bluuebunny/crossref_metadata_2025_split huggingface dataset:
AT2‐antagonist sensitive potentiation of angiotensin II‐induced vasoconstrictions by blockade of nitric oxide synthesis in rat renal vasculature
Authors: Muller Catherine , Endlich Karlhans , Barthelmebs Mariette , Helwig Jean‐Jacques 
Published: January 2005

Although the actions of angiotensin II (Ang II) on renal haemodynamics appear to be mediated by activation of the AT1 receptor subtype, AT2 binding sites have also been evidenced in the adult kidney vasculature. As NO is known to mask part of the renal effects of vasoconstrictor drugs, we queried whether the Ang II‐induced vasoconstrictions could occur via multiple receptor subtypes during inhibition of NO synthesis. We explored the effect of AT1 and AT2 receptor (AT‐R) antagonists on Ang II‐induced pressure increases during NO synthase or soluble guanylyl cyclase inhibition in rat isolated kidneys perfused in the presence of indomethacin at constant flow in a single‐pass circuit.
In the absence of NO blockade, the AT1‐R antagonist L‐158809 (500 nM) antagonized the Ang II‐induced vasoconstrictions, while the AT2‐R antagonist PD‐123319 (500 nM) had no effect.
Perfusing kidneys in the presence of either NO synthase inhibitors, L‐NAME (100 μM) or L‐NOARG (1 mM), or soluble guanylyl cyclase inhibitor, LY‐83583 (10 μM), significantly increased both molar pD2 (from 9.40±0.25 to 10.36±0.11) and Emax values (from 24.9±3.1 to 79.9±4.9 mmHg) of the concentration–response curve for Ang II‐induced vasoconstriction.
In the presence of L‐NAME, 500 nM L158809 abolished the Ang II‐induced vasoconstrictions whatever the concentration tested. On the other hand, 500 nM PD‐123319 reversed the left shift of the concentration–response curve for Ang II (molar pD2 value 9.72±0.13) leaving Emax value unaffected (91.3±7.6 mmHg).
In the presence of L‐NAME, the potentiated vasoconstriction induced by 0.1 nM and the augmented vasoconstriction induced by 10 nM Ang II were fully inhibited in a concentration‐dependent manner by L‐158809 (0.05–500 nM). By contrast, PD‐123319 (0.5–500 nM) did not affect the 10 nM Ang II‐induced vasoconstriction and concentration‐dependently decreased the 0.1 nM Ang II‐induced vasoconstriction plateauing at 65% inhibition above 5 nM antagonist.
Similar to PD‐123319, during NO blockade the AT2‐R antagonist CGP‐42112A at 5 nM decreased by 50% the 0.1 nM Ang II‐induced vasoconstriction and at 500 nM had no effect on 10 nM Ang II‐induced vasoconstriction.
In conclusion, the renal Ang II‐induced vasoconstriction, which is antagonized only by AT1‐R antagonist in the presence of endogenous NO, becomes sensitive to both AT1‐ and AT2‐R antagonists during NO synthesis inhibition. While AT1‐R antagonist inhibited both L‐NAME‐potentiated and‐augmented components of Ang II‐induced vasoconstriction, AT2‐R antagonists inhibited only the L‐NAME‐potentiated component.
Pharmacological evidence for α1D‐adrenoceptors in the rabbit ventricular myocardium: analysis with BMY 7378
Authors: Yang Huang‐Tian , Endoh Masao 
Published: January 2005

It was examined by means of BMY 7378, a selective antagonist of α1D‐adrenoceptors, whether α1D‐adrenoceptors contribute to the regulation of myocardial contractility and hydrolysis of phosphoinositide (PI) in rabbit ventricular muscle.
BMY 7378 had a biphasic antagonistic action on the positive inotropic effect (PIE) of phenylephrine depending on the concentration. BMY 7378 at 1–10 nm shifted the concentration–response curve (CRC) for the PIE of phenylephrine to the right and downward and at 100 nm to 1 μm it antagonized the PIE in a competitive manner, the slope of Schild plot being 0.93 and the pA2 being 7.17±0.09.
The inhibitory action of BMY 7378 at 1–10 nm is ascribed to the selective action on α1‐adrenoceptors because the PIE of neither isoprenaline nor endothelin‐3 and angiotensin II was affected by this compound over this concentration range.
In the presence of 100 nm WB 4101, the antagonistic action of BMY 7378 at 1–10 nm remained unchanged but the antagonistic action of BMY 7378 at 100–300 nm disappeared. The antagonistic action of BMY 7378 at 1 nm was unaffected by 100 nm (+)‐niguldipine.
Following pretreatment with chloroethylclonidine, BMY 7378 at 1 nm inhibited the maximal response to phenylephrine but the pD2 value for phenylephrine was increased in the presence of BMY 7378. The CRC for phenylephrine was shifted to the left in the presence of 10–100 nm BMY 7378 but it was shifted to the right by BMY 7378 at 300 nm.
Stimulation of PI hydrolysis induced by phenylephrine was not affected by BMY 7378 up to 10 nm but it was reduced significantly by BMY 7378 at higher concentrations (100 nm to 1 μm).
BMY 7378 inhibited the [3H]prazosin specific binding to the rabbit ventricular membrane fraction in a monophasic manner with a pKi value of 7.53±0.09.
The results indicate that in rabbit ventricular muscle, BMY 7378 at 1–10 nm suppressed the maximal response to phenylephrine (probably mediated by α1D‐adrenoceptors) and at 10–100 nm it inhibited the negative inotropic effect of phenylephrine, the mechanisms of which remain to be characterized. At higher concentrations (100 nm to 1 μm) BMY 7378 antagonized the functional and biochemical response via a presumed interaction mainly with the α1B‐adrenoceptor and partially with the α1A‐adrenoceptor.
Dobesilate enhances endothelial nitric oxide synthase‐activity in macro‐ and microvascular endothelial cells
Authors: Suschek Christoph , Kolb Hubert , Kolb‐Bachofen Victoria 
Published: January 2005

Dobesilate is used for normalizing vascular dysfunction in a number of diseases. In search for an effect on endothelial NO production, macrovascular endothelial cells from rat aorta, microvascular endothelial cells from rat exocrine pancreatic tissue, and capillary endothelial cells from rat islets, were cultured in the presence or absence of Mg‐Dobesilate. The activity of constitutive nitric oxide synthase (ecNOS) in resident cells as well as of inducible nitric oxide synthase (iNOS) in cytokine‐activated cells was measured indirectly by recording the citrulline concentrations in culture supernatants.
In each of the different endothelial cells Mg‐Dobesilate incubation (0.25–1 mM) for 24 h led to a significant and concentration‐dependent increase in ecNOS‐activities. With cytokine‐activated endothelial cell cultures only moderate effects were seen with little or no concentration‐dependency. Addition of the NOS‐inhibitor NG‐monomethyl‐L‐arginine led to a significant suppression of citrulline formation in all cultures as an evidence for the enzyme specificity of these effects.
iNOS‐ and ecNOS‐specific reverse transcription and semi‐quantitative polymerase chain reaction (RT–PCR) with RNA from resident or cytokine‐activated endothelial cells gave no evidence for an increase in NOS‐specific mRNA after Mg‐Dobesilate‐treatment. Furthermore, Dobesilate‐mediated enhancement of NO synthesis in resting endothelial cells was not due to iNOS induction in these cells, as no iNOS‐specific signal was found by RT–PCR.
The influence of 5‐HT2and 5‐HT4receptor antagonists to modify drug induced disinhibitory effects in the mouse light/dark test
Authors: Costall Brenda , Naylor Robert J. 
Published: January 2005

The ability of 5‐HT2and 5‐HT4receptor antagonists to modify the disinhibitory profile of diazepam and other agents was investigated in male BKW mice in the light/dark test box.The 5‐HT2A/2B/2Creceptor antagonists ritanserin, MDL11939 and RP62203 and also methysergide, which failed to modify mouse behaviour when administered alone, caused dose‐related enhancements (4 to 8 fold) in the potency of diazepam to disinhibit behavioural responding to the aversive situation of the test box.Ritanserin was shown to enhance the disinhibitory potency of other benzodiazepines, chlordiazepoxide (4 fold), temazepam (10 fold) and lorazepam (10 fold), the 5‐HT1Areceptor ligands, 8‐OH‐DPAT (25 fold), buspirone (100 fold) and lesopitron (500 fold), the 5‐HT3receptor antagonists, ondansetron (100 fold)R(+)‐zacopride (100 fold) andS(−)‐zacopride (greater than a 1000 fold), the substituted benzamides, sulpiride (10 fold) and tiapride (5 to 10 fold) and the cholecystokinin (CCK)Areceptor antagonist, devazepide (100 fold). It also reduced the onset of action of disinhibition following treatment with the 5‐HT synthesis inhibitor parachlorophenylalanine. Ritanserin failed to enhance the disinhibitory effects of the CCKBreceptor antagonist CI‐988, the angiotensin AT1receptor antagonist losarten or the angiotensin converting enzyme inhibitor ceranapril.The 5‐HT4receptor antagonists SDZ205‐557, GR113808 and SB204070 caused dose‐related reductions in the disinhibitory effect of diazepam, returning values to those shown in vehicle treated controls. The antagonists failed to modify mouse behaviour when administered alone.GR113808 was also shown to cause a dose‐related antagonism of the disinhibitory effects of chlordiazepoxide, lorazepam, 8‐OH‐DPAT, buspirone, lesopitron, ondansetron,R(+)‐zacopride, sulpiride, tiapride, devazepide, CI‐988, losarten, ceranapril and parachlorophenylalanine.It was concluded that in BKW mice (a) the failure of 5‐HT2and 5‐HT4receptor antagonists when administered alone to modify behaviour in the light/dark test indicates an absence of an endogenous 5‐HT tone at the 5‐HT2and 5‐HT4receptors and (b) the enhancement by the 5‐HT2receptor antagonists and attenuation by the 5‐HT4receptor antagonists of drug‐induced disinhibition indicates a plurality of 5‐HT receptor involvement in the mediation of drug‐induced disinhibitory profiles in the mouse.British Journal of Pharmacology(1997)122, 1105–1118; doi:10.1038/sj.bjp.0701513
Evidence of an important and direct role for protein kinase C in agonist‐induced phosphorylation leading to desensitization of the angiotensin AT1A receptor
Authors: Balmforth A. J. , Shepherd F. H. , Warburton P. , Ball S. G. 
Published: January 2005

The role of protein kinase C (PKC) in the mechanism underlying rapid agonist‐induced desensitization of angiotensin AT1 receptors remains unresolved. A major problem has been to isolate these receptors in a sufficiently purified form to allow study of their phosphorylation state.
A cleavable (His)6 affinity tag was introduced into the N‐terminus of the recombinant AT1A receptor and stably expressed in human embryonic kidney cells. This affinity tag allowed rapid isolation, purification and determination of the phosphorylation state of the AT1A receptor. Using these cells, we determined the role of PKC in both agonist‐induced receptor phosphorylation and desensitization under identical conditions.
Agonist‐induced phosphorylation of the AT1A receptor was observed at both low and high concentrations of angiotensin II (AII). Preincubation of cells with Ro‐31‐8220 (a PKC specific inhibitor) revealed that at low concentrations of AII (1 nM), PKC appeared to be the main kinase involved in receptor phosphorylation. In contrast, at high concentrations of AII (100 nM), although PKC‐mediated phosphorylation of the receptor was observed, this was overshadowed by a second kinase.
In preliminary desensitization studies we observed that at a low concentration of AII, preincubation with Ro‐31‐8220 attenuated desensitization, whilst at high concentrations of AII (100 nM) it had little or no effect on the level of desensitization observed.
These data directly demonstrate an association between PKC‐induced receptor phosphorylation and desensitization at low concentrations of AII. Since circulating concentrations of AII are in the picomolar range, we propose that PKC is the physiologically relevant mediator of AT1 receptor desensitization.
Inhibitory effects of genistein on ATP‐sensitive K+ channels in rabbit portal vein smooth muscle
Authors: Ogata Rika , Kitamura Kenji , Ito Yushi , Nakano Hitoo 
Published: January 2005

Effects on the pinacidil‐induced outward current of inhibitors of tyrosine kinases and phosphatases were investigated by use of a patch‐clamp method in smooth muscle cells of the rabbit portal vein.
A specific tyrosine kinase inhibitor, genistein, inhibited the pinacidil‐induced current in a concentration‐dependent manner with an IC50 of 5.5 μM. Superfusion of Ca2+‐free solution did not affect this inhibitory effect of genistein. At higher concentrations, genistein inhibited the voltage‐dependent Ba2+ and K+ currents with IC50 values of >100 μM and 75 μM respectively. Tyrphostin B46 (30 μM), a tyrosine kinase inhibitor, also inhibited the pinacidil‐induced current by 70 % of the control.
Sodium orthovanadate (100 μM), an inhibitor of tyrosine phosphatase, slightly but significantly enhanced both the pinacidil‐induced and delayed rectifier K+ currents. Daidzein (100 μM), an inactive analogue of genistein, did not inhibit these currents.
Neither herbimycin A (1 μM), lavendustin A (30 μM), tyrphostin 23 (10 μM), which are also tyrosine kinase inhibitors, nor wortmannin (10 μM), a phosphatidylinositol 3‐kinase inhibitor, had an effect on either the pinacidil‐induced or delayed rectifier K+ currents. Epidermal growth factor (EGF; 1 μg ml−1) did not induce an outward current or enhance the pinacidil‐induced current.
Pinacidil alone, in the cell‐attached configuration, or pinacidil with GDP, in the inside‐out configuration, activated a 42 pS channel in the smooth muscle cells of the rabbit portal vein. Genistein (30 μM) reduced the channel's open probability without inducing a change in unitary conductance at any holding potential (−30 to +20 mV).
In the inside‐out configuration, genistein at 30 μM did not change the mean channel open time, but reduced the burst duration. At 100 μM genistein abolished channel opening. The inhibitory potencies with which 30 and 100 μM genistein acted on the unitary current of the ATP‐sensitive K+ channel were similar to those seen in the whole‐cell voltage‐clamp configuration.
Although direct inhibitory actions of genistein on the ATP‐sensitive K+ channels are not ruled out, our results suggest that a protein tyrosine kinase may play a role in the regulation of ATP‐sensitive K+ channel activity in the rabbit portal vein.
Effects of a nonpeptide bradykinin B2 receptor antagonist, FR167344, on different in vivo animal models of inflammation
Authors: Asano Masayuki , Hatori Chie , Inamura Noriaki , Sawai Hiroe , Hirosumi Jiro , Fujiwara Tatsujiro , Nakahara Kunio 
Published: January 2005

The effects of a novel, potent and orally active nonpeptide bradykinin B2 receptor antagonist, FR167344 (N ‐[N ‐[3 ‐[(3 ‐ bromo‐ 2 ‐methylimidazo[1,2‐a]pyridin‐8‐yl)oxymethyl]‐2,4‐dichlorophenyl]‐N‐methylaminocarbonylmethyl]‐4‐(dimethylaminocarbonyl) cinnamylamide hydrochloride) were tested in three different in vivo models of inflammation.
Oral administration of FR167344 inhibited carrageenin‐induced paw oedema in rats (carrageenin: 1%, 0.1 ml per animal, intraplantar), with an ID50 of 2.7 mg kg−1 at 2 h after carrageenin injection (n=10 or 11).
Oral administration of the compound also inhibited kaolin‐induced writhing (kaolin: 250 mg kg−1, i.p.) in mice, with ID50 of 2.8 mg kg−1 in 10 min writhing and 4.2 mg kg−1 in 15 min writhing (n=19 or 20).
Additionally, oral administration of FR167344 inhibited caerulein‐induced pancreatic oedema with an ID50 of 13.8 mg kg−1 as well as increases in amylase and lipase of blood samples with ID50 of 10.3 and 7.4 mg kg−1, respectively, in rats (n=10).
These results show that FR167344 is an orally active, anti‐inflammatory and anti‐nociceptive agent in carrageenin‐induced paw oedema, kaolin‐induced writhing and caerulein‐induced pancreatitis. FR167344 may have therapeutic potential against inflammatory diseases by oral administration and it may be a useful tool for studying the involvement of B2 receptors in various in vivo models of inflammation.
Activation of soluble guanylyl cyclase by YC‐1 in aortic smooth muscle but not in ventricular myocardium from rat
Authors: Wegener Jörg W. , Gath Ingolf , Förstermann Ulrich , Nawrath Hermann 
Published: January 2005

The effects of YC‐1 (3‐(5′‐hydroxymethyl‐2′‐furyl)‐1‐benzyl indazole), an activator of soluble guanylyl cyclase, on tension, levels of cyclic GMP and cyclic AMP, and cardiac L‐type Ca2+‐current (ICa(L)) were investigated in aortic smooth muscle and ventricular heart muscle from rat.
YC‐1 (0.1–30 μM) induced a concentration‐dependent relaxation in aortic rings precontracted with phenylephrine (3 μM). The relaxant effects of YC‐1 were reversed by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (30 μM; ODQ), potentiated by zaprinast (10 μM) and antagonized by Rp‐8‐Br‐cGMPS (100 μM).
In ventricular heart muscle strips, YC‐1 (30 μM) exhibited no effects on force of contraction (Fc) in the absence or presence of either zaprinast (10 μM) or 3‐isobutyl‐1‐methylxanthine (30 μM). Fc was slightly increased by YC‐1 (30 μM) in the presence of isoprenaline (100 nM), but this effect was not influenced by ODQ (30 μM).
Cardiac ICa(L) was not significantly affected by YC‐1 (30 μM), either in the absence or presence of isoprenaline (30 nM).
In aortic rings, cyclic GMP levels were increased almost 3 fold by YC‐1 (30 μM); this effect was abolished by ODQ (30 μM). In isolated ventricular cardiomyocytes, cyclic GMP levels were not affected by YC‐1 (30 μM) but almost doubled by activation of particular guanylyl cyclase with atriopeptin II (100 nM).
YC‐1 (30 μM) did not increase cyclic AMP levels either in aortic rings or in ventricular cardiomyocytes. In contrast, isoprenaline (3 μM) increased cyclic AMP levels about two fold in both tissues. In cardiomyocytes, the effect of isoprenaline (3 μM) was slightly enhanced by YC‐1 (30 μM).
It is concluded that relaxation of smooth muscle preparations by YC‐1 is mediated mainly by activation of soluble guanylyl cyclase and subsequent increase in cyclic GMP levels. The failure of YC‐1 to affect cardiac Fc, levels of cyclic GMP, and ICa(L) suggests that soluble guanylyl cyclase is not influenced by YC‐1 in rat heart muscle or only barely present in this tissue.
Effect of fluoxetine on a neuronal, voltage‐dependent potassium channel (Kv1.1)
Authors: Tytgat J. , Maertens Ch , Daenens P. 
Published: January 2005

Fluoxetine (Prozac) is widely used as an antidepressant drug and is assumed to be a selective 5‐hydroxytryptamine (5‐HT) reuptake inhibitor (SSRI). Claims that its beneficial psychotropic effects extend beyond those in treatment of depression have drawn clinical and popular attention to this compound, raising the question of whether there is anything exceptional about the supposed selective actions.
We have used the voltage clamp technique to study the effect of fluoxetine on a neuronal, voltage‐dependent potassium (K+) channel (RCK1; Kv1.1), expressed in Xenopus laevis oocytes. This channel subunit is abundantly expressed in the central nervous system and K+ channels containing this subunit are involved in the repolarization process of many types of neurones.
Blockade of the K+ currents by fluoxetine was found to be use‐ and dose‐dependent. Wash‐out of this compound could not be achieved. Fluoxetine did not affect the ion selectivity of this K+ channel, as the reversal potential was unaltered.
Slowing of both activation and deactivation kinetics of the channel by fluoxetine was observed, including tail current crossover upon repolarization.
Hodgkin‐Huxley type of models and more generalized Markov chain models were used to fit the kinetics of the data. Based upon a Markov kinetic scheme, our data can be interpreted to mean that blockade of fluoxetine consists of two components: a voltage‐independent occurring in the last closed, but available state of the channel, and a voltage‐dependent occurring in the open state.
This study describes the first biophysical working model for the mechanism of action of fluoxetine on a neuronal, voltage‐dependent K+ channel, RCK1. Although this channel is not very potently blocked by fluoxetine when expressed in oocytes, this study may help us to understand some of the clinical symptoms seen with elevated serum concentrations of this SSRI.
Comparative effects of the dual metallopeptidase inhibitor, MDL 100,240 and of enalaprilat on regional and on cardiac haemodynamics in conscious, hypertensive, transgenic ((mRen‐2)27) rats
Authors: Gardiner S M. , Kemp P A. , Brunner‐Ferber F. , Bennett T. 
Published: January 2005

Heterozygous, male, hypertensive, transgenic ((mRen‐2)27) rats (350–450 g) were instrumented for the measurement of regional or cardiac haemodynamics (n = 16, in both groups). Animals were given continuous i.v. infusions of the angiotensin‐converting enzyme inhibitor, enalaprilat, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg−1, 3 mg kg−1 h−1; n = 8 for regional and cardiac haemodynamics), for 32 h. Twenty four hours after the onset of infusion of enalaprilat or MDL 100,240, the bradykinin (B2)‐receptor antagonist, Hoe 140 (1 mg kg−1, i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin.
Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had significant antihypertensive effects, accompanied by similar regional vasodilatations. However, the blood pressure lowering effect of MDL 100,240 (−54 ± 9 mmHg) was greater than that of enalaprilat (−38 ± 4 mmHg), because the former caused a significantly greater reduction in cardiac index.
Between 8–24 h after the onset of infusion, there was a reduction in the effect of enalaprilat on blood pressure, because cardiac index rose, with no further increase in total peripheral conductance. In contrast, the antihypertensive effect of MDL 100,240 persisted, in spite of a recovery in cardiac index, because there was further vasodilatation, particularly in the mesenteric and hindquarters vascular beds.
There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference between the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either drug.
These results are more consistent with the antihypertensive effects of enalaprilat or MDL 100,240 in transgenic ((mRen‐2)27) rats being due to suppression of angiotensin II production, than due to inhibition of bradykinin degradation. The additional effects of MDL 100,240 may be accounted for by inhibition of the degradation of natriuretic peptides reducing cardiac output, initially, and decreasing vascular tone, subsequently. Alternatively, the additional increase in vascular conductance following treatment with MDL 100,240 may represent an autoregulatory response to the reduced pressure.