bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancement of arterial relaxation by long‐term atenolol treatment in spontaneously hypertensive rats
Authors: Kähönen Mika , Mäkynen Heikki , Arvola Pertti , Pörsti Ilkka 
Published: July 2012

The effects of long‐term atenolol (25 mg kg−1 day−1) therapy on arterial function were studied in spontaneously hypertensive rats (SHR) and Wistar‐Kyoto (WKY) rats. The 14‐week treatment attenuated the increase in blood pressure by approximately 30 mmHg in SHR, but did not affect blood pressure in WKY rats.
Responses of mesenteric arterial rings in vitro were examined at the end of the study. The relaxation to acetylcholine was similar in WKY rats and atenolol‐treated SHR and more pronounced than in untreated SHR, whereas the relaxation to the nitric oxide donor 3‐morpholinosydnonimine (SIN‐1) was comparable in all study groups. Moreover, after maximal relaxations to acetylcholine, marked recontractions developed in untreated SHR but not in the other groups. Vasorelaxation to isoprenaline was also attenuated in SHR and was moderately improved by the atenolol therapy.
Arterial relaxation induced by return of potassium to the organ bath upon precontractions elicited by potassium‐free solution were used to evaluate vascular smooth muscle Na+,K+‐ATPase. The rate of potassium relaxation was fastest in WKY rats and was also faster in atenolol‐treated than in untreated SHR.
The ability of vascular smooth muscle to sequester calcium was evaluated by eliciting responses to caffeine or noradrenaline after loading periods in different organ bath calcium concentrations. The subsequent contractions were lower in untreated SHR than in WKY rats, and augmented in SHR by the atenolol treatment.
Smooth muscle contractions to noradrenaline were comparable in SHR and WKY rats, while atenolol treatment slightly increased the maximal response to this agonist in SHR. Responses to potassium chloride were not affected by atenolol and contractions following cumulative re‐addition of calcium to the organ bath after precontraction with potassium chloride and noradrenaline in calcium‐free solution were comparable in all study groups.
In conclusion, the moderate antihypertensive effect of atenolol in SHR was accompanied by enhancement of β‐adrenoceptor‐mediated and normalization of endothelium‐dependent arterial relaxation. Furthermore, ability to sequester calcium into cellular stores, and function of Na+,K+‐ATPase were augmented in vascular smooth muscle. Therefore, the present results suggest that the long‐term blood pressure‐lowering action of atenolol in this type of genetic hypertension is accompanied by improved arterial relaxation and normalization of endothelial function.
Mediation by 5‐HT1D receptors of 5‐hydroxytryptamine‐induced contractions of rabbit middle and posterior cerebral arteries
Authors: Deckert Valérie , Pruneau Didier , Elghozi Jean‐Luc 
Published: July 2012

5‐Hydroxytryptamine (5‐HT) receptor‐mediated contraction of endothelium denuded rabbit middle (MCA) and posterior (PCA) cerebral arteries was characterized by use of selective agonists and antagonists for different 5‐HT receptor subtypes.
5‐HT and various 5‐HT receptor agonists contracted the arteries with the following rank order of potency in MCA: 5‐carboxamidotryptamine (5‐CT) > 5‐HT > 5‐methoxytryptamine (5‐MeOT) > sumatriptan > α‐methyl‐5‐HT (α‐Me‐5‐HT) >> 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and in PCA: 5‐CT > 5‐HT >sumatriptan > 5‐MeOT > α‐Me‐5‐HT >> 8‐OH‐DPAT. With few exceptions, the maximal contractile responses of these agonists were similar to that induced by 5‐HT.
The selective antagonists of 5‐HT2A/2C (ketanserin), 5‐HT4 (SDZ 205–557) and 5‐HT1A/1B (S‐(−)‐propranolol) sites were devoid of inhibitory effect on 5‐HT‐mediated contraction in both MCA and PCA, thus excluding activation of the corresponding receptors.
In both arteries, the contraction‐response curve to 5‐HT was unaffected by the 5‐HT3 receptor antagonist, ICS 205–930 (0.01 and 0.1 μm) whilst a small (3 and 6 fold displacement) was seen with MDL 72222 (0.1 and 1 μm).
The mixed 5‐HT1‐like/5‐HT2A receptor antagonist, methiothepin (0.001–0.1 μm), was a potent antagonist of 5‐HT‐induced contractions in both arteries, giving pA2 values of 9.4 ± 0.7 and 9.6 ± 0.8 in MCA and PCA, respectively.
Rauwolscine (0.1–10 μm) and yohimbine (0.3, 3 μm) inhibited contractions to 5‐HT in a competitive manner, pA2 values of 7.1 ± 0.6 and 6.7 ± 0.6 were determined for rauwolscine in MCA and PCA, respectively. An apparent pA2 value of 6.9 ± 0.2 was calculated for yohimbine (3 μm) in both MCA and PCA.
In conclusion, these results suggest that the contractile response to 5‐HT in rabbit isolated MCA and PCA is predominantly mediated by the 5‐HT1D receptor subtype, although a small contribution by 5‐HT3 receptors cannot be excluded.
Potentiation by adenosine of ATP‐evoked dopamine release via a pertussis toxin‐sensitive mechanism in rat phaeochromocytoma PC12 cells
Authors: Koizumi Schuichi , Watano Tomokazu , Nakazawa Ken , Inoue Kazuhide 
Published: July 2012

The effects of adenosine on adenosine 5′‐triphosphate (ATP)‐evoked dopamine release from rat phaeochromocytoma PC12 cells was investigated to determine whether adenosine exerts a regulatory effect on the ATP‐evoked response. Adenosine potentiated ATP (30 μm)‐evoked dopamine release in a concentration‐dependent manner over a concentration‐range of 1 to 100 μm. Adenosine (100 μm) shifted the concentration‐dependence of the ATP‐evoked response to the left without affecting the maximal response.
Aminophylline, a non‐selective adenosine receptor antagonist, and CP66713, a selective antagonist at the A2 subclass of adenosine receptors, abolished the adenosine‐induced potentiation. Furthermore, 8‐cyclopentyltheophylline, a selective antagonist at the adenosine A1 receptor partially inhibited the adenosine‐evoked potentiation. CGS22492, a selective A2 receptor agonist, potentiated ATP‐evoked dopamine release whereas N6‐cyclohexyladenosine (CHA), a selective A1 receptor agonist, had no effect.
Pertussis toxin (PTX), a bacterial exotoxin which catalyzes the ADP‐ribosylation of guanosine 5′‐triphosphate (GTP)‐binding proteins (G‐proteins), inhibited the adenosine‐induced potentiation of dopamine release. Dibutyryl cyclic AMP (db cyclic AMP), an analogue of cyclic AMP, had no effect on the release on the ATP‐evoked response.
Adenosine potentiated the ATP‐evoked rise in intracellular Ca2+ concentration ([Ca]i) in PC12 cells. This potentiation was also observed with CGS 22492 but not with CHA. PTX completely inhibited the adenosine‐induced potentiation of the rise in [Ca]i.
On the basis of these findings, we suggest that the adenosine‐induced potentiation of ATP‐evoked dopamine release was due to an increase in [Ca]i in the cells. Although the potentiation is most likely mediated by a subclass of A2 receptors, the subclass may be different from those previously reported since the potentiation was sensitive to PTX and was not reproduced by db cyclic AMP.
Reduced endothelium‐dependent relaxation at enhanced NO release in hearts of hypercholesterolaemic rabbits
Authors: Woditsch Isabelle , Schrör Karsten 
Published: July 2012

Langendorff hearts, perfused at constant volume, were prepared from rabbits fed a cholesterol‐enriched diet for 4 months. Coronary perfusion pressure and nitric oxide (NO) release (oxyhaemoglobin technique) into the coronary effluent were measured continuously. Prostacyclin (PGI2) in the effluents was determined by radioimmunoassay (6‐oxo‐PGF1α).
Basal NO release was not different between control and hypercholesterolaemic rabbits. However, the coronary vasculature of hypercholesterolaemic rabbits showed a considerably (> 50%) reduced endothelium‐dependent relaxation in response to short‐term (3 min) infusion of bradykinin (50 nm) and substance P (50 nm) (P<0.05, n = 8–9). Under these conditions, NO release into the vessel lumen was increased, by 26%, in hypercholesterolaemic hearts (P<0.05, n = 8–9). NG‐nitro‐l‐arginine (l‐NOARG, 30 μm) significantly attenuated both bradykinin‐induced NO formation and vessel relaxation in control hearts but only NO release in hypercholesterolaemia. l‐Arginine (200 μm) restored the response to that before l‐NOARG but did not improve the reduced endothelium‐dependent relaxation in cholesterol‐fed rabbits.
Superoxide dismutase (10 u ml−1) significantly improved vessel relaxation without changing the hypercholesterolaemia‐related coronary dysfunction. Vasodilatation in response to exogenous NO donors (linsidomine) was diminished in hypercholesterolaemia as compared to controls.
Basal PGI2 release was unchanged in hypercholesterolaemic hearts. There was a tendency in these hearts for greater PGI2 formation after stimulation by substance P and bradykinin (P ≥ 0.05). The coronary relaxation to iloprost was unchanged.
The data demonstrate impaired endothelium‐dependent relaxation of coronary arterial resistance vessels in hypercholesterolaemia. This diminished vascular response was not due to reduced NO generation but probably a reduced action of released NO, either by accelerated degradation and/or disturbed signal transduction pathways to vascular smooth muscle cells. There was no significant change in PGI2 related pathways of vasomotor control in hypercholesterolaemia.
A nucleotide receptor that mobilizes Ca2+in the mouse submandibular salivary cell line ST885
Authors: Gibb C.A. , Singh S. , Cook D.I. , Poronnik P. , Conigrave A.D. 
Published: July 2012

We have identified a Ca2+‐mobilizing receptor that responds to extracellular ATP (0.1–1000 μm) in a salivary epithelial cell line (ST885). The activated receptor also stimulates Ca2+entry from the extracellular fluid.
The receptor shows an agonist selectivity profile consistent with the behaviour of the nucleotide receptor class. In particular, the pyrimidine nucleotide, UTP, was equipotent with ATP.
Analysis of concentration‐response data for the ATP and UTP‐activated receptor using the Hill equation yielded EC50 values (concentrations of agonist inducing a half‐maximal response) for ATP of 4.2 μm and for UTP of 4.6 μm.
ATP and UTP induced cross‐desensitization and were not additive when administered simultaneously at maximal concentration. These findings are consistent with the hypothesis that both nucleotides act upon a common receptor.
The ATP analogue, 2‐methylthio ATP, mobilized Ca2+ions with higher potency (EC50 = 0.23 μm) but lower efficacy than either ATP or UTP. However, 2‐methylthio ATP was not a partial agonist of the ATP/UTP receptor. At maximal concentration (30 μm), it failed to antagonize the effects of near maximal concentrations of ATP or UTP. We conclude that 2‐methylthio ATP acts upon a distinct receptor.
Bradykinin binding sites in healthy and carcinomatous human lung
Authors: Trifilieff Alexandre , Lach Estelle , Dumont Pascal , Gies Jean‐Pierre 
Published: July 2012

Direct ligand binding techniques have been used to compare bradykinin receptors in squamous‐ or adeno‐carcinoma and healthy lung membranes removed from patients during operations.
The binding of [3H]‐bradykinin to healthy lung membrane is time‐dependent and saturable with a KD value of 1.08 ± 0.18 nm and a Bmax value of 46.1 ± 3.1 fmol mg−1protein (n = 10). In squamous‐carcinoma tissue (n = 8) the same amount of receptors are present, Bmax = 52.2 ± 3.3 fmol mg−1protein (P = 0.22) but the KD value is significantly higher 2.57 ± 0.40 nm (P = 0.004). Similar measurements were obtained for adeno‐carcinoma tissue (n = 3), KD = 2.80 ± 0.29 mm (P = 0.001) and Bmax = 49.8 ± 2.1 fmol mg−1protein (P = 0.56).
In both healthy and squamous‐carcinoma preparations, bradykinin analogues displace [3H]‐bradykinin binding with the following relative order of potency: Hoe 140 > bradykinin > kallidin > d‐Arg0[Hyp3,d‐Phe7]bradykinin >>>des‐Arg9‐bradykinin. Of the analogues used, bradykinin and d‐Arg0[Hyp3,d‐Phe7]bradykinin appear to be able to differentiate the bradykinin receptors present in both preparations.
It is concluded that bradykinin receptors present in healthy and carcinomatous human lung are of the B2 type.
Photon pharmacology of an iron‐sulphur cluster nitrosyl compound acting on smooth muscle
Authors: Matthews E.K. , Seaton E.D. , Forsyth M.J. , Humphrey P.P.A. 
Published: July 2012

The mechanisms of action on smooth muscle of the iron‐sulphur cluster nitrosyl compound, heptanitrosyl‐tri‐μ3‐thioxotetraferrate (1‐), (RBS), a photosensitive nitric oxide donor, have been investigated in the guinea‐pig taenia caeci (coli) in vitro.
After exposure to RBS (50 μm) for 30 min, and subsequent washout, a sustained contraction was recorded in the absence of light to either the agonist carbachol (50 μm) or a depolarizing concentration of KC1 (23.5 mm). Photon irradiation (>400 nm) caused a prompt relaxation of precontracted RBS‐treated muscle, the magnitude of which depended upon the intensity (1.1 × 103 to 1.1 × 105 lux), duration (30 s to 20 min) and wavelength (400 to 800 nm), of the incident illumination.
Repeated periods of illumination at 1.1 × 104 lux produced a reversible relaxation of both carbachol and KC1‐evoked tone in muscle pretreated with RBS (50 μm). These photorelaxations were reproducible at 10 min intervals for several hours with a maximal relaxation amounting to 80 to 90% that of the tone produced by carbachol (50 μm).
The nitric oxide synthase inhibitor, NG‐nitro‐l‐arginine (60 μm), caused no inhibition of the photon‐induced relaxation of RBS‐treated muscle. In contrast, N‐methylhydroxylamine (2 mm), l‐cysteine (10 mm), dl‐dithiothreitol (2 mm), methylene blue (30 μm), and haemoglobin (20 μm), all reversibly but significantly inhibited (P < 0.001) the photorelaxation response. However, neither the aminothiol N‐acetyl‐l‐cysteine (10 mm) nor the tripeptide glutathione (10 mm) blocked the RBS‐induced photorelaxation.
The photolytic cleavage of RBS depended on the intensity and duration of illumination; it was accompanied by a corresponding decrease in absorbance and by the liberation of NO as measured by the Griess diazo reaction with sulphanilic acid. l‐Cysteine (10 mm) prevented the decrease in absorbance and the photolytic liberation of NO.
It is concluded that (i) sequestered or bound RBS, when photon‐activated, liberates NO by a process which can be controlled by the wavelength, intensity and duration of the incident light, (ii) the photon‐released NO rapidly relaxes the smooth muscle cells of the taenia coli primarily via cyclic GMP‐dependent pathways which can be blocked by use of appropriate inhibitors, and (iii) the RBS‐induced photorelaxation effect does not involve the activation of NO synthase. RBS is therefore a valuable photosensitive NO donor for establishing the functional and pharmacological significance of NO.
Anti‐ischaemic efficacy of a nitric oxide synthase inhibitor and a N‐methyl‐d‐aspartate receptor antagonist in models of transient and permanent focal cerebral ischaemia
Authors: Dawson D.A. , Graham D.I. , McCulloch J. , Macrae I.M. 
Published: July 2012

We have recently developed a new model of transient focal ischaemia in the rat utilising topical application of endothelin‐1 to the left middle cerebral artery (MCA). In order to validate this approach the present study assessed the neuroprotective efficacy of the NMDA receptor antagonist dizocilpine (MK‐801) in the endothelin‐1 model. The anti‐ischaemic efficacy of the nitric oxide (NO) synthase inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME) was subsequently evaluated, and contrasted with its efficacy against permanent focal ischaemia, to determine the utility of the endothelin‐1 model for identification of novel pharmacoprotective agents.
MK‐801 (0.12 mg kg−1 bolus, 108 μg kg−1 h−1 infusion i.v., either 1 or 2.5 h pre‐transient MCA occlusion (MCAO)) induced hypotension that persisted for approximately 1.5 h so that mean arterial blood pressure (MABP) at the time of MCAO was significantly lower in the 1 h group compared with control (MABP: 86 ± 11, 68 ± 6 and 84 ± 4 mmHg (mean ± s.d.) for saline, 1h MK‐801 and 2.5 h MK‐801 groups respectively). The 2.5 h pretreatment schedule resulted in significant reduction (71%) in the volume of hemispheric damage (assessed 4 h post onset of ischaemia) while the 1 h pretreatment schedule did not (volumes of hemispheric damage: 59 ± 38, 51 ± 51 and 17 ± 28 mm3 for saline, 1 h and 2.5 h MK‐801 groups).
Thus the considerable neuroprotective effect of MK‐801 in the endothelin‐1 model of transient focal cerebral ischaemia was highly sensitive to drug‐induced hypotension. This result is in contrast to previous studies of permanent MCAO where MK‐801‐induced hypotension did not compromise its neuroprotective action.
l‐NAME (3 mg kg−1, i.v. 30 min pre‐MCAO) moderately, but significantly, reduced (16%) the volume of ischaemic damage 4 h post‐permanent MCA occlusion, whereas the 29% reduction in volume of damage achieved in the model of transient focal ischaemia did not attain significance due to the greater variability associated with this model. l‐NAME did not significantly alter MABP in either model.
The modest neuroprotection achieved with NO synthase inhibition suggests NO is of relatively minor importance as a mediator of neurotoxicity following permanent focal cerebral ischaemia. In addition the comparable efficacy of l‐NAME against transient focal ischaemia suggests the presence of reperfusion does not enhance the contribution of NO to neuronal injury in the acute (4 h) phase following a focal ischaemic insult.
In vivo pharmacological characterization of the non‐peptide endothelin receptor antagonist SB 209670
Authors: Douglas Stephen A. , Edwards Richard M. , Elliott John D. , Ohlstein Eliot H. 
Published: July 2012

The aim of the present study was to assess the ability of SB 209670, a high affinity non‐peptide endothelin receptor antagonist (0.4 and 18 nm Kis at human cloned ETA and ETB receptors, respectively), to inhibit the haemodynamic actions of endothelin‐1 in vivo.
Systemic administration of (±)‐SB 209670, given either as a bolus i.v. injection or as a continuous i.v. infusion, did not alter basal haemodynamic parameters in the anaesthetized rat.
Infusion of (±)‐SB 209670 (10 μg kg−1 min−1) selectively inhibited the depressor and carotid vasodilator response to exogenous endothelin‐1: 100 μg kg−1 min−1 was required to inhibit significantly the biphasic haemodynamic actions of endothelin‐1. The haemodynamic actions of angiotensin II and calcitonin gene‐related peptide were unaltered by 100 μg kg−1 min−1 (±)‐SB 209670.
Bolus i.v. administration of (±)‐SB 209670 (1 mg kg−1) selectively inhibited the depressor and carotid vasodilator actions of endothelin‐1: 10 mg kg−1 (±)‐SB 209670 was required to inhibit the secondary vasoconstrictor actions of endothelin‐1.
(±)‐SB 209670 (10 mg kg−1) was also effective at antagonizing the pressor actions of endothelin‐1 in the conscious rat for up to 3 h after intraduodenal administration thereby demonstrating that the antagonist was bioavailable upon enteric administration. This dose of (±)‐SB 209670 did not alter basal haemodynamic parameters in the conscious rat.
Thus, (±)‐SB 209670 is an effective endothelin receptor antagonist in vivo. Using the doses defined in this study, SB 209670 may, therefore, serve as a useful tool for understanding the role of endogenous endothelin‐1 in the control of cardiovascular function under both physiological and pathophysiological conditions.
Pharmacological evidence that nitric oxide may be a retrograde messenger in the enteric nervous system
Authors: Yuan S.Y. , Bornstein J.C. , Furness J.B. 
Published: July 2012

The effects of inhibition of nitric oxide synthase on neuro‐neuronal and neuromuscular transmission during motility reflexes in the small intestine of the guinea‐pig were examined.
Isolated segments of intestine were secured in a three chambered organ bath so that different parts of the reflex pathways could be independently exposed to drug‐containing solutions. Reflexes were evoked by distension or compression of the mucosa in two adjacent chambers and reflex responses were recorded from the circular muscle with intracellular microelectrodes in the third chamber. Thus, the actions of drugs at connections between sensory neurones and interneurones, between interneurones and other interneurones and at motor neurones could be distinguished.
NG‐monomethyl‐l‐arginine (l‐NMMA; 100 μm), an inhibitor of nitric oxide synthase, did not affect the ascending excitatory reflex when added to either the central stimulation chamber or the recording chamber.
In contrast, l‐NMMA (100 μm) enhanced the descending inhibitory reflex when added to the chamber in which stimuli were applied. This effect was prevented by prior exposure to l‐arginine (100 μm), which had no effect by itself. Conduction of reflexes between the stimulus chamber and the recording chamber was unaffected by the presence of l‐NMMA in an intervening chamber.
l‐NMMA (100 μm) added to the recording chamber depressed the descending inhibitory reflex, an effect that was prevented by previous exposure to l‐arginine.
The nitric oxide donor, sodium nitroprusside (100 μm), added to the stimulus chamber, depressed both ascending excitatory and descending inhibitory reflexes. When added to the middle chamber, sodium nitroprusside had no effect on conduction of reflexes through this chamber.
It is deduced that nitric oxide, released from the cell bodies of descending interneurones, suppresses transmission from synaptic connections made with them by enteric sensory neurones.
Desensitization of the nicotine‐induced mesolimbic dopamine responses during constant infusion with nicotine
Authors: Benwell Maureen E.M. , Balfour David J.K. , Birrell Claire E. 
Published: July 2012

The effects of constant nicotine infusions (0.25, 1.0 and 4.0 mg kg−1 day−1) on extracellular dopamine levels in the nucleus accumbens (NAc) and on locomotor activity have been compared with the changes evoked by repeated daily injections (0.4 mg kg−1 day−1 for 5 days) of the drug.
The extracellular dopamine concentration in the NAc was significantly increased (P<0.05) following a challenge dose of nicotine (0.4 mg kg−1, s.c.) in animals which had been pretreated with daily injections of the drug. This effect was accompanied by an enhanced locomotor response to nicotine.
The stimulant effects of nicotine on mesolimbic dopamine secretion and on locomotor activity were significantly inhibited (P<0.01) by the prior administration of mecamylamine (2.0 mg kg−1, s.c.) but not by hexamethonium (2.0 mg kg−1, s.c).
The constant infusion of nicotine at a rate of 1 and 4 but not 0.25 mg kg−1 day−1 abolished the sensitized dopamine response in the NAc to an injection of nicotine in animals pretreated with the drug. The locomotor responses to nicotine in the nicotine‐pretreated rats were significantly attenuated by the infusion of nicotine at all 3 doses, although the nicotine induced locomotor activity, in the rats infused with 0.25 mg kg−1 day−1 was also significantly (P<0.05) higher than that observed in the rats treated acutely with nicotine.
Significantly (P<0.01) enhanced mesolimbic dopamine responses, to a challenge injection of nicotine (0.4 mg kg−1, s.c), were observed 2 and 7 days after termination of the infusion of nicotine (4 mg kg−1 day−1 for 14 days); locomotor responses were enhanced (P<0.01) 1, 2 and 7 days after termination of the infusion.
The results suggest that sensitized mesolimbic dopamine responses to nicotine occur as a result of stimulation of centrally located nicotinic receptors but that these receptors may be desensitized during periods of chronic exposure to nicotine at doses which may be relevant to smoking.