bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human liver morphine UDP‐glucuronyl transferase enantioselectivity and inhibition by opioid congeners and oxazepam
Authors: Wahlström Agneta , Pacifici Gian Maria , Lindström Björn , Hammar Lena , Rane Anders 
Published: July 2012

Morphine uridine diphosphate glucuronyl transferase (UDP‐GT) was studied in human liver microsomes. The (−)− and (+)‐morphine enantiomers were used as substrates and inhibitors, such as oxazepam and various opioid congeners were employed to characterize the different glucuronidation pathways. The kinetics of the oxazepam inhibition were studied in the rat liver.
The overall glucuronidation of (+)‐morphine was higher than that of (−)‐morphine. The morphine congeners tested, potently inhibited the formation of (−)‐morphine‐3‐glucuronide ((−)‐M3G), except for normorphine and codeine. The formation of (+)‐morphine‐6‐glucuronide ((+)‐M6G) was potently inhibited by only dextromethorphan and (+)‐naloxone. All drugs except normorphine inhibited the formation of (+)‐M3G by 18–50%.
The metabolism of (−)‐morphine to (−)‐M3G was more sensitive to oxazepam inhibition than the formation of (+)‐M3G from (+)‐morphine in the rat liver.
The glucuronidation of natural morphine is subject to in vitro interaction with oxazepam and several opiate drugs. Our study supports the theory of more than one type of UDP‐GT being involved in morphine glucuronidation.
Effect of phenobarbitone pretreatment upon endothelium‐dependent relaxation to acetylcholine in rat superior mesenteric arterial bed
Authors: Randall Michael D. , Hiley C. Robin 
Published: July 2012

Pretreatment of rats for 5 days with phenobarbitone (80 mg kg−1 day−1) enhanced the potency of acetylcholine in opposing noradrenaline‐induced vasoconstriction in the isolated perfused superior mesenteric arterial bed; in 10 saline‐pretreated control animals the ED50 was 14.0 ± 3.9 ng whereas it was 3.23 ± 1.00 ng in 10 phenobarbitone‐pretreated animals.
In both saline‐ and phenobarbitone‐pretreated rats acetylcholine was ineffective at opposing noradrenaline vasoconstriction after the mesentery had been perfused for 90s with a 0.3% solution of the detergent CHAPS in distilled water (to remove the endothelium), but pressor responses to noradrenaline were unaffected.
Pretreatment with phenobarbitone had no effect on the opposition by sodium nitroprusside of noradrenaline pressor responses. Also, the effects of nitroprusside were not affected by perfusion with CHAPS in either control or barbiturate‐pretreated groups.
Inclusion of indomethacin (10 μm) in the perfusion fluid had no effect on the enhancement by phenobarbitone pretreatment of the endothelium‐dependent opposition by acetylcholine of noradrenaline pressor responses; the ED50 values in the absence and presence of indomethacin were, respectively, 2.40 ± 0.31 ng and 1.87 ± 0.27 ng (n = 6).
The concentration of cytochrome P450 in the microsomal fraction obtained from the mesenteric preparation was increased from 204 ± 32 (saline‐pretreated; n = 7) to 784 ± 249 pmol g−1 wet wt (n = 7) by the phenobarbitone pretreatment.
It is concluded that the increase in potency of acetylcholine as an endothelium‐dependent vasodilator by phenobarbitone pretreatment is most probably at the level of the endothelium rather than the vascular smooth muscle.
Effects of furosemide on renal haemodynamics and proximal tubular sodium reabsorption in conscious rats
Authors: Christensen Sten , Petersen Jørgen S. 
Published: July 2012

The effects of furosemide given as constant i.v. infusion (7.5 mg kg−1 h−1) or bolus injections (0.5, 7.5 and 120 mg kg−1) on renal haemodynamics and proximal tubular Na reabsorption were studied in conscious water diuretic rats. The clearance of Li (CLi) was used as marker for Na delivery from the proximal tubules, and clearance of [14C]‐tetraethylammonium (CTEA) and [3H]‐inulin (CIn) as markers for renal plasma flow (RPF) and glomerular filtration rate (GFR), respectively.
Furosemide caused a transient increase of RPF and GFR followed by a secondary decrease below baseline levels; the latter could in part be counteracted by volume replacement. The filtration fraction (FF = GFR/RPF) was not significantly changed by furosemide. Fractional proximal Na excretion (CLi/CIn) was significantly increased by all doses of furosemide independent of changes in RPF, GFR and FF.
The peak diuretic/natriuretic effect of furosemide was markedly potentiated by volume replacement, probably due to prevention of antinatriuretic mechanisms triggered by volume depletion.
It is concluded that following i.v. furosemide administration there is a biphasic change in renal haemodynamics in conscious, restrained rats, and that the inhibition of proximal Na reabsorption, as manifested by changes in fractional Li excretion, is not likely to be due to changes in total renal haemodynamics.
An examination of the postjunctional α‐adrenoceptor subtypes for (−)‐noradrenaline in several isolated blood vessels from the rabbit
Authors: Daly C.J. , McGrath J.C. , Wilson V.G. 
Published: July 2012

Postjunctional α‐adrenoceptors in several isolated blood vessels from the rabbit have been characterized on the basis of the relative potency of the agonists noradrenaline (NA, non‐selective), phenylephrine (α1‐selective) and UK‐14304 (α2‐selective), and the potency of antagonists rauwolscine (α2‐selective) and corynanthine (α1‐selective) against contractions elicited by NA. In addition, the potency of prazosin against NA was also assessed in the venous preparations.
The thoracic aorta, ear artery and left renal vein appear to possess α1‐adrenoceptors since the agonist potency order was NA > phenylephrine > UK‐14304, while corynanthine was 3–10 fold more potent than rauwolscine.
The ear vein appears to possess α2‐adrenoceptors. The rank order of agonist potency was UK‐14304 > NA > phenylephrine and all three agonists elicited responses of similar magnitude. Furthermore, rauwolscine was 30 fold more potent than corynanthine while prazosin failed to produce a concentration‐dependent inhibition.
The saphenous vein and the plantaris vein appear to possess a mixture of both subtypes since the rank order of agonist potency was UK‐14304 > NA ≫ phenylephrine, while responses elicited by UK‐14304 were smaller than those to the other agonists. However, although rauwolscine was 20 to 100 fold more potent than corynanthine in both preparations, suggestive of predominantly α2‐adrenoceptors, prazosin was either potent (saphenous vein) or relatively inactive (plantaris vein).
The characteristics of postjunctional α1‐ and α2‐adrenoceptors on isolated blood vessels from the rabbit are discussed in relation to the value of both the agonists, particularly NA, and the antagonists used in this study.
An attempt at selective protection from phenoxybenzamine of postjunctional α‐adrenoceptor subtypes mediating contractions to noradrenaline in the rabbit isolated saphenous vein
Authors: Daly C.J. , Dunn W.R. , McGrath J.C. , Wilson V.G. 
Published: July 2012

An attempt has been made, with the irreversible α‐adrenoceptor antagonist phenoxybenzamine, to find the conditions under which postjunctional α1‐adrenoceptors in the rabbit isolated saphenous vein can be inactivated, such that postjunctional α2‐adrenoceptors can be studied in isolation.
Following exposure to various concentrations of phenoxybenzamine, no evidence was found for a selective inactivation of the postjunctional population of α1‐adrenoceptors: the ‘rauwolscine‐resistant’ (α1‐) and the ‘rauwolscine‐sensitive’ (α2‐) responses to (—)‐noradrenaline were similarly affected.
However, in ‘receptor protection’ experiments following exposure to a combination of phenoxybenzamine and the selective α2‐adrenoceptor antagonist rauwolscine, the remaining response to (—)‐noradrenaline appeared to be mediated by a single population of postjunctional α2‐adrenoceptors: the response was insensitive to prazosin and rauwolscine was more potent than corynanthine.
Partial isolation of the α1‐adrenoceptor population was attempted by pre‐exposure of the preparation to a combination of phenoxybenzamine and a selective α1‐adrenoceptor antagonist, i.e. prazosin or YM‐12617. Following receptor protection, the inhibition produced by ‘selective’ concentrations of either of these α1‐adrenoceptor antagonists were not significantly different from that observed in control preparations (no phenoxybenzamine). However, the selective α2‐adrenoceptor antagonists rauwolscine and CH‐38083 were still able to inhibit part of the remaining responses to NA. This is interpreted as indicating that, in addition to protecting the putative postjunctional α1‐adrenoceptors, these procedures fail to produce complete inactivation of postjunctional α2‐adrenoceptors.
It is concluded that, although phenoxybenzamine appeared to be non‐selective for the two populations of postjunctional α‐adrenoceptors in the rabbit isolated saphenous vein, inclusion of a ‘selective’ concentration of a competitive antagonist during the inactivation period results in differing degrees of functional protection of each subtype. Pharmacological isolation was possible for α2‐adrenoceptors but not convincingly for α1‐adrenoceptors.
The contractile activities of lipoxin A4 and lipoxin B4 for guinea‐pig airway tissues
Authors: Jacques Crawford A.J. , Spur Bernd W. , Crea Attilio E.G. , Lee Tak H. 
Published: July 2012

The isometric contractile activities of lipoxin A4 (LxA4) and lipoxin B4 (LxB4) were evaluated on guinea‐pig lung tissue over the concentration range, 10−8 to 10−5 m.
LxA4 contracted guinea‐pig lung parenchymal strips; the concentration eliciting 50% maximum histamine response was 3 × 10−6 m. LxA4 did not contract tracheal spirals.
The LxA4 dose‐response curve was parallel to that of leukotriene D4 (LTD4) with LxA4 being approximately 10,000 fold less potent than LTD4.
The time course of the contraction elicited by LxA4 was similar to that of LTD4 and it was slow in onset and did not plateau for 20 min.
Pre‐incubation of parenchymal strips with leukotriene receptor antagonists at a concentration of 1 × 10−6 m to 3 × 10−5 m FPL 55712 or 3 × 10−5 m L 649923 inhibited LxA4 activity.
Pre‐incubation of tissues with 1 × 10−5 m L 651392, a 5‐lipoxygenase inhibitor, or 1 × 10−5 m indomethacin, a cyclo‐oxygenase inhibitor, did not affect the contractile activity of LxA4.
LxB4 did not constrict parenchymal strips or tracheal spirals.
Effects of magnesium, ouabain and bumetanide on 86rubidium uptake in a human atrial cell line
Authors: Borchgrevink P.C. , Ryan M.P. 
Published: July 2012

The effects of extracellular magnesium concentrations (0, 0.6, 1.2 mm) on 86Rb (used as an analogue of potassium) uptake were investigated in the Girardi human atrial cell line in the presence and absence of drugs.
Increasing extracellular magnesium resulted in significantly higher 86Rb uptake. Compared to uptake in 0.6 mm (the physiological extracellular magnesium concentration), uptake of 86Rb was significantly higher in the 1.2 mm magnesium medium and significantly lower in the magnesium‐free medium.
Ouabain (10−3 m) and bumetanide (10−4 m) were added to inhibit, respectively, the Na‐K‐ATPase and the Na‐K‐Cl co‐transport system in the media containing the three magnesium concentrations. The ouabain‐sensitive, bumetanide‐sensitive and residual transport were found to be 58%, 29% and 13% of the total uptake in the medium containing 0.6 mm magnesium.
The oubain‐sensitive 86Rb uptake was inhibited significantly by reducing the magnesium concentrations to zero whereas the bumetanide‐sensitive and residual uptake were not significantly affected by different magnesium concentrations.
At three different ouabain concentrations (10−7 m, 10−5 m, 10−3 m) studied there was significantly greater uptake of 86Rb in 1.2 mm magnesium compared to uptake in 0 mm magnesium.
The present findings indicate that extracellular magnesium is important for 86Rb (potassium) transport in cardiac cells, and suggest that the main effect is on the Na‐K‐ATPase component of transport.
Vascular smooth muscle sensitivity to endothelium‐derived relaxing factor is different in different arteries
Authors: Christie M.I. , Lewis M.J. 
Published: July 2012

The relaxation responses of pre‐constricted pig coronary artery (PCA) and rabbit aorta (RA) without endothelium, to endothelium‐derived relaxing factor (EDRF) released from either a PCA or RA with intact endothelium have been studied by use of a bioassay cascade system. Effects of EDRF have been compared with sodium nitroprusside (NaNP) and 8‐bromo‐cyclic GMP.
The time course of changes in cyclic GMP levels in response to EDRF in PCA and RA have also been studied.
EDRF (released from a PCA or RA) caused significantly greater relaxation in the PCA than the RA, whether 5‐hydroxytryptamine or high extracellular potassium was used as the constrictor agonist.
These differences in sensitivity to EDRF were paralleled by NaNP but not 8‐bromo‐cyclic GMP.
Cyclic GMP levels peaked earlier in the RA (30 s) than in the PCA (180 s) but the peak levels were significantly greater in the PCA (2.45 fold) than the RA (1.48 fold).
These data show that the previously described differences in EDRF activity between different artery types can be explained in part by differences in the responsiveness of the smooth muscle to EDRF.
Actions mediated by P2‐purinoceptorsubtypes in the isolated perfused mesenteric bed of the rat
Authors: Ralevic V. , Burnstock G. 
Published: July 2012

The effects of adenosine 5′‐triphosphate (ATP) and its analogues on the perfusion pressure of the isolated mesenteric bed of the rat were examined in preparations at resting tone, and with tone raised by noradrenaline.
In the preparations at resting tone, the effect of the analogues was to produce vasoconstriction, their rank order of potency being α,β‐methylene ATP > 2‐methylthio ATP > ATP.
In raised tone preparations, dose‐dependent vasodilatations were produced by ATP and 2‐methylthio ATP although, at the highest doses tested, responses decreased in magnitude. The rank order of potency of the analogues in eliciting this vasodilator response was 2‐methylthio ATP > ATP, while α,β‐methylene ATP was without effect.
Following desensitization of contractile responses to α,β‐methylene ATP, contractile responses to ATP and 2‐methylthio ATP were abolished while their relaxant responses were potentiated.
Removal of the endothelium with sodium deoxycholate totally abolished the vasodilator responses and enhanced the contractile responses.
It is concluded that, in the rat mesentery, ATP and its analogues cause vasoconstriction via P2x‐purinoceptors and vasodilatation via P2y‐purinoceptors and that these are located on the smooth muscle and on the endothelium, respectively.
Endothelium‐dependent modulation of the pressor activity of arginine vasopressin in the isolated superior mesenteric arterial bed of the rat
Authors: Randall Michael D. , Kay Alexander P. , Hiley C. Robin 
Published: July 2012

Pressor responses to arginine vasopressin (AVP) were determined in the rat isolated superior mesenteric arterial bed perfused with Krebs‐Henseleit solution and compared with those to noradrenaline.
In control preparations the maximum pressor response to the peptide was 34 ± 3 mmHg and the ED50 was 21 ±4mu (n = 11). The maximal pressor response to noradrenaline (30 μg) was 100 ± 6 mmHg (n = 8). After removal of the functional endothelium with the detergent CHAPS, the maximum pressor response to AVP increased to 64 ± 4 mmHg and the ED50 decreased to 7.7 ± 2.0 mu (n = 11) but the response to 10 μg noradrenaline was unaffected.
Nordihydroguaiaretic acid (2.5 μm) significantly increased the maximum pressor response to AVP from 41 ±2 mmHg to 86 ±8 mmHg (n = 9); the ED50 was unchanged. Methylene blue (50 μm) also increased the maximum response from 41 ± 3 mmHg to 87 + 13 mmHg (n = 8) without affecting the ED50. Neither treatment significantly affected the response to 10 μg noradrenaline.
Neither indomethacin (10 μm) nor BW755C (10 μm) had significant effects upon either the maximal response or ED50 for AVP nor did they affect the response to 10 μg noradrenaline.
In 6 preparations SKF‐525A significantly increased both the ED50, from 9.8 ± 2.1 to 22 ± 2 mu, and the maximum response, from 36 ± 2 to 70 ± 3 mmHg.
It is concluded that the pressor response to AVP in this vascular bed is modulated, in the presence of functional endothelium, by the simultaneous release of endothelium‐derived relaxing factor.
Flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries through an action on vascular smooth muscle
Authors: Iqbal Amjad , Vanhoutte Paul M. 
Published: July 2012

Hypoxia augments contractile responses to several vasoactive agents in canine isolated coronary arteries with intact endothelium. Calcium antagonists inhibit the further increases in tension caused by hypoxia. The present experiments were designed to determine whether the calcium‐antagonist flunarizine would inhibit hypoxic contractions in isolated blood vessels through an action on the endothelium or on the vascular smooth muscle.
Rings of canine coronary arteries, with or without endothelium, were suspended at optimal length for isometric tension recording in organ chambers filled with modified Krebs‐Ringer bicarbonate solution.
Hypoxia (95% N2 and 5% CO2) augmented contractile responses to prostaglandin F2α (2 × 10−6m); removal of the endothelium abolished this hypoxic facilitation.
Flunarizine (5 × 10−5‐5 × 10−7 m) exerted a long‐lasting inhibition of the hypoxic facilitation in a concentration‐dependent manner. Flunarizine did not inhibit the response to prostaglandin F2α.
To differentiate between the response of smooth muscle and the endothelium, strips of coronary arteries without endothelium were layered with strips with or without endothelium. Hypoxia augmented contractions only in layered preparations with endothelium. Flunarizine prevented the hypoxic contractions in layered preparations in which only the smooth muscle was treated with flunarizine. In contrast, when only the endothelium was treated, no or minimal inhibition of the hypoxic contraction occurred with flunarizine (10−5 and 5 × 10−5 m, respectively).
These experiments indicate that the calcium antagonist flunarizine inhibits endothelium‐dependent hypoxic facilitation in canine coronary arteries primarily through its action on vascular smooth muscle.
Ventral tegmental area: site through which dopamine D2‐receptor agonists evoke behavioural and electrocortical sleep in rats
Authors: Bagetta Giacinto , de Sarro Giovambattista , Priolo Elisabetta , Nisticò Giuseppe 
Published: July 2012

In freely moving rats the effects on behaviour and electrocortical (ECoG) spectrum power of some dopamine agonists, i.e. apomorphine and (+)−3PPP, given directly into different areas of the rat brain were studied. In particular, dopamine agonists were microinfused in the ventral tegmental area (VTA) and substantia nigra (SN) or into the caudate nucleus, n. accumbens and prefrontal cortex. The ECoG spectrum power effects were continuously analysed by means of a computerized Berg‐Fourier analyser as total spectrum power and power in preselected frequency bands.
Apomorphine and (+)−3PPP (0.01, 0.1 and 1.0 nmol) given bilaterally into the VTA produced behavioural and ECoG sleep in a dose‐dependent fashion. A statistically significant (P < 0.01) increase in ECoG total spectrum power with a predominant increase in the lower frequency bands (0.25–3, 3–6 and 6–9 Hz) occurred. No behavioural and ECoG changes were evoked by the same doses of apomorphine bilaterally microinfused into the SN or into the caudate nucleus or by (+)−3PPP (1.0 nml) microinjected into the n. accumbens or applied onto the prefrontal cortex.
Behavioural and ECoG sleep was also induced in rats after systemic administration of apomorphine (263 nmol kg−1, i.p.).
The behavioural and ECoG spectrum power effects of apomorphine (1.0 nmol) bilaterally microinfused into the VTA were prevented by a previous microinjection into the same site of (−)‐sulpiride (9.8 nmol). Similarly, behavioural and ECoG effects evoked by (+)−3PPP (0.1 nmol) given bilaterally into the VTA, were completely antagonized by a previous injection into the same site of haloperidol (16 pmol given 10 min before). In contrast, pretreatment with SCH 23390 (50 μg kg−1, s.c.), a selective antagonist at dopamine D1‐receptors, was unable to antagonize the behavioural and ECoG spectrum power effects of (+)−3PPP.
Soporific effects induced by systemic administration of apomorphine were antagonized by (−)‐sulpiride (9.8 nmol) given bilaterally into the VTA 10 min before, whereas, yohimbine (1.3 nmol), (an antagonist at α2‐adrenoceptors) bilaterally microinfused into the VTA, was ineffective in this respect.
The present experiments provide evidence suggesting that stimulation of dopamine D2‐receptors located at the cell body level and/or the dendrites of dopaminergic neurones in the VTA may represent the mechanism through which apomorphine or (+)−3PPP exert their soporific effects in rats.
Centrally acting hypotensive agents with affinity for 5‐HT1A binding sites inhibit forskolin‐stimulated adenylate cyclase activity in calf hippocampus
Authors: Schoeffter Philippe , Hoyer Daniel 
Published: July 2012

A number of centrally acting hypotensive agents and other ligands with high affinity for 5‐hydroxytryptamine1A (5‐HT1A) recognition sites have been tested on forskolin‐stimulated adenylate cyclase activity in calf hippocampus, a functional model for 5‐HT1A‐receptors.
Concentration‐dependent inhibition of forskolin‐stimulated adenylate cyclase activity was elicited by the reference 5‐HT1‐receptor agonists (mean EC50 value, nm): 5‐HT (22), 5‐carboxamidotryptamine (5‐CT, 3.2), 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT, 8.6), N,N‐dipropyl‐5‐carboxamidotryptamine (DP‐5‐CT, 2.3), l‐[2‐(4‐aminophenyl)ethyl]‐4‐(3‐trifluoromethylphenyl)‐piperazine (PAPP or LY 165163, 20), 5‐methoxy‐3‐(l,2,3,6‐tetrahydro‐4‐pyridinyl)−1H indole (RU 24969, 20), buspirone (65) and ipsapirone (56). amounted to 18–20% inhibition for all but the latter two agonists (14%).
The following hypotensive agents with high affinity for 5‐HT1A sites were potent agonists in this system (mean EC50 value, nm): flesinoxan (24), indorenate (99), erythro‐l‐(1‐[2‐(l,4‐benzodioxan‐2‐yl)−2‐hydroxyethyl]‐4‐piperidyl)−2‐benzimidazolinone (R 28935, 2.5), urapidil (390) and 5‐methylurapidil (3.5). The first two agents were full agonists, whereas the latter three acted as partial agonists with 60–80% efficacy.
Metergoline and methysergide behaved as full agonists and cyanopindolol as a partial agonist with low efficacy. Spiroxatrine and 2‐(2,6‐dimethoxyphenoxyethyl)aminomethyl‐l,4‐benzodioxane (WB 4101) which bind to 5‐HT1A sites with nanomolar affinity, were agonists and inhibited potently forskolin‐stimulated adenylate cyclase in calf hippocampus, showing mean EC50 values of 23 and 15 nM, respectively. Spiroxatrine and WB 4101 yielded 90% and 50% efficacy, respectively.
Spiperone and methiothepin (each 1 μm) caused rightward shifts of the concentration‐effect curve to 8‐OH‐DPAT, without loss of the maximal effect, as did the partial agonist cyanopindolol (0.1 μm) and the (−)− and (+)‐enantiomers of pindolol (1 μm and 0.1 mM, respectively).
There was an excellent correlation (r = 0.90, P = 0.0001) between the pEC50 values (ranging from 6.4 to 8.7) of the 19 agonists tested at adenylate cyclase and their pKD for 5‐HT1A recognition sites. Apparent pKB values of antagonists at adenylate cyclase and their pKD values for 5‐HT1A binding sites were also significantly correlated.
This study further indicates that the 5‐HT1A recognition site and the 5‐HT receptor mediating inhibition of adenylate cyclase in hippocampus are the same. The data show that a number of centrally acting hypotensive agents with high affinity for the 5‐HT1A site are potent agonists in this model, suggesting an involvement of central 5‐HT1A‐receptors in the control of blood pressure.