bluuebunny/crossref_metadata_2025_split huggingface dataset:
A quantitative comparison of functional and anti‐ischaemic effects of the phosphodiesterase‐inhibitors, amrinone, milrinone and levosimendan in rabbit isolated hearts
Authors: Rump A.F.E. , Acar D. , Klaus W. 
Published: July 2012

The functional and anti‐ischaemic effects of the phosphodiesterase (PDE)‐inhibitors, amrinone, milrinone and levosimendan, a new agent combining PDE‐inhibitory with calcium‐sensitizing properties, were investigated in rabbit isolated hearts (Langendorff, constant pressure: 70 cmH2O, Tyrode solution, Ca2+ 1.8 mmol l−1, 37°C). Anti‐ischaemic effects were studied in electrically‐driven hearts (200 beats min−1). Acute regional ischaemia was induced by ligature of a branch of the circumflex coronary artery and quantified from epicardial NADH‐fluorescence photography.
Cumulative concentration‐response curves in spontaneously beating hearts in the presence of isoprenaline (10−1 m), showed a higher inotropic and coronary vasodilator potency for levosimendan (EC50: 7 × 10−7 m) compared to milrinone (EC50: 7.7 × 10−6 m) or amrinone (EC50: 2 × 10−5 m). Although the maximal coronary dilator activity was similar for the three agents, the maximal inotropic and chronotropic effects were lower for levosimendan than for amrinone or milrinone (P < 0.05).
In regionally ischaemic hearts, milrinone (10−5 m) or levosimendan (5 × 10−6 m) similarly enhanced the left ventricular pressure (+15–20%) (P < 0.05) and the global coronary flow (+ 40–50%) (P < 0.05). The epicardial NADH‐fluorescence area was significantly diminished by milrinone or levosimendan (– 20–30%) (P < 0.05) and there was no significant difference between the anti‐ischaemic effects of either agent (P > 0.05).
It is concluded that amrinone and milrinone possess similar functional profiles in rabbit isolated hearts and a higher inotropic and chronotropic efficacy than levosimendan. At functionally equieffective concentrations, milrinone and levosimendan show similar anti‐ischaemic effects, related to an improvement of myocardial perfusion. The calcium‐sensitizing properties seem not to be relevant for cardioprotection by levosimendan at the concentration used.
The effects of SB 204070, a highly potent and selective 5‐HT4 receptor antagonist, on guinea‐pig distal colon
Authors: Wardle K.A. , Ellis E.S. , Baxter G.S. , Kennett G.A. , Gaster L.M. , Sanger G.J. 
Published: July 2012

The pharmacology of a novel 5‐HT4 receptor antagonist, SB 204070 has been evaluated in the guinea‐pig isolated distal colon longitudinal muscle‐myenteric plexus (LMMP).
SB 204070 is a highly potent antagonist of 5‐HT‐evoked cholinergically‐mediated contractions in the guinea‐pig distal colon. Low concentrations (10–100 pm) produced a shift to the right of the curve (apparent pA2 10.8 ± 0.1) with no significant effect on the maximum response. With higher concentrations of SB 204070 (300 pm and above), the maximum response to 5‐HT was reduced.
When tested against the partial 5‐HT4 receptor agonist, BIMU 1, SB 204070 was active at similar low concentrations (10 pm and above) but produced a reduction in maximum, with no prior shift to the right of the curve, at all concentrations tested (10–300 pm).
The antagonism seen with SB 204070 is unlikely to be due to a non‐selective effect since high concentrations (10 nm and 1 μm) of the compound had no effect on cholinergically‐mediated contractions evoked by the nicotinic receptor agonist, DMPP, in the same preparation. SB 204070 is unlikely to be an irreversible antagonist since the effects of the compound could be reversed upon washing of the tissue.
Radioligand binding studies show that SB 204070 has a greater that 5000 fold selectivity for the 5‐HT4 receptor over 5‐HT1A, 5‐HT1D, 5‐HT1E, 5‐HT2A, 5‐HT2C, 5‐HT3, GABAA, BDZ, TBPS, A1 adenosine receptors, α1, α2, β1, β2 adrenoceptors and D1, D2 and D3 dopamine receptors.
SB 204070 is a highly potent, highly selective 5‐HT4 receptor antagonist and as such is an important new tool in evaluating the functional role of the 5‐HT4 receptor.
Comparison of antinociception induced by supraspinally administered l‐arginine and kyotorphin
Authors: Kawabata Atsufumi , Manabe Sachiko , Takagi Hiroshi 
Published: July 2012

Intracerebroventricular (i.c.v.) or intracisternal (i.cist.) administration of kyotorphin (KTP), an endogenous Met‐enkephalin releaser, at 5 μg per mouse, and l‐arginine (l‐Arg), a possible KTP precursor, at 30 μg per mouse, elicited antinociception in mice to a similar extent, as assessed by the tail‐flick test.
Intracisternal preadministration of anti‐KTP serum abolished the effects of i.cist. KTP and i.c.v. or i.cist. l‐Arg, but not of i.c.v. KTP.
The antinociceptive effects of i.cist. KTP and of i.c.v. or i.cist. l‐Arg disappeared in reserpinized mice, whereas the effect of i.c.v. KTP was unaffected by treatment of mice with reserpine.
Intrathecal (i.t.) phentolamine markedly reduced the antinocieption induced by i.cist. KTP and by i.c.v. or i.cist. l‐Arg, but not by i.c.v. KTP.
Intrathecal methysergide attenuated the antinociceptive effects of i.cist. KTP, but not of i.c.v. KTP and i.c.v. or i.cist. l‐Arg.
These results suggest that the antinociception produced by i.cist. KTP, but not by i.c.v. KTP, is mediated by the brainstem‐spinal noradrenergic and 5‐hydroxytryptaminergic systems, and that l‐Arg given i.c.v. or i.cist. increases KTP formation in the lower brain, possibly the brainstem, resulting in antinociception mediated by the descending noradrenergic system. Therefore, the regional distribution of KTP receptors and KTP synthetase in the brain does not appear to be common.
The effect of 5‐HT1A receptor agonists on locomotor activity in the guinea‐pig
Authors: Evenden J.L. 
Published: July 2012

The present study examined the effects of 8‐hydroxy‐2‐(din‐propylamino)tetralin (8‐OH‐DPAT), flesinoxan, ipsapirone and buspirone, all agonists at the 5‐HT1A receptor, on the locomotor activity of guinea‐pigs. The effects of these drugs were contrasted with those of the non‐selective 5‐HT agonist, 5‐methoxy‐N,N‐dimethyl tryptamine (5‐MeO‐DMT) and the dopamine D2 antagonist, raclopride.
8‐OH‐DPAT, flesinoxan and 5‐MeO‐DMT markedly increased the locomotor activity of naive, unhabituated guinea‐pigs in a dose‐dependent manner. Buspirone also did so, although to a lesser extent and for a shorter time. The doses at which this effect was seen were higher than those normally employed in rats. Ipsapirone and raclopride had no significant effects on locomotor activity.
The locomotor activity increasing effect of 1.0 mg kg−1 8‐OH‐DPAT was blocked by the selective 5‐HT1A antagonist (S)‐UH‐301 (3.0 and 10.0 mg kg−1), but not by (−)‐alprenolol (15.0 mg kg−1). Ipsapirone (30.0 mg kg−1) and raclopride (3.0 mg kg−1) antagonized 8‐OH‐DPAT‐induced locomotor activity but only to a small extent. The 5‐HT reuptake inhibitor, zimelidine (10.0 mg kg−1) had no effect.
The effect of the 5‐HT1A agonists in the guinea‐pig contrasts with the effects of 8‐OH‐DPAT on the locomotor activity of unhabituated rats and mice tested in the same apparatus, but are similar to the effects of 8‐OH‐DPAT on habituated rats, which show a low baseline of activity.
These results support the suggestion that 5‐HT1A agonists may have an intrinsic activating effect which may be masked by other effects of the drug (e.g. hypothermia, 5‐HT syndrome). The rank ordering of the 5‐HT1A agonists also suggests that the degree to which the drugs increase locomotor activity is related to their agonist efficacy at the postsynaptic 5‐HT1A receptor.
All‐or‐nothing responses to carbachol in single intestinal smooth muscle cells of rat
Authors: Ohta Toshio , Ito Shigeo , Nakazato Yoshikazu 
Published: July 2012

Concentration‐response relationships for carbachol (CCh)‐induced increases in the cytosolic calcium concentration ([Ca2+]i) and membrane currents were studied by use of fura‐2 microfluorimetry and nystatin‐perforated whole‐cell recording in single smooth muscle cells isolated from rat intestine.
CCh produced an initial peak rise in [Ca2+]i followed by a small sustained rise. In individual cells, the peak rise in [Ca2+]i did not increase in amplitude even with increasing concentrations of CCh, though the threshold concentration varied in different cells. The initial peak rise in [Ca2+]i, but not the sustained rise, was due to the release of stored Ca2+, because it was unchanged after removal of external Ca2+ and the addition of nifedipine (1 μm) or La3+ (1 mm).
CCh elicited an outward and inward current in a cell dialyzed with a pipette solution containing KCl at a holding potential of – 30 mV and with one containing NaCl at – 60 mV, respectively. In individual cells, the amplitude of each current was similar in cells stimulated at over the threshold concentration of CCh, but the threshold was different among cells.
The percentage of cells showing Ca2+‐transient responses to CCh at given concentrations was similar to those showing current responses and contractile responses.
In thin muscle bundles, a concentration‐dependent contraction was evoked by CCh in the absence of external Ca2+. Its threshold was similar to those of Ca2+‐transient and current responses in single cells.
These results suggest that CCh‐induced release of stored Ca2+ takes place in an all‐or‐nothing fashion in individual cells of the rat intestinal smooth muscle.
Possible role of cyclic AMP phosphodiesterases in the actions of ibudilast on eosinophil thromboxane generation and airways smooth muscle tone
Authors: Souness John E. , Villamil Maria E. , Scott Lisa C. , Tomkinson Adrian , Giembycz Mark A. , Raeburn David 
Published: July 2012

The possible role of cyclic AMP phosphodiesterase (PDE) in the inhibitory actions of ibudilast on tracheal smooth muscle contractility and eosinophil thromboxane generation was investigated.
Ibudilast was a non‐selective inhibitor of partially purified cyclic nucleotide PDE isoenzymes from pig aorta and bovine tracheal smooth muscle, exhibiting only moderate potency against bovine tracheal PDE IV (IC50 = 12 ± 4 μm, n = 3). Similar or slightly lower potencies were displayed against PDEs I, II, III and V. In contrast, rolipram exhibited selectivity for PDE IV (3 ± 0.5 μm, n = 3).
Ibudilast (IC50 = 0.87 ± 0.37 μm, n = 3), like rolipram (IC50 = 0.20 ± 0.04 μm, n = 3), was a more potent inhibitor of membrane‐bound PDE IV from guinea‐pig eosinophils than of partially purified PDE IV from bovine tracheal smooth muscle. The potency of ibudilast increased when the eosinophil enzyme was solubilised with deoxycholate and NaCl (IC50 = 0.11 ± 0.05 μm, n = 3) or exposed to vanadate/glutathione complex (V/GSH) (IC50 = 0.11 ± 0.02 μm, n = 3). The potency of rolipram was also increased by solubilization (IC50 = 0.012 ± 0.003, n = 3) or V/GSH (IC50 = 0.012 ± 0.003, n = 3).
In intact eosinophils, ibudilast (0.032 μm − 20 μm) potentiated isoprenaline‐induced cyclic AMP accumulation in a concentration‐dependent manner, being approximately 20 fold less potent than rolipram. Little or no effect on basal cyclic AMP levels was observed with either compound. The cyclic AMP‐dependent protein kinase activity ratio was significantly increased following incubation of eosinophils with either ibudilast (20 μm) or rolipram (20 μm) in the absence or presence of isoprenaline.
Leukotriene B4 (300 nm)‐induced thromboxane generation from guinea‐pig eosinophils was inhibited by ibudilast (IC50 = 11.3 ± 3.7 μm, n = 5) and rolipram (IC50 = 0.280 ± 0.067 μm, n = 5) in a concentration‐dependent manner.
Ibudilast (10 nm − 1 μm), whilst generally less potent than rolipram (1 nm − 1 μm), produced concentration‐dependent relaxation of spasmogen (methacholine, histamine, LTD4)‐induced tone in the guinea‐pig isolated tracheal strip. Ibudilast was less potent in reversing the methacholine (IC30 = 1.95 ± 0.40 μm, n = 6)‐induced contraction than those of histamine (IC50 = 0.18 ± 0.70 μm, n = 6) or leukotriene D4 (LTD4, IC50 = 0.12 ± 0.05 μm, n = 6). Rolipram also exhibited a similar pattern of activity, although the difference in potency against methacholine (IC50 = 0.1 ± 0.01 μm, n = 6) compared with the other two spasmogens, histamine (IC50 = 0.034 ± 0.017 μm, n = 7) and LTD4 (IC50 = 0.026 ± 0.008 μm, n = 7), was not as great.
These results demonstrate that ibudilast, like rolipram, has several biological actions on the eosinophil and airways smooth muscle which may be attributed to inhibition of cyclic AMP PDE. These actions may account, at least in part, for the recently reported anti‐asthma effects of ibudilast.
Regional haemodynamic effects of dopamine and its prodrugs l‐dopa and gludopa in the rat and in the glycerol‐treated rat as a model for acute renal failure
Authors: Drieman J.C. , van Kan F.J.P.M. , Thijssen H.H.W. , van Essen H. , Smits J.F.M. , Boudier H.A.J. Struijker 
Published: July 2012

In this study the renal selectivity of dopamine and its prodrugs l‐dopa and gludopa, with respect to their effects on regional blood flow, vascular resistance and central haemodynamics was investigated in normal rats and in rats with glycerol‐induced acute renal failure (ARF).
In normal, anaesthetized rats, dopamine as well as its prodrugs caused a dose‐dependent reduction of vascular resistance in the kidney (RR), mesentery (MR) and hindquarters (HQR) (dose range: dopamine: 0.1–5 μmol kg−1h−1; l‐dopa and gludopa: 1–200 μmol kg−1h−1). Blood pressure and heart rate were affected at the highest dose only.
Administration of glycerol induced a preferential renal vasoconstriction; renal blood flow (– 60%) and vascular resistance (+ 190%) were significantly more affected than MR (+ 40%) and HQR (+ 60%). This was only ameliorated by a low rate (10 μmol kg−1h−1) infusion of gludopa: the glycerol‐induced reduction of renal flow and increase in RR were significantly attenuated. A high dose of gludopa (100 μmol kg−1h−1) or any dose of l‐dopa or dopamine did not induce this beneficial effect. The glycerol‐induced increase in MR and HQR was not attenuated by any of the treatments used.
The results indicate that gludopa is not renally selective at a pharmacodynamic level in normal, anaesthetized rats. Contrary to this, a low dose of gludopa does cause a renal selective vasodilatation and reduction of RR in rats with glycerol‐induced ARF. This difference could be explained by a difference in renal vascular tone between normal rats and glycerol‐induced ARF rats. A high dose of gludopa does not cause these renal‐selective effects: renal resistance and renal flow are at the same level as following glycerol and saline. This is probably due to the systemic effects of the released dopamine.
Effects of Cl channel blockers on Ca‐activated chloride and potassium currents in smooth muscle cells from rabbit portal vein
Authors: Hogg R.C. , Wang Q. , Large W.A. 
Published: July 2012

The effects of some chloride channel antagonists were studied on the calcium‐activated chloride current (ICl(ca)) in smooth muscle cells from the rabbit portal vein with the perforated patch technique.
4‐Acetamido‐4′‐isothiocyanatostilbene‐2,2′‐disulphonic acid (SITS) and 4,4′‐diisothiocyanato‐stilbene‐2,2′‐disulphonic acid (DIDS) reduced the amplitude of spontaneous transient inward currents (STICs, calcium‐activated chloride currents) in a concentration‐dependent manner. The concentrations required to reduce the amplitude by 50% (IC50) of STICs were 2.1 × 10−4m and 6.4 × 10−4m for DIDS and SITS, respectively. This effect was not voltage‐dependent.
The time constant of decay of STICs (τ), which is voltage‐dependent, was increased by about 30% by SITS and decreased by about 20% by DIDS. The effect of DIDS and SITS on τ was similar at holding potentials of − 50 and + 50 mV.
These compounds did not modify the characteristics of spontaneous transient outward currents (STOCs, calcium‐activated potassium currents).
DIDS and SITS decreased the amplitude of ICl(Ca) evoked by noradrenaline and caffeine less potently than STICs with IC50 values of 7.5 × 10−4m and 1.8 × 10−3m, respectively.
DIDS and SITS increased the calcium‐activated potassium current (IK(Ca)) evoked by noradrenaline and caffeine by 3–6 fold.
Anthracene‐9‐carboxylic acid (A‐9‐C) inhibited STICs in a voltage‐dependent fashion and was about 3 fold more active at + 50 mV than at − 50 mV. A‐9‐C increased STIC τ and this effect was enhanced by depolarization.
A‐9‐C also inhibited caffeine‐evoked ICl(ca) but less potently than STICs and also increased the evoked IK(ca) without altering spontaneous IK(ca).
The results from the present work are compared with the pharmacology of other chloride conductances and the mechanism of action of the chloride channel antagonists in vascular smooth muscle is discussed.
Phorbol ester‐induced M‐current suppression in bull‐frog sympathetic ganglion cells: insensitivity to kinase inhibitors
Authors: Chen Hsinyo , Jassar Balvinder S. , Kurenny Dmitry E. , Smith Peter A. 
Published: July 2012

The effects of 1‐oleoyl‐2‐acetyl‐sn‐glycerol (OAG), phorbol 12‐myristate 13‐acetate (PMA), 4‐α‐phorbol and muscarine on B‐neurones from bull‐frog sympathetic ganglion were studied by means of whole‐cell patch‐clamp recording. With the exception of 4‐α‐phorbol, all of these agonists reduced the steady‐state outward current recorded at −30 mV as a result of suppression of a voltage‐dependent, non‐inactivating K+‐current, the M‐current, (IM).
Of the cells tested, 34% displayed bona fide responses to OAG (20 μm). The chance of recording a response was not decreased when the protein kinase inhibitor, 1‐(5‐isoquinolinylsulphonyl)‐2‐methyl‐piperazine (H‐7; 50 or 75 μm) was included simultaneously in the extracellular solution and in the pipette solution.
The presence of 50 μm H‐7 on both sides of the membrane or 500 nm staurosporine in the pipette solution did not prevent responses to brief (1–2 min) or prolonged (>20 min) applications of PMA.
Brief (1–2 min) extracellular application of H‐7 (300 μm) suppressed IM by about 29%.
The most likely explanation of these data is that PMA and OAG modulate IM via a mechanism that is independent of protein kinase C (PKC). The availability of such a mechanism poses new questions as to the mechanism of muscarine‐induced IM suppression.
Role of intrathecal tachykinins for micturition in unanaesthetized rats with and without bladder outlet obstruction
Authors: Ishizuka Osamu , Igawa Yasuhiko , Lecci Alessandro , Maggi Carlo Alberto , Mattiasson Anders , Andersson Karl‐Erik 
Published: July 2012

The effects on micturition of RP 67,580, a selective NK1 receptor antagonist, and SR 48,968, a highly potent antagonist at NK2 receptor sites, given intrathecally (i.t.) or intra‐arterially (i.a.) near the bladder, were investigated in unanaesthetized rats with and without bladder outlet obstruction.
In normal rats, RP 67,580, given i.t. in doses of 2 and 20 nmol per rat, decreased micturition pressure, but did not change other cystometric parameters. After 20 nmol of RP 67,580, dribbling incontinence due to retention was observed in 1 out of 7 animals. This effect was reversible. I.t. RP 67,580 in a dose of 2 nmol, had no effect on hyperactivity induced by intravesically instilled capsaicin.
In animals with bladder hypertrophy secondary to outflow obstruction, RP 67,580, given i.t. in a dose of 2 nmol per rat, decreased the micturiton pressure, but had no effect on other cystometric parameters. After 20 nmol, dribbling incontinence due to retention was observed in 5 out of 7 animals.
RP 67,580, given i.a. in a dose of 4 nmol, had little effect on the cystometric parameters investigated, both in normal animals and rats with bladder hypertrophy.
SR 48,968, given i.t. in doses of 2 and 20 nmol per rat, had no clear‐cut effects on the micturition pattern in normal rats, or rats with bladder hypertrophy. However, the drug reduced capsaicin‐induced bladder hyperactivity. When given i.a. in a dose of 4 nmol, SR 48,968 had no effect on cystometric parameters in normal rats or rats with bladder hypertrophy.
The effects of both RP 67,580 and SR 48,968 were stereoselective, their enantiomers (RP 68,651 and SR 48,965) being inactive.
These results thus suggest that at the spinal level there is a tachykinin involvement (via NK1 receptors) in the micturition reflex induced by bladder filling, both in normal rats, and, more clearly, in animals with bladder hypertrophy secondary to outflow obstruction. The bladder response to filling was not influenced by blockade of vesical NK1 and NK2 receptors. On the other hand, the bladder hyperactivity evoked by intravesical capsaicin seems to involve NK2 receptors both at the bladder and spinal levels.
Infection by HIV‐1 blocked by binding of dextrin 2‐sulphate to the cell surface of activated human peripheral blood mononuclear cells and cultured T‐cells
Authors: Shaunak Sunil , Gooderham Nigel J. , Edwards Robert J. , Payvandi Nassrin , Javan Caroline M. , Baggett Neil , MacDermot John , Weber Jonathan N. , Davies Donald S. 
Published: July 2012

Structural analogues of a sulphated polysaccharide, dextrin sulphate, were synthesized and tested for their ability to block infection by HIV‐1. Using the T‐cell lines, C8166 and HPB‐ALL, and the laboratory adapted strains of HIV‐1.MN, HIV‐1.IIIb and HIV‐1.RF, dextrin 2‐sulphate (D2S) combined the best combination of high anti‐HIV‐1 activity (95% inhibitory concentration (IC95) = 230 nM) and low anticoagulant activity. It also blocked infection of activated peripheral blood mononuclear (PBMN) cells by five primary viral isolates at an IC95 of 230–3700 nM depending upon the primary viral isolate tested.
In saturation binding studies, [3H]‐D2S bound to a cell surface protein on HPB‐ALL cells in a specific and saturable manner with a Kd of 82 ± 14 nM and a Bmax of 4.8 ± 0.3 pmol/106 cells. It bound to other human T‐cell lines in a similar manner.
There was very little binding of [3H]‐D2S to freshly isolated PBMN cells (Bmax 0.18 ± 0.03 pmol/106 cells) and these cells could not be infected by HIV‐1. Culture of PBMN cells in lymphocyte growth medium (LGM) containing IL‐2 did not significantly change the Bmax of [3H]‐D2S. In contrast, PBMN cells which had been cultured with phytohaemagglutinin (PHA; 5 μg ml−1) for 72 h had a Bmax of [3H]‐D2S binding of 7.2 ± 0.1 pmol/106 cells and these cells could be infected by HIV‐1. Removal of the PHA and further culture of the PBMN cells in LGM containing IL‐2 resulted in a fall in the Bmax to 2.0 ± 0.1 pmol/106 cells. The Kd of binding did not change significantly during the course of these experiments.
[3H]‐D2S did not bind to freshly isolated erythrocytes or to erythrocytes which had been cultured in PHA for 72 h.
These results suggest that there is a relationship between the expression of the [3H]‐D2S binding protein on the plasma membrane of PBMN cells and the susceptibility of these cells to infection by HIV‐1.