bluuebunny/crossref_metadata_2025_split huggingface dataset:
Kinetic modulation of guinea‐pig cardiac L‐type calcium channels by fendiline and reversal of the effects of Bay K 8644
Authors: Schreibmayer Wolfgang , Tripathi Onkar , Tritthart Helmut A. 
Published: July 2012

The modulation of L‐type calcium channel current (ICa) by fendiline, a diphenylalkylamine type of calcium channel blocker was investigated on guinea‐pig ventricular myocytes by use of the whole‐cell patch‐clamp technique.
Fendiline‐induced block of ICa is accompanied by modulation of the channel kinetics in a complex manner. The time course of ICa inactivation is significantly faster and the channel availability (f∞) curve is shifted considerably to more negative potentials by fendiline. These findings can be interpreted qualitatively in terms of a modulated receptor.
When the 1,4‐dihydropyridine agonist (4R, 4S)‐Bay K 8644 was added in presence of 30 μm fendiline a further reduction of ICa instead of the expected stimulatory effect was observed.
A similar ‘paradoxical’ inhibition of ICa was produced by the pure agonist enantiomer (4S)‐Bay K 8644. Thus this novel effect of Bay K 8644 cannot be attributed to changes in affinity of the 1,4‐dihydropyridine receptor site for (4R)‐Bay K 8644 during fendiline action.
The IC50 for fendiline was reduced to 3.0 ± 0.1 μm (control value: 17.0 ± 2.4 μm) and the Hill slope in its presence was increased to 1.90 ± 0.1 (control value: 1.39 ±0.23) by 1 μm (4R, 4S)‐Bay K 8644.
(4R,4S)‐Bay K 8644 caused the expected stimulation of ICa in the presence of verapamil, diltiazem and nifedipine, overcoming the inhibitory effect of these calcium channel blockers.
The ‘paradoxical’ inhibitory effect of the agonist Bay K 8644 can be explained in terms of an allosteric interaction between fendiline and the dihydropyridine agonist.
Effects of the neutral endopeptidase inhibitor, SQ 28,603, on regional haemodynamic responses to atrial natriuretic peptide or proendothelin‐1 [1–38] in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , Bennett T. 
Published: July 2012

Regional haemodynamic responses to atrial natriuretic peptide (ANP, 0.5 nmol kg−1) or proendothelin‐1 [1–38] (1.0 nmol kg−1) were assessed in the same conscious Long Evans rats before and 20 min after administration of the novel neutral endopeptidase (NEP) inhibitor, SQ 28,603 (50 mg kg−1, i.v.). In a separate experiment, responses to endothelin‐1 (0.5 nmol kg−1), angiotensin I (0.25 nmol kg−1) and angiotensin II (0.12 nmol kg−1) were measured before and after administration of SQ 28,603.
SQ 28,603 alone had no significant cardiovascular effects but caused significant prolongation of the hypotensive, tachycardic and renal and mesenteric vasoconstrictor effects of ANP. However, the early vasodilator and late vasoconstrictor responses in the hindquarters were not affected significantly.
SQ 28,603 caused significant attenuation of the pressor effects of proendothelin‐1 [1–38] but the associated bradycardia was unchanged. SQ 28,603 caused a significant inhibition of the renal and mesenteric vasoconstrictor effects of proendothelin‐1 and also inhibited the initial vasodilator and subsequent vasoconstrictor responses in the hindquarters vascular bed.
SQ 28,603 had no significant effects on the haemodynamic responses to endothelin‐1, angiotensin I, or angiotensin II.
The results are consistent with SQ 28,603 not only inhibiting NEP that is involved in the degradation of ANP, but also suppressing activity of the enzyme involved in the conversion of proendothelin‐1 [1–38] to endothelin‐1.
Effect of the hypoglycaemic drug (−)‐AZ‐DF‐265 on ATP‐sensitive potassium channels in rat pancreatic β‐cells
Authors: Ronner Peter , Le Hang Tu , Kraebber Markus J. , Higgins Timothy J. 
Published: July 2012

It has previously been shown that the hypoglycaemic drug (−)‐AZ‐DF‐265 stimulates insulin release from mouse islets; in the presence of 3 mm glucose it also inhibits 86Rb‐efflux from 86Rb‐loaded islets. Based on these data we tested the hypothesis that (−)‐AZ‐DF‐265 inhibits ATP‐sensitive potassium channels.
We voltage‐clamped the plasma membrane of single rat pancreatic β‐cells in the whole‐cell configuration and measured the current flowing through ATP‐sensitive potassium channels. (−)‐AZ‐DF‐265 was applied to the outside of the cell; it inhibited the current half‐maximally at a concentration of 1.2 ± 0.2 nm with a Hill coefficient of 0.7 ± 0.1. The inhibition was reversible on washing.
In intact RINm5F cells, the sulphonylurea [3H]‐glibenclamide bound with an affinity of 0.24 ± 0.01 nm and a Hill coefficient of 2.1 ± 0.4. Treatment with (−)‐AZ‐DF‐265 led to the displacement of [3H]‐glibenclamide; this effect was half‐maximal at 8.6 ± 1.7 nm and displayed a Hill coefficient of 0.53 ± 0.01. Meglitinide and tolbutamide, which represent, respectively, the benzamido and sulphonylurea moieties of glibenclamide, showed Hill coefficients of 0.8 ± 0.1 and 0.9 ± 0.1, respectively.
At pH 7.4 and with phosphate/borate buffer, (−)‐AZ‐DF‐265 had an apparent octanol/water partition coefficient of about 53, which is intermediate between the partition coefficients of glibenclamide and glipizide. Nevertheless, (−)‐AZ‐DF‐265 bound only to a minor degree to glass and plastic.
In conclusion, (−)‐AZ‐DF‐265 inhibits ATP‐sensitive potassium channels and displaces [3H]‐glibenclamide from the sulphonylurea receptor.
Impaired cyclic nucleotide‐mediated vasorelaxation may contribute to closure of the human umbilical artery after birth
Authors: Renowden S. , Edwards D.H. , Griffith T.M. 
Published: July 2012

The mechanical and biochemical effects of agents that relax vascular smooth muscle either through elevation of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) or adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels were compared in isolated ring preparations of human umbilical artery and rat aorta. Tone was established by preconstriction with 5‐hydroxytryptamine.
The endothelium‐dependent vasodilator calcium ionophore (A23187) (which stimulates endothelium‐derived relaxing factor [EDRF] release and thus acts through soluble guanylyl cyclase), sodium nitroprusside (which stimulates soluble guanylyl cyclase directly), and atrial natriuretic peptide (which stimulates particulate guanylyl cyclase) relaxed rat aorta but not human umbilical artery.
Sodium nitroprusside, 10 μm, increased cyclic GMP levels from 10 to 390 pmol mg−1 protein at 2 min in rat aorta, as compared with a slower, relatively attenuated rise from 5 to 116 pmol mg−1 protein after 15 min in human umbilical artery. The rise in cyclic GMP in the umbilical artery was not significantly augmented by the cyclic GMP phosphodiesterase inhibitor, MB22948. Atrial natriuretic peptide increased cyclic GMP levels in rat aorta but not in human umbilical artery.
Forskolin, 10 μm, which stimulates both soluble and particulate adenylyl cyclase, maximally relaxed rat aorta and increased cyclic AMP levels from 15 to 379 pmol mg−1 protein at 15 min, but did not significantly relax or increase cyclic AMP levels in human umbilical artery. After preincubation with the cyclic nucleotide phosphodiesterase inhibitor, IBMX, 10 μm forskolin increased cyclic AMP levels to 1365 pmol mg−1 protein at 30 min in human umbilical arteries, but these high levels were not accompanied by mechanical relaxation.
8‐Bromo‐cyclic GMP and 8‐bromo‐cyclic AMP which are lipophilic analogues of cyclic GMP and cyclic AMP, both maximally relaxed the rat aorta at a concentration of 10 μm, but did not significantly relax the human umbilical artery.
The findings indicate that elevated cyclic nucleotide levels are not associated with mechanical relaxation of the post‐partum human umbilical artery, as in other vessels such as rat aorta. This impaired response to cyclic nucleotides may contribute to closure of the umbilical artery after birth.
Cibacron blue stimulation of surfactant secretion in rat type II pneumocytes
Authors: Griese Matthias , Gobran Laurice I. , Rooney Seamus A. 
Published: July 2012

The effect of cibacron blue, a selective P2y‐purinoceptor antagonist in some systems, on the stimulatory effect of adenosine 5′‐triphosphate (ATP) on [3H]‐phosphatidylchloine secretion was examined in primary cultures of rat type II pneumocytes prelabelled by overnight culture with [3H]‐choline.
Cibacron blue alone stimulated phosphatidylcholine secretion in a concentration‐dependent manner in the range 10−4−10−3 m. At a concentration of 10−4 or lower, cibacron blue had no effect on ATP‐induced phosphatidylcholine secretion but at 10−4−10−3 m it increased the effect of ATP. Enhancement of the ATP effect was apparent whether cibacron blue was added before or together with ATP. Cibacron blue also increased ATP‐induced secretion in the presence of the P1‐purinoceptor antagonist, xanthine amine congener (10−5 m).
The stimulatory effect of cibacron blue on phosphatidylcholine secretion was additive to those of 5′ (N‐ethylcarboxyamido) adenosine (NECA) and terbutaline but less than additive to that of ATP.
Cibacron blue alone had no effect on formation of cyclic AMP or inositol phosphate and when added stimultaneously with ATP it did not affect the ATP‐induced increase in these second messengers. Preincubation of the cells with cibacron blue before addition of ATP, however, resulted in antagonism of the ATP‐induced increase in cyclic AMP and inositol phosphates. Preincubation with ATP had the same effect. The stimulatory effects of NECA and terbutaline on cyclic AMP formation were enhanced by preincubation with cibacron blue.
Thus, ATP‐induced phosphatidylcholine secretion in type II cells is not diminished by the P2y‐antagonist, cibacron blue. On the contrary, cibacron blue stimulates phosphatidylcholine secretion. Cibacron blue may act as a P2‐agonist in type II pneumocytes.
Inhibitory effect of methysergide on calcitonin gene‐related peptide‐induced vasodilatation and ocular irritative changes in the rabbit
Authors: Krootila Kari , Oksala Olli , Zschauer Aino , Palkama Arto , Uusitalo Hannu 
Published: July 2012

Calcitonin gene‐related peptide (CGRP) is involved in ocular neurogenic inflammation in the rabbit, causing vasodilatation in the anterior uvea, breakdown of the blood‐aqueous barrier, increase in the intraocular pressure (IOP) and rise in the adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) content in the aqueous humour. So far there is no means of preventing these CGRP‐induced ocular effects.
In the present study, the effect of intravenous methysergide (1–10 mg kg−1, b.w.) on CGRP‐induced changes in the IOP, blood‐aqueous barrier and cyclic AMP content in the aqueous humour was studied in vivo. The effect of methysergide on CGRP‐induced vasodilatation both in vivo and in vitro was also investigated.
Methysergide decreased intraocular pressure but had only a transient effect on blood pressure. Methysergide decreased the regional blood flow in ocular tissues by 53–65%, but did not have such a vasoconstrictor effect in most extra‐ocular tissues studied.
Methysergide inhibited CGRP‐induced vasodilatation, increase in the IOP, breakdown of the blood‐aqueous barrier and increase in the cyclic AMP content in the aqueous humour in vivo.
In vitro, methysergide alone did not have effects on the vascular tone in isolated ophthalmic artery of rabbit. However, it potentiated noradrenaline (NA)‐induced contraction. There were no differences in the IC50 values for CGRP on the NA‐induced contraction in the presence and absence of methysergide, indicating that methysergide has no direct effect on the vasorelaxant effect of CGRP in vitro.
The present study demonstrates that in the rabbit eye methysergide inhibits CGRP‐induced changes. One inhibitory mechanism of methysergide may be to enhance the effect of a vasoconstrictor (NA) to antagonize the vasodilator effect of CGRP. The present findings suggest that a methysergide‐sensitive mechanism may be used to limit some pathophysiological conditions in the eye that involve neurogenic inflammation and the release of CGRP.
Study of mechanisms of glucocorticoid hypertension in rats: endothelial related changes and their amelioration by dietary fish oils
Authors: Yin K. , Chu Z.M. , Beilin L.J. 
Published: July 2012

To investigate possible mechanisms of increased systolic blood pressure after 1 weeks treatment with dexamethasone and its amelioration by fish oil feeding, we have examined the reactivity of aortic rings and perfused mesenteric resistance vessels.
Thirty six Sprague‐Dawley rats were initially divided into two groups and fed a semisynthetic diet containing either (10% by weight) hydrogenated coconut oil and safflower oil mixture (HCO/S) (24 rats) or fish oil (12 rats) for 5 weeks. From the end of the fourth week, dexamethasone (1.25 mg ml−1) in drinking water, was given to half the rats on hydrogenated coconut oil (HCO/S + Dex) and to the fish oil‐fed group (fish oil + Dex).
One week of dexamethasone treatment raised systolic blood pressure in the HCO/S + Dex rats but not in the fish oil + Dex group.
Endothelium‐dependent relaxation to acetylcholine (ACh) was decreased in aortic rings taken from HCO/S + Dex rats compared to rats on HCO/S alone. Relaxant responses to ACh of aortic rings from rats given fish oil + Dex were intermediate between the three groups. Aortic endotlielium‐independent responses to sodium nitroprusside (SNP) were unchanged between the groups, while aortic contractile responses to noradrenaline were similar in all the groups.
In the perfused mesenteric resistance artery, sensitivity to noradrenaline was decreased in rats given fish oil and dexamethasone compared to the other two groups. There were no differences in resistance vessel relaxation to ACh or SNP between groups.
Serum corticosterone levels, used as a marker of dexamethasone absorption, were substantially suppressed in dexamethasone‐treated rats but levels were higher in rats on fish oil than on HCO/S diets.
We suggest that the glucocorticoid‐induced rise in systolic blood pressure may be due in part to decreased aortic compliance as a consequence of impaired endothelium‐dependent relaxation and perhaps reduced nitric oxide synthesis. Fish oil feeding may ameliorate this rise in blood pressure through (i) changes in dexamethasone absorption, (ii) decrease in reactivity to noradrenaline of perfused mesenteric resistance arteries, (iii) an increase in endothelium‐dependent relaxation to ACh or a combination of these three factors.
Effects of imipramine on the transient outward current in rabbit atrial single cells
Authors: Delpón Eva , Tamargo Juan , Sánchez‐Chapula José 
Published: July 2012

. The effects of imipramine on action potential characteristics and transient outward potassium current (It) of rabbit isolated atrial myocytes were studied using the whole‐cell configuration of the patch‐clamp technique.
Imipramine, 3 μm, decreased action potential amplitude and lengthened the action potential duration measured at 50% of repolarization, whereas it did not modify the final phase of repolarization or the resting membrane potential. These results are similar to those reported in multicellular rabbit atrial preparations.
Imipramine, 0.1–100 μm, induced a concentration‐dependent inhibition of the peak amplitude of It, a shortening of the time to peak current and an increase in the inactivation rate. The acceleration of the current inactivation is to a major extent responsible for the decrease in the integral of the outward current measured at 50 ms after the start of the pulse.
The drug‐induced block of It was not associated with changes in the voltage‐dependence of the steady‐state inactivation curve or in the process of recovery from inactivation of the current. Extrapolation to zero block shows that imipramine did not block It before its activation at the onset of the depolarization. These results suggested that imipramine does not affect the inactivated or the resting state of It channels.
It is concluded that in rabbit isolated atrial cells, imipramine inhibits It and that this effect is responsible for the lengthening of the action potential duration produced by this drug.
Coeliac haemodynamic effects of endothelin‐1, endothelin‐3, proendothelin‐1 [1–38] and proendothelin‐3 [1–41] in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , Compton A.M. , Bennett T. 
Published: July 2012

Conscious, chronically‐instrumented, Long Evans rats were given bolus doses of endothelin‐1, endothelin‐3 (both at 0.01 and 0.1 nmol kg−1), proendothelin‐1 [1–38] and proendothelin‐3 [1–41] (both 0.1 and 1 nmol kg−1) in order to compare their effects on coeliac haemodynamics, because it has been reported that, in conscious dogs, endothelin‐1 has paradoxical, prolonged hyperaemic vasodilator effects in this vascular bed. Measurements were made also of mesenteric and hindquarters haemodynamics for comparison. In a separate experiment, endothelin‐1 (0.1 nmol kg−1) was given before and 20 min after the onset of an infusion of mecamylamine (50 μmol kg h−1) to ensure that the responses measured were not confounded by rapid reflex changes in autonomic activity.
None of the peptides caused any increases in coeliac flow or any sustained rises in coeliac vascular conductance, although such changes were clear‐cut in the hindquarters vascular bed following the higher dose of endothelin‐1 and endothelin‐3. In animals treated with mecamylamine the regional haemodynamic effects of the higher dose endothelin‐1 were not different from those in animals with intact baroreflexes.
Although the lower dose of both endothelin‐1 and endothelin‐3 caused less marked coeliac than mesenteric vasoconstriction, this difference was not apparent with the higher dose of the peptides, or with proendothelin‐1 [1–38]. However, proendothelin‐3 [1–41] had less marked coeliac and hindquarters vasoconstrictor effects than proendothelin‐1 [1–38], in spite of both peptides causing similar changes in mesenteric haemodynamics. These differences could have been due to regional differences in the conversion of proendothelin‐1 [1–38] and proendothelin‐3 [1–41] to endothelin‐1 and endothelin‐3, respectively. Our findings contradict the proposition that exogenous proendothelin‐3[1–41] is not converted into endothelin‐3 in vivo.
Since, in contrast to endothelin‐1 and endothelin‐3, proendothelin‐1 [1–38] and proendothelin‐3 [1–41] caused only small hindquarters vasodilatations, but large vasoconstrictions, it is feasible that the vasodilator responses to exogenous endothelin‐1 and endothelin‐3 are pharmacological phenomena, and that, in vivo, the production of endothelins from proendothelins exerts widespread vasoconstrictor effects.
Characterization of 8‐OH‐DPAT‐induced hypothermia in mice as a 5‐HT1A autoreceptor response and its evaluation as a model to selectively identify antidepressants
Authors: Martin Keith F. , Phillips Ian , Hearson Mitchell , Prow Michael R. , Heal David J. 
Published: July 2012

8‐Hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) dose‐dependently induced hypothermia in mice.
The 5‐HT1A receptor partial agonists, buspirone, gepirone and ipsapirone, also dose‐dependently induced hypothermia.
The 8‐OH‐DPAT temperature response was antagonized by the 5‐HT1 receptor antagonists quipazine (2 mg kg−1, i.p.), (±)‐propranolol (10 mg kg−1, i.p.). (±)‐pindolol (5 mg kg−1, i.p.), spiroxatrine (0.5 mg kg−1, i.p.) and metitepine (0.05 mg kg−1, i.p.), but not by 5‐HT2 (ketanserin) or 5‐HT3 (MDL 72222, GR 38032F) receptor antagonists.
The response was also antagonized by the dopamine D2 receptor antagonists, haloperidol and BRL 34778. No other catecholamine or muscarinic receptors were involved in mediating the response.
Destruction of 5‐hydroxytryptamine (5‐HT)‐containing neurones with the neurotoxin, 5,7‐dihydroxytryptamine (75 μg, i.c.v.), abolished the response to 8‐OH‐DPAT indicating that the 5‐HT1A receptors involved were located on 5‐HT neurones.6 Chronic antidepressant treatment down‐regulated this 8‐OH‐DPAT response. In addition, chronic administration of anxiolytics and neuroleptics was also effective in this respect. Down‐regulation was also observed following repeated administration of 8‐OH‐DPAT (0.5 mg kg−1, s.c.), (±)‐pindolol (10 mg kg−1, i.p.) and ketanserin (0.5 mg kg−1, i.p.).7 In conclusion, these data confirm that 8‐OH‐DPAT‐induced hypothermia is mediated by 5‐HT1A autoreceptors. They also indicate that the response involves D2 receptors. The present study also shows that a wide range of antidepressant drugs down‐regulate this response although this property is not restricted to antidepressant treatments. Therefore, care should be exercised when interpreting data from this paradigm.
Pharmacodynamics of the anticonvulsant effect of oxazepam in aging BN/BiRij rats
Authors: Stijnen Annemiek M. , Postel‐Westra Ineke , Langemeijer Mariska W.E. , Hoogerkamp Arendien , Voskuyl Rob A. , van Bezooijen Cornelis F.A. , Danhof Meindert 
Published: July 2012

The purpose of this investigation was to examine the influence of increasing age on the pharmacokinetics and the time course of the anticonvulsant response of oxazepam in BN/BiRij rats as an animal model of aging.
Oxazepam was administered intravenously in a dose of 12 mg kg−1 body weight and the anticonvulsant effect intensity was measured as elevation above baseline of a threshold for induction of localized seizure activity (TLS). Direct cortical stimulation with ramp shaped electrical pulse trains of increasing intensity was used to determine this threshold.
The pharmacological effect vs. time profile showed in young rats an anticonvulsant component followed by proconvulsant component which is suggestive for the occurrence of acute tolerance and/or withdrawal syndrome. With increasing age the proconvulsant component disappeared, resulting in a monophasic effect profile (anticonvulsant effect only) at the age of 35 months with significantly higher anticonvulsant effect intensity immediately following drug administration. No age‐related changes in the pharmacokinetic parameters of oxazepam were observed.
In five animals of each age group, benzodiazepine receptor binding characteristics were determined in vitro with [3H]‐flunitrazepam as a ligand. Both receptor density and affinity did not show age‐related changes. Available literature data on post‐receptor events do not indicate conclusive age‐related changes.
It is concluded, that the observed change in the pharmacodynamics of anticonvulsant effect of oxazepam can be explained by the disappearance of the tolerance/withdrawal phenomenon. This is compatible with a decreased efficiency of homeostatic control mechanisms in the elderly.