calcium influx to the maintenance of tonic contractions to endothelin and PGF2α may be different. If protein kinase C activation should be the predominant mechanism for endothelin in pulmonary artery, then it may be more difficult to reverse this with relaxant drugs that lower intracellular calcium.
The study indicates that the airway‐vascular selectivity of relaxant drugs can be spasmogen‐dependent as well as dependent on the mechanism of action of the relaxant drug. Thus, relaxant drugs, whether of interest for their airway or vascular effects, should be tested against a full range of spasmogens of likely pathophysiological importance.
Pharmacokinetic characterization of phosphatidylserine liposomes in the rat
Authors: Palatini Pietro , Viola Giampietro , Bigon Emilio , Menegus Anna Maria , Bruni Alessandro 
Published: July 2012

The plasma decay, tissue uptake and biotransformation of radiolabelled phosphatidylserine (PS) liposomes have been investigated in rats following bolus i.v. injection (2 mg kg−1).
PS plasma concentration showed a biexponential decay with half‐lives of 0.85 and 40 min. The following interpretation of the biphasic decay is proposed: (1) The rapid initial decline is due to the irreversible uptake of PS liposomes by the mononuclear phagocyte system, as demonstrated by the almost exclusive accumulation of PS in liver and spleen. (2) The slow decay phase reflects the elimination of that fraction of PS that has been incorporated into high density plasma lipoproteins (HDL). A kinetic model has been developed to describe these phenomena and a good agreement has been observed between experimental data and theoretical values.
Evidence has been obtained that a large fraction of PS is hydrolyzed at the injection site, probably by phospholipase A2 and other hydrolytic enzymes released by platelets. Hydrolysis at the injection site has also been observed following intraperitoneal and intramuscular injections.
As shown by the comparative analysis of the biotransformation products found in tissues after administration of either [3H]‐glycerol‐PS or [14C]‐serine‐PS, parenterally administered PS follows two distinct metabolic pathways: (1) decarboxylation to phosphatidylethanolamine and (2) extensive hydrolytic degradation with release of the individual components of the molecule. These pathways probably reflect the two main mechanisms of PS uptake, incorporation into the plasma membrane and internalization by endocytosis, respectively.
Secretion of growth hormone elicited by intravenous desipramine in the conscious, unrestrained rat
Authors: Grealy M. , O'Donnell J.M. 
Published: July 2012

Acute intravenous administration of either clonidine (Clon) (50 μg kg−1) or desipramine (DMI) (5 mg kg−1) elicited a pulse of growth hormone (GH) and corticosterone secretion in conscious, unrestrained rats.
The responses to DMI were similar to those with Clon, except that the GH pulse following DMI was delayed and was not dose‐dependent.
The GH response to DMI was inhibited by prior administration of idazoxan (1 mg kg−1) or yohimbine (0.5 mg kg−1), but not by atropine (10 μg kg−1), sulpiride (5 mg kg−1) or prazosin (1 mg kg−1).
The corticosterone secretion following DMI was not altered by prior atropine, sulpiride or prazosin, but was augmented by idazoxan (1 mg kg−1).
GH secretion was not influenced by atropine, sulpiride, prazosin or idazoxan given alone. Idazoxan or yohimbine given alone elicited significant secretion of corticosterone.
It is concluded that i.v. DMI caused an activation through indirect mechanisms of α2‐adrenoceptors specifically involved in hypothalamic‐pituitary regulation of GH release and also a distinct, independent and transient generalized activation of the pituitary‐adrenal axis.
Evidence for regulatory control of iron uptake from ferric maltol across the small intestine of the rat
Authors: Barrand Margery A. , Callingham Brian A. 
Published: July 2012

59Fe absorption from the novel iron compound, ferric maltol, was studied in rats pretreated twice daily for two weeks with non‐radioactive ferric maltol in oral doses containing 7 mg elemental iron. Tissue accumulation of 59Fe 2 h after administration of radioactive ferric maltol into the stomach was significantly lower in iron pretreated animals than in saline‐treated controls.
59Fe uptake from ferric maltol into isolated fragments of ileum and of duodenum was of similar magnitude in control animals but in iron‐treated animals, duodenal uptake was significantly lower than that of the ileum.
Absorption of 59Fe was also investigated in anaesthetized rats after intestinal perfusion with saline (controls) or with 5 mm chenodeoxycholate to render the intestines more permeable.
Changes in permeability of the small intestine were monitored by estimating the amount of [14C]‐mannitol absorbed and fluid secreted with reference to the non‐absorbable [3H]‐inulin in the perfusate effluents.
Despite the increased permeability of the intestines after bile salt treatment, there was little difference from control in the tissue accumulation of 59Fe from ferric maltol 2 h after intraduodenal administration. However 59Fe absorption from ferrous sulphate was significantly increased after bile salt treatment.
Gel filtration profiles of plasma made 5 and 60 min after intraduodenal administration of [59Fe]‐ferric [3H]‐maltol demonstrated that metal and ligand do not enter the circulation as the complex even when intestinal permeability is increased.
Uptake of 59Fe was investigated in isolated fragments of rat small intestine after saline or bile salt perfusion. Although 59Fe uptake from ferric maltol was somewhat greater in the bile salt‐treated intestinal fragments, saturable kinetics were still observed. By contrast, 59Fe uptake from ferrous sulphate: ascorbate was greatly enhanced by bile salt pretreatment and a very large diffusional component of uptake was evident.
It is concluded that iron uptake from ferric maltol may well be under endogenous regulatory control even in damaged intestines, so it is unlikely that this novel iron compound can bring about iron overload when administered orally.
The mechanism of action of endothelin in human lung
Authors: McKay K.O. , Black J.L. , Armour C.L. 
Published: July 2012

The peptides endothelin‐1 (ET‐1) and endothelin‐2 (ET‐2) elicited potent and sustained contractions of human isolated bronchus and pulmonary artery.
ET‐1 is one of the most potent contractile agonists investigated in these tissues with an EC50 value of 18.3 nm (95% confidence interval: 12.9, 25.9 nm; n = 26) in bronchus and 3.2 nm (95% confidence interval: 0.4, 23.9 nm; n = 5) in the arterial preparation.
ET‐1 is 2.5 times more potent than ET‐2 in both the airway and vascular tissues, and both forms of the peptide have geometric mean EC50 values 5 times greater in the isolated bronchial tissue than in the pulmonary artery.
Neither pretreatment with the voltage‐dependent calcium (VDC) channel antagonist verapamil (10 μm) nor with indomethacin (25 μm) significantly altered the response curve to ET‐1 in human isolated bronchus. Removal of calcium from the Krebs‐Henseleit solution did not affect ET‐1‐induced responses.
Specific binding on the smooth muscle of human airway and pulmonary arterial tissue to both ET‐1 and ET‐2 was detected in autoradiographic studies. There appeared to be no difference between the peptides in the location nor the density of binding sites.
We conclude that contraction of human bronchial tissue by ET‐1 is not dependent upon influence of extracellular calcium nor release of prostaglandins or thromboxane A2. It is likely that the action of ET‐1 in this tissue is due to binding of this peptide to specific receptors located on the smooth muscle.
Sympathetic co‐transmission to the cauda epididymis of the rat: characterization of postjunctional adrenoceptors and purinoceptors
Authors: Ventura Sabatino , Pennefather Jocelyn N. 
Published: July 2012

Electrical field stimulation (10 Hz, 60 V, 1 ms, for 10 s) produced monophasic contractions of isolated preparations of rat cauda epididymis which could be abolished by guanethidine, and attenuated by prazosin and α,β‐methylene ATP.
The rank order of potency of adrenoceptor agonists in causing contraction of the preparation in the presence of the neuronal uptake blocker, nisoxetine (0.1 μm) was: adrenaline ≥ phenylephrine ≥ noradrenaline > clonidine > methoxamine > metaraminol > dopamine ≥ isoprenaline > xylazine.
Responses to the agonists were blocked by prazosin but not by propranolol or idazoxan.
The rank order of potency of purinoceptor agonists in causing contraction of the cauda epididymis was: α,β‐methylene ATP > β,γ‐methylene ATP ≥ 2‐methylthioATP > ATP > ADP. AMP and adenosine did not cause contractions.
Contractile responses to the purine nucleotide analogues were blocked by repeated application of α,β‐methylene ATP.
It is concluded that both ATP and noradrenaline may act as co‐transmitters in the sympathetic nerves supplying the smooth muscle of the rat cauda epididymis, and that α1‐adrenoceptors and P2X‐purinoceptors are present postjunctionally.
Beneficial effects of N‐acetylcysteine and cysteine in stunned myocardium in perfused rat heart
Authors: Tang Li‐Da , Sun Jian‐Zhong , Wu Ke , Sun Cun‐Pu , Tang Zhong‐Ming 
Published: July 2012

The objective of this study was to evaluate the effects of three sulphydryl (SH) compounds, N‐acetylcysteine (NAC), cysteine (Cys) and cystamine, on functional recovery and ventricular arrhythmias (VF) in stunned myocardium in the isolated perfused heart of the rat.
Hearts (n = 7–8 per group) were perfused by the Langendorff procedure for 20 min to stabilize and then assigned to one of five groups: saline, sham, NAC, Cys and cystamine. After the stabilizing period, the drugs (at 3.6 μm min−1) or their vehicle (saline) were infused into coronary vessels throughout the experimental period. Ten min after administration of drugs, the left anterior descending coronary artery (LAD) was ligatured for 20 min and then untied to reperfuse for 30 min. In the sham group, a ligature was placed around the LAD but not tied.
NAC and Cys had a significant effect in attenuating myocardial stunning: the percentage recovery of rate‐pressure product measured 30 min after reperfusion as an index of heart function, was improved with the NAC (98.3 ± 4.5) and Cys groups (104.0 ± 6.5) compared with the saline (only 73.6 ± 3.8, P < 0.01) group. Cystamine did not show these beneficial effects. This may be due to the difference in chemical structure between NAC, Cys and cystamine since the latter does not have a free SH group with a disulphide bond formed. This phenomenon suggests that a free SH group is essential for the protective effects of compounds like NAC and Cys in myocardial injury.
NAC and Cys prevented the fall in coronary flow during the LAD occlusion and enhanced coronary flow during reperfusion but cystamine did not have such a beneficial effect.
The incidence of VF in the saline, cystamine, Cys and NAC groups was 6/8 (75.0%), 4/7 (57.1%), 3/8 (37.5%) and 2/7 (28.6%), respectively, and no significant differences (P > 0.05) were noted between the saline‐ and drug‐treated groups.
An in vitro study with electron spin resonance indicated that Cys effectively scavenged the hydroxyl radical (OH) generated by Fenton's reaction but did not scavenge superoxide generated in an irradiated riboflavin system. NAC and cystamine showed a scavenging effect on OH to a certain extent but this effect did not reach statistical significance (P > 0.05 vs saline).
Our results demonstrate that NAC and Cys treatment before ischaemia and reperfusion can reduce myocardial stunning. This beneficial effect may be mainly due to their ability to preserve and enhance coronary flow during coronary occlusion and reperfusion and in part due to scavenging OH and/or replenishing intracellular glutathione. The results also indicate that the condition of coronary perfusion can produce a great impact on postischaemic ventricular performance.
Evidence that the 5‐HT3 receptors of the rat, mouse and guinea‐pig superior cervical ganglion may be different
Authors: Newberry Nigel R. , Cheshire Sarah H. , Gilbert Michael J. 
Published: July 2012

Using grease‐gap recordings from the isolated superior cervical ganglion of mouse, rat and guinea‐pig, we have compared the depolarization evoked by 5‐hydroxytryptamine (5‐HT) with that evoked by the selective 5‐HT3 receptor agonist 2‐methyl‐5‐HT (2‐Me‐5‐HT).
The maximum depolarization induced by 2‐Me‐5‐HT was smaller than that induced by 5‐HT in all three species, and particularly in the guinea‐pig.
The 5‐HT2 receptor antagonist ketanserin (1 μm) caused a clear rightward shift of the dose‐response curve to 5‐HT on the guinea‐pig ganglion, but not on the mouse or rat ganglion. Spiperone (0.03 μm) had a quantitatively similar action to ketanserin (0.1 μm) on the 5‐HT dose‐response curve of the guinea‐pig ganglion. Ketanserin had no significant effect on the dose‐response curve to 2‐Me‐5‐HT on any of these ganglia.
Using 2‐Me‐5‐HT as the agonist, we determined the pA2 values for two 5‐HT3 receptor antagonists. The potency of ICS 205–930 varied by approximately 100 fold between the species and that of (+)‐tubocurarine varied by over 1000 fold. The differences in the pA2 values of these compounds varied independently among the species.
We conclude that 5‐HT3 receptors are present on the superior cervical ganglion from the rat, mouse and guinea‐pig, but these receptors may be pharmacologically distinct from each other. In addition, the depolarization of the guinea‐pig superior cervical ganglion by low concentrations of 5‐HT is largely mediated by ketanserin‐sensitive receptors.
Effects of vasoactive intestinal peptide (VIP) on contractile responses of smooth muscle in rat stomach
Authors: Ohta Toshio , Ito Shigeo , Ohga Akira 
Published: July 2012

The effects of vasoactive intestinal peptide (VIP) on contractile responses to carbachol (CCh), KCl and caffeine of the circular smooth muscle in rat stomach were examined by the isometric tension recording method and by measurement of the intracellular Ca level, [Ca]i, with fura 2.
Removal of extracellular Ca or nifedipine (0.1 μm) inhibited contractions induced by KCl (40 mm) and a low concentration (1 μm) of CCh but not that induced by caffeine (3 mm). After these treatments, the contraction induced by a high concentration of CCh (100 μm) changed to a phasic response.
VIP dose‐dependently inhibited the contraction induced by 1 μm CCh, but not those caused by 40 mm KCl or 3 mm caffeine.
In Ca‐free solution containing 2 mm EGTA, VIP inhibited the phasic contraction induced by 100 μm CCh, but not that induced by 30 mm caffeine.
CCh caused dose‐dependent tension development concomitant with the increase in [Ca]i. VIP reduced both responses and thus did not affect the [Ca]1‐force relation for CCh. In the chemically skinned muscle fibres, VIP had no effect on the pCa‐tension relation.
It is suggested that the inhibitory effects of VIP on CCh‐induced contractions are due to the inhibition of the processes of signal transduction from muscarinic receptors to voltage‐dependent Ca channels and to intracellular Ca stores.
Block of cardiac sodium channels by amiodarone studied by using of action potential in single ventricular myocytes
Authors: Honjo Haruo , Kodama Itsuo , Kamiya Kaichiro , Toyama Junji 
Published: July 2012

Acute effects of amiodarone on cardiac sodium channels were investigated in ventricular myocytes isolated from guinea‐pig hearts, and compared with those of lignocaine.
Transmembrane potential was recorded and controlled by whole‐cell current‐clamp and voltage‐clamp respectively through suction pipette electrodes. The maximum upstroke velocity () of the action potential was used as a qualitative index of sodium channel availability.
In myocytes treated with amiodarone (1 μm) or lignocaine (40 μm), of reference action potential elicited at 0.03 Hz was decreased by 6 ∼ 11%, indicating minimal tonic block of sodium channels.
Application of a single conditioning depolarization to those myocytes resulted in a significant decrease in of a subsequent test action potential. The reduction was enhanced in a single exponential function as the clamp pulse duration was prolonged. Time constants at 0 mV clamp were 25 ms for amiodarone and 122 ms for lignocaine.
recovery of test action potential following a 1000 ms 0 mV clamp was approximated by a dual exponential function. Time constants for the late slow component (τR) at the resting potential level were 418 ms for amiodarone and 178 ms for lignocaine. τR values were shortened in a voltage‐dependent manner by hyperpolarization during the coupling interval.
These findings suggested that amiodarone, like lignocaine, blocks the sodium channel primarily when it is in the inactivated state. Both onset and offset kinetics of the block are very rapid. Such sodium channel blocking characteristics may contribute to its potent antiarrhythmic activity.
The effects of the stereoisomers of propafenone and diprafenone in guinea‐pig heart
Authors: Groschner Klaus , Lindner Wolfgang , Schnedl Herbert , Kukovetz Walter R. 
Published: July 2012

Optically pure enantiomers of propafenone and diprafenone were prepared from their racemic mixtures and tested for their ability to block β‐adrenoceptors and to prolong functional refractory period in the guinea‐pig heart. β‐Adrenoceptor affinity of the enantiomers was determined by the radioligand binding technique and in functional experiments.
Propafenone and diprafenone inhibited specific binding of the β‐adrenoceptor antagonist (−)‐[3H]‐CGP‐12177 to guinea‐pig myocardial membranes. β‐Adrenoceptor affinities of diprafenone enantiomers exceeded those of corresponding propafenone enantiomers by one order of magnitude. Displacement of (−)‐[3H]‐CGP‐12177 by both antiarrhythmics was highly stereoselective, in that the (S)‐enantiomers were 40–60 fold, i.e. 1.6–1.8 log units more potent than the (R)‐enantiomers.
Propafenone and diprafenone antagonized the positive inotropic action of isoprenaline in isolated atria. β‐Adrenoceptor antagonist potencies of diprafenone enantiomers were about one order of magnitude higher than those of corresponding propafenone enantiomers. For both drugs the (S)‐enantiomer was found to be considerably more potent (14–40 fold) than the (R)‐enantiomer.
Propafenone and diprafenone prolonged functional refractory period of isolated auricles with equal potency and no difference in the antiarrhythmic activity of purified enantiomers was found.
It is concluded that the enantiomers of propafenone and diprafenone exert comparable antiarrhythmic activity, whereas only (S)‐enantiomers block cardiac β‐adrenoceptors with high affinity, which explains the β‐adrenoceptor antagonist effects of the racemic drugs.
In vitro characterization of prostanoid EP‐receptors in the non‐pregnant human myometrium
Authors: Senior J. , Marshall K. , Sangha R. , Baxter G.S. , Clayton J.K. 
Published: July 2012

Prostaglandin receptors of the PGE type have been characterized in the non‐pregnant human myometrium in vitro according to the scheme of Coleman et al. (1984) by use of the agonists PGE2, sulprostone, rioprostil, AY23626, butaprost, misoprostol, 16,16‐dimethylprostaglandin E2, enprostil and iloprost, and, the antagonist AH6809.
All prostanoids tested were active in non‐pregnant human myometrium either as stimulators and/or inhibitors of spontaneous activity or both. Biphasic responses to PGE2 indicate that at least two receptor types of the EP‐receptor exist, one mediating relaxation and the other mediating contraction.
Further evidence for the EP‐receptor mediating excitation and relaxation was provided by the action of the EP2‐/EP3‐receptor selective prostanoids rioprostil, AY23626 and misoprostol, and the EP1‐/EP2‐receptor selective agonist 16,16‐dimethylprostaglandin E2.
Butaprost, an EP2‐receptor selective agonist, produced potent inhibition of spontaneous activity in the tissue which was generally longer‐lasting than that evoked by the natural prostanoid PGE2.
The EP1‐/EP3‐receptor selective agonist sulprostone and the EP3‐receptor agonist enprostil produced potent contractile responses supporting the presence of contractile EP3‐receptors in the non‐pregnant human myometrium in vitro.
The EP1‐/IP‐receptor selective agonist, iloprost, produced mixed responses in non‐pregnant human myometrium. The contractile response was inhibited by the EP1‐receptor antagonist AH6809. However, responses to the EP1‐/EP3‐receptor selective agonist sulprostone were unaffected by AH6809 which may indicate that only a small population of EP1‐receptors is present.
Therefore it would seem that a heterogeneous population of EP‐receptors is present in the non‐pregnant human myometrium.
The role of nitric oxide as an endogenous regulator of platelet and neutrophil activation within the pulmonary circulation of the rabbit
Authors: May G.R. , Crook P. , Moore P.K. , Page C.P. 
Published: July 2012

Intravenous (i.v.) administration of adenosine diphosphate (ADP), platelet activating factor (PAF) and thrombin induced a dose‐related accumulation of 111indium‐labelled platelets within the thoracic region of anaesthetized rabbits.
I.v. administration of the inhibitor of NO biosynthesis, l‐NG‐nitro arginine methyl ester (l‐NAME; 10 mg kg−1) significantly potentiated the peak platelet accumulation induced by ADP, PAF and thrombin. Additionally l‐NAME prolonged the disaggregation of platelets in comparison to d‐NAME (10 mg kg−1). Such changes were reversible by the administration of l‐arginine (900 mg kg−1).
I.v. administration of PAF induced a small accumulation of 111indium‐labelled neutrophils within the pulmonary circulation which could be greatly potentiated by pretreatment of the animals with l‐NAME. In contrast, thrombin administration did not cause significant accumulation of 11indium‐labelled erythrocytes in the pulmonary circulation of anaesthetized rabbits.
Intracarotid (i.c.) administration of thrombin induced a marked accumulation of radiolabelled platelets within the cranial vasculature which was not potentiated by the prior administration of l‐NAME (at either 10 mg kg−1 or 100 mg kg−1).
These results suggest that endogenous NO may regulate platelet and polymorphonuclear leukocyte activation within the pulmonary but not the cerebral circulation of rabbits.