bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of shear stress in nitric oxide‐dependent modulation of renal angiotensin II vasoconstriction
Authors: Endlich Karlhans , Muller Catherine , Barthelmebs Mariette , Helwig Jean‐Jacques 
Published: January 2005

Renal vasoconstriction in response to angiotensin II (ANGII) is known to be modulated by nitric oxide (NO). Since shear stress stimulates the release of a variety of vasoactive compounds from endothelial cells, we studied the impact of shear stress on the haemodynamic effect of ANGII in isolated perfused kidneys of rats under control conditions and during NO synthase inhibition with L‐NAME (100 μM).
Kidneys were perfused in the presence of cyclo‐oxygenase inhibitor (10 μM indomethacin) with Tyrode's solution of relative viscosity ζ=1 (low viscosity perfusate, LVP) or, in order to augment shear stress, with Tyrode's solution containing 7% Ficoll 70 of relative viscosity ζ=2 (high viscosity perfusate, HVP).
Vascular conductance was 3.5±0.4 fold larger in HVP as compared with LVP kidneys, associated with an augmentation of overall wall shear stress by 37±5%. During NO inhibition, vascular conductance was only 2.5±0.2 fold elevated in HVP vs LVP kidneys, demonstrating shear stress‐induced vasodilatation by NO and non‐NO/non‐prostanoid compound(s).
ANGII (10–100 pM) constricted the vasculature in LVP kidneys, but was without effect in HVP kidneys. During NO inhibition, in contrast, ANGII vasoconstriction was potentiated in HVP as compared with LVP kidneys.
The potentiation of ANGII vasoconstriction during NO inhibition has been shown to be mediated by endothelium‐derived P450 metabolites and to be sensitive to AT2 receptor blockade in our earlier studies. Accordingly, in HVP kidneys, increasing concentrations of the AT2 receptor antagonist PD123319 (5 and 500 nM) gradually abolished the potentiation of ANGII vasoconstriction during NO inhibition, but did not affect vasoconstriction in response to ANGII in LVP kidneys.
Our results demonstrate, that augmentation of shear stress by increasing perfusate viscosity induces vasodilatation in the rat kidney, which is partially mediated by NO. Elevated levels of shear stress attenuate renal ANGII vasoconstriction through enhanced NO production and are required for AT2 sensitive potentiation during NO inhibition.

British Journal of Pharmacology (1999) 127, 1929–1935; doi:10.1038/sj.bjp.0702739
Electroencephalographic effects of thiopentone and its enantiomers in the rat: correlation with drug tissue distribution
Authors: Mather Laurence E , Edwards Stephen R , Duke Colin C 
Published: January 2005

To better understand the pharmacology of the thiopentone enantiomers, we studied their quantitative electroencephalographic effects and their distribution into vital tissues.
Adult Wistar rats were infused with rac‐, R‐ or S‐thiopentone at 4 mg kg−1min−1 until death ensued. The EEG signal was acquired continuously; serial arterial plasma and terminal tissue thiopentone concentrations were measured enantiospecifically. Relevant drug tissue : plasma distribution coefficients and plasma concentration‐EEG effect relationships were determined.
Doses (mg kg−1) (mean±s.e.mean) for anaesthesia (toe pinch) and lethality (respiratory failure), respectively, decreased in the order R‐thiopentone (55.8±2.4 and 176.2±11.2)> rac‐thiopentone (39.3±2.1 and 97.5±3.9)> S‐thiopentone (35.6±1.9 and 74.2±5.2); plasma drug concentrations (μg ml−1) decreased in the order R‐thiopentone (66.3±4.5 and 89.8±5.2)> rac‐thiopentone (56.7±2.0 and 77.8±2.8)> S‐thiopentone (55.0±1.9 and 64.1±2.8).
Initial EEG activation was similar for all thiopentone forms. Plasma drug concentrations for the same extent of EEG deactivation reflected the potency order.
After infusion of rac‐thiopentone, tissue : plasma distribution coefficients were higher for R‐ than for S‐thiopentone in brain and visceral regions, but not in fat or muscle. After infusion of the separate enantiomers, the relative heart : brain distribution ratio was for S‐thiopentone was double that for R‐thiopentone.
The therapeutic index of R‐thiopentone (3.16±0.14) was more advantageous than either rac‐thiopentone (2.52±0.13) or S‐thiopentone (2.10±0.14), possibly due to the relatively greater distribution into CNS tissues than heart. The data suggest that R‐thiopentone could make a satisfactory single enantiomer substitute for rac‐thiopentone.

British Journal of Pharmacology (1999) 128, 83–91; doi:10.1038/sj.bjp.0702745
[Phe1ψ(CH2‐NH)Gly2]nociceptin‐(1–13)‐NH2 activation of an inward rectifier as a partial agonist of ORL1 receptors in rat periaqueductal gray
Authors: Chiou Lih‐Chu 
Published: January 2005

[Phe1ψ(CH2‐NH)Gly2]nociceptin‐(1–13)‐NH2 (Pheψ), a tridecapeptide analogue of orphanin FQ/nociceptin (OFQ/N), was introduced as a competitive antagonist of opioid receptor‐like orphan receptor (ORL1) in guinea‐pig ileum and mouse vas deferens preparations in vitro but was recently found to act as an agonist in vivo.
In the periaqueductal gray, a site enriched with both OFQ/N and ORL1 and involved in OFQ/N‐induced hyperalgesia and anti‐analgesia, the effects of Pheψ and OFQ/N on the membrane current were studied using whole cell patch clamp recording technique in rat brain slices.
OFQ/N (0.01–1 μM) activated an inwardly rectifying type of K+ channels in ventrolateral neurons of PAG. Pheψ (0.03–1 μM), like OFQ/N, also activated this inward rectifier but had only 30% efficacy of OFQ/N.
At maximal effective concentration (1 μM), Pheψ reversed the increment of K+ conductance induced by OFQ/N (300 nM) by 46%. On the other hand, Pheψ also prevented the effect of OFQ/N if pretreated before OFQ/N.
It is suggested that Pheψ acts as a partial agonist of ORL1 that mediates the activation of inwardly rectifying K+ channels in ventrolateral neurons of rat periaqueductal gray.

British Journal of Pharmacology (1999) 128, 103–107; doi:10.1038/sj.bjp.0702746
Modulation by fluoxetine of striatal dopamine release following Δ9‐tetrahydrocannabinol: a microdialysis study in conscious rats
Authors: Malone Daniel T , Taylor David A 
Published: January 2005

The present study was undertaken to investigate the effect of Δ9‐tetrahydrocannabinol (Δ9‐THC) and possible serotoninergic involvement on the extracellular level of dopamine (DA) in the striatum using microdialysis in conscious, freely‐moving rats.
A dose‐dependent increase in striatal DA release occurred after i.v. administration of 0.5–5 mg kg−1 Δ9‐THC when compared with vehicle (n=5–8, P<0.05). Maximum increases, ranging from 42.1±5.4% to 97.4±5.9% (means±s.e.mean) of basal levels occurred 20 min after Δ9‐THC. This effect was abolished by pretreatment with the cannabinoid CB1 receptor antagonist, SR 141716 (2.5 mg kg−1 i.p.).
Pretreatment with fluoxetine (10 mg kg−1 i.p.) abolished the Δ9‐THC‐induced DA release. Fluoxetine 10 mg kg−1 i.p. administered 40 min after Δ9‐THC had no significant effect on Δ9‐THC‐induced DA release. However, fluoxetine perfused locally into the striatum by adding it to the microdialysis perfusion fluid (10 μM) 40 min after Δ9‐THC significantly potentiated the Δ9‐THC‐induced DA release (n=6–8, P<0.05).
These results suggest that DA release induced by Δ9‐THC is modulated by serotoninergic changes induced by fluoxetine, the effect of which depends on the time of its administration relative to that of Δ9‐THC. Fluoxetine induces an acute increase in extracellular 5‐HT through reuptake inhibition, which can activate autoreceptors which may decrease serotoninergic neuronal activity. This may be the reason fluoxetine pretreatment abolished the Δ9‐THC‐induced DA release. The potentiation of Δ9‐THC‐induced DA release by fluoxetine perfusion added 40 min after Δ9‐THC may be due to an acute increase in 5‐HT produced by reuptake inhibition.

British Journal of Pharmacology (1999) 128, 21–26; doi:10.1038/sj.bjp.0702753
Inhibition of quantal release from motor nerve by wortmannin
Authors: Hong S J , Chang C C 
Published: January 2005

The effects of wortmannin, an inhibitor of phosphatidylinositol (PI) kinases and myosin light chain kinase, on the quantal release of neurotransmitter from mouse phrenic nerve were investigated.
Wortmannin (10–100 μM) initially enhanced, thereafter progressively depressed spontaneous quantal discharge (miniature endplate potential, mepp). The mean amplitude and the amplitude distribution of mepp were not altered.
The compound inhibited and prevented the intensive quantal release evoked by high KC1 solution as well as the mepp burst induced by α‐latrotoxin, a polypeptide toxin that possesses Ca2+‐independent synaptic action to trigger quantal release. The inhibitory actions of wortmannin were partially reversible.
Wortmannin depressed the amplitude of endplate potentials (epps) and increased the coefficient of variance of epps. The profile of epps in response to high frequency nerve stimulation exhibited fluctuations between run‐down and run‐up. The phenomenon is thus different from the consistency of run‐up characteristic as the motor nerve Ca2+ channel is blocked by ω‐agatoxin IVA.
LY294002, another inhibitor of PI 3‐kinase, raised mepp frequency without causing late phase suppressions. The compound did not inhibit KC1‐, α‐latrotoxin‐ or nerve stimulation‐evoked quantal release.
The results suggest that wortmannin could depress quantal release beyond the step of Ca2+ channel blockade, probably by interfering with the exocytotic cascade.

British Journal of Pharmacology (1999) 128, 142–148; doi:10.1038/sj.bjp.0702754
Electrochemical and electrophysiological characterization of neurotransmitter release from sympathetic nerves supplying rat mesenteric arteries
Authors: Dunn William R , Brock James A , Hardy Todd A 
Published: January 2005

Characteristic features of noradrenaline (NA) and adenosine 5′‐triphosphate (ATP) release from postganglionic sympathetic nerves in rat small mesenteric arteries in vitro have been investigated on an impulse‐by‐impulse basis. NA release was measured using continuous amperometry and ATP release was monitored by intracellular recording of excitatory junction potentials (e.j.ps).
Electrical stimuli evoked transient increases in oxidation current. During trains of ten stimuli at 0.5–4 Hz there was a depression in the amplitude of oxidation currents evoked following the first stimulus in the train.
The neuronal NA uptake inhibitor, desmethylimipramine (1 μM), increased the amplitude of the summed oxidation current evoked by ten stimuli at 1 Hz and slowed the decay of oxidation currents evoked by trains of ten stimuli at 1 and 10 Hz.
The α2‐adrenoceptor antagonist, idazoxan (1 μM), increased the amplitudes of the oxidation currents evoked during trains of ten stimuli at 0.5–10 Hz but had no effect on the oxidation currents evoked by the first stimulus in the train.
Idazoxan (1 μM) increased the amplitude of all e.j.ps evoked during trains of stimuli at 0.5 and 1 Hz. In addition, the facilitatory effect of idazoxan on e.j.ps was significantly greater than that on oxidation currents.
The findings indicate that NA release from sympathetic nerves supplying small mesenteric arteries is regulated by activation of presynaptic α2‐adrenoceptors and that clearance of released NA in this tissue depends, in part, upon neuronal uptake. The different effects of idazoxan on the oxidation currents and e.j.ps may indicate that the release of NA and ATP is differentially modulated.

British Journal of Pharmacology (1999) 128, 174–180; doi:10.1038/sj.bjp.0702760
Evidence for 5‐HT7 receptors mediating relaxation of human colonic circular smooth muscle
Authors: Prins Nicolaas H , Briejer Michel R , Van Bergen Patrick J E , Akkermans Louis M A , Schuurkes Jan A J 
Published: January 2005

5‐HT4 receptors mediate relaxation of human colon circular muscle. However, after 5‐HT4 receptor blockade (SB 204070 10 nM), 5‐HT still induced a relaxation (pEC50 6.3). 5‐HT4 receptors were sufficiently blocked, as the curves to 5‐HT obtained in the presence of 10 and 100 nM SB 204070 were indistinguishable. This 5‐HT‐induced relaxation was tetrodotoxin‐insensitive, indicative of a smooth muscle relaxant 5‐HT receptor. This, and the rank order of potency (5‐CT=5‐MeOT=5‐HT) suggested involvement of 5‐HT1 or 5‐HT7 receptors. Mesulergine, a 5‐HT7 receptor antagonist at nanomolar concentrations, and a 5‐HT1 receptor antagonist at micromolar concentrations, competitively antagonized the 5‐HT‐induced relaxation (pKB 8.3) and antagonized the relaxation to 5‐CT. Methysergide antagonized the 5‐HT‐induced relaxation (pA2 7.6). It is concluded that the profile of the smooth muscle inhibitory 5‐HT receptor resembles that of the 5‐HT7 receptor. These data provide the first evidence for functional human 5‐HT7 receptors.British Journal of Pharmacology (1999) 128, 849–852; doi:10.1038/sj.bjp.0702762
Effects of C‐type natriuretic peptide on rat cardiac contractility
Authors: Brusq Jean‐Marie , Mayoux Eric , Guigui Laurent , Kirilovsky Jorge 
Published: January 2005

Natriuretic peptide receptors have been found in different heart preparations. However, the role of natriuretic peptides in the regulation of cardiac contractility remains largely elusive and was, therefore, studied here.
The rate of relaxation of electrically stimulated, isolated rat papillary muscles was enhanced (114.4±1.4%, P<0.01) after addition of C‐type natriuretic peptide (CNP; 1 μM). Time to peak tension decreased in parallel (88±3 and 75±2 msec before and 5 min after addition of CNP, respectively, P<0.01). On the other hand, the rate of contraction slowly decreased when CNP was added to the papillary muscles. These results show that CNP displays a positive lusitropic effect associated with a negative inotropic effect. The effects of CNP were mimicked by 8‐bromo‐guanosine 3′,5′ cyclic monophosphate.
Addition of CNP to isolated adult rat cardiomyocytes, induced a 25 fold increase in guanosine 3′,5′ cyclic monophosphate (cGMP) levels and stimulated the phosphorylation of phospholamban and troponin I, two proteins involved in the regulation of cardiac contractility. The levels of adenosine 3′,5′ cyclic monophosphate (cAMP) were not affected by the addition of CNP to the myocytes. The CNP‐dependent phospholamban phosphorylation was accompanied by the activation of the sarcoplasmic reticulum Ca2+‐ATPase.
In summary, CNP exerts a positive lusitropic effect, in rat papillary muscles. The putative mechanism involved in the lusitropism induced by this peptide, a cGMP‐dependent enhancement of the rate of relaxation with a slowly developing negative inotropic effect, seems different to that described for catecholamines.

British Journal of Pharmacology (1999) 128, 206–212; doi:10.1038/sj.bjp.0702766
Block of gating currents related to K+ channels as a mechanism of action of clofilium and d‐sotalol in isolated guinea‐pig ventricular heart cells
Authors: Malécot Claire O , Argibay Jorge A 
Published: January 2005

The possibility that the class III antiarrhythmic drugs clofilium and d‐sotalol might affect delayed rectifier potassium channels at the level of their gating currents was assessed with the whole‐cell patch‐clamp technique in guinea‐pig isolated ventricular heart cells.
Clofilium (up to 20 μM) and d‐sotalol (1 μM) did not decrease the Na current, the L‐type Ca current or the background K current iKl, but significantly depressed the time‐dependent delayed outward K current iK.
Clofilium partially decreased in a dose‐dependent manner (1–20 μM) QON of intramembrane charge movements (ICM) elicited by a depolarizing pulse applied from a holding potential of −110 mV or following a 100 ms inactivating prepulse to −50 mV. D‐sotalol (1 μM) also decreased QON. Channel density estimated from the clofilium‐sensitive ICM closely matched that of the delayed rectifier channels.
Clofilium and d‐sotalol decreased QOFF seen on repolarization in a dose‐ and voltage‐dependent manner. The kinetics of the decay of the OFF gating currents were not affected, and only the fast phase was depressed.
In control conditions, QON availability with voltage was most of the time well described by two inactivating components. In the presence of clofilium and d‐sotalol, a complex behaviour of QON availability was observed, unmasking additional components. The reactivation kinetics of QON after a 500 ms inactivating pulse to 0 mV was not affected.
We conclude that delayed rectifier K channels significantly contribute to QON and QOFF of ICM in guinea‐pig ventricular heart cells, besides Na and Ca channels, and that clofilium and d‐sotalol directly interact with these K channels proteins by affecting their gating properties.

British Journal of Pharmacology (1999) 128, 301–312; doi:10.1038/sj.bjp.0702768
Differential sensitivity of normal and cystic fibrosis airway epithelial cells to epinephrine
Authors: Goncz Kaarin K , Feeney Luz , Gruenert Dieter C 
Published: January 2005

Exposure to epinephrine has been shown to have a range of effects on cells and tissues. A recent study suggested that the proliferative ability of CF epithelial cells, exposed to high concentrations of epinephrine (200–300 μM), was reduced when compared to that of normal cells. This approach could potentially provide a means to effectively separate cells with functional cyclic AMP‐dependent Cl‐ion transport from those defective in this pathway.
The sensitivity to killing by epinephrine is reported here for four different CF cell lines, three normal cell lines, and two CF epithelial cell lines complemented with wild‐type (wt) CF transmembrane conductance regulator (CFTR) cDNA.
While each cell line exhibited varying sensitivity to 200 μM epinephrine, no predictable pattern was observed between the expression of wt‐CFTR and cell survival following epinephrine exposure. Overall, normal cell lines did exhibit a greater resistance to epinephrine‐induced cell death although, the most resistant cell line was derived from CF tracheal epithelium (ΣCFTE29o‐).
The expression of exogenous wt‐CFTR increased the survival of one cell line (CFDEo‐) when compared to the parent line, but in another complemented line, survival was reduced.
These findings suggest that while epinephrine induces cell killing, it is not consistently effective for preferential selection of normal over CF cells. Although CFTR may play a role in the mechanism(s) of epinephrine killing, other factors such as cell density, proliferative ability, cell type origin and phenotype are involved.

British Journal of Pharmacology (1999) 128, 227–233; doi:10.1038/sj.bjp.0702772
Contractile 5‐HT1B receptors in human cerebral arteries: pharmacological characterization and localization with immunocytochemistry
Authors: Nilsson Torun , Longmore Jenny , Shaw David , Olesen Inger Jansen , Edvinsson Lars 
Published: January 2005

The cerebrovascular receptor(s) that mediates 5‐hydroxytryptamine (5‐HT)‐induced vasoconstriction in human cerebral arteries (HCA)has proven difficult to characterize, yet these are essential in migraine. We have examined 5‐HT receptor subtype distribution in cerebral blood vessels by immunocytochemistry with antibodies selective for human 5‐HT1B and human 5‐HT1D receptors and also studied the contractile effects of a range of 5‐HT receptor agonists and antagonists in HCA.
Immunocytochemistry of cerebral arteries showed dense 5‐HT1B receptor immunoreactivity (but no 5‐HT1D receptor immunoreactivity) within the smooth muscle wall of the HCA. The endothelial cell layer was well preserved and weak 5‐HT1B receptor immunoreactivity was present.
Pharmacological experiments on HCA with intact endothelium showed that 5‐carboxamidotryptamine was significantly more potent than α‐methyl‐5‐HT, 2‐methyl‐5‐HT and 5‐HT in causing vasoconstriction. The 5‐HT1B/1D receptor agonists naratriptan, sumatriptan, zolmitriptan and 181C91 (N‐desmethyl zolmitriptan), all induced equally strong contractions and with similar potency as 5‐HT. The maximum contractile response was significantly less for avitriptan and dihydroergotamine. There was a significant correlation between vasoconstrictor potency and 5‐HT1B‐ and 5‐HT1D‐receptor affinity, but not with 5‐HT1A‐, 5‐ht1F or 5‐HT2‐ receptor affinity.
The 5‐HT1B/1D‐receptor antagonist GR 55562 (10−7–10−6 M) inhibited the contractile responses to sumatriptan and 5‐CT in a competitive manner with a pKB value for GR 55562 of 7.4. Furthermore, ketanserin (10−7 M), prazosin (10−7 M), and sulpiride (10−7 M) were devoid of significant antagonistic activity of 5‐HT‐induced contraction in the HCA.
The results are compatible with the hypothesis that the 5‐HT1B receptors play a major role in 5‐HT‐induced vasoconstriction in HCA.

British Journal of Pharmacology (1999) 128, 1133–1140; doi:10.1038/sj.bjp.0702773
Endothelium‐derived hyperpolarizing factor but not NO reduces smooth muscle Ca2+ during acetylcholine‐induced dilation of microvessels
Authors: Bolz Steffen‐Sebastian , De Wit Cor , Pohl Ulrich 
Published: January 2005

We hypothesized that nitric oxide (NO) and the endothelium‐dependent hyperpolarizing factor (EDHF) may dilate microvessels by different cellular mechanisms, namely Ca2+‐desensitization versus decrease in intracellular free calcium.
Effects of acetylcholine (ACh) and the NO donors sodium nitroprusside (SNP, 0.1–10 μmol l−1) and S‐Nitroso‐N‐acetyl‐D,L‐penicillamine (SNAP, 0.01–10 μmol l−1) on intracellular calcium ([Ca2+]i, fura 2) and vascular diameter (videomicroscopy) were studied in isolated resistance arteries from hamster gracilis muscle (194±12 μm) pretreated with indomethacin and norepinephrine. Membrane potential changes were determined using 1,3‐dibutylbarbituric acid trimethineoxonol (DiBAC4(3)).
ACh (0.1 and 1 μmol l−1)‐induced dilations were associated with a [Ca2+]i decrease (by 13±3 and 32±4%) and hyperpolarization of vascular smooth muscle (VSM, by 12±1% at 1 μmol l−1 ACh). Nω‐nitro‐L‐arginine (L‐NA, 30 μmol l−1) partially inhibited the dilation but did not affect VSM [Ca2+]i decreases or hyperpolarization. In contrast, the KCa channel inhibitors tetrabutylammonium (TBA, 1 mmol l−1) and charybdotoxin (ChTX, 1 μmol l−1) abolished the ACh‐induced [Ca2+]i decrease and the hyperpolarization in VSM while a significant dilation remained (25 and 40%). This remaining dilation was abolished by L‐NA. ChTX did not affect [Ca2+]i increase and hyperpolarization in endothelial cells. SNP‐ or SNAP‐induced dilations were not associated with decreases in VSM [Ca2+]i or hyperpolarization although minor transient decreases in VSM [Ca2+]i were observed at high concentrations.
These data suggest that ACh‐induced dilations in microvessels are predominantly mediated by a factor different from NO and PGI2, presumably EDHF. EDHF exerts dilation by activation of KCa channels and a subsequent decrease in VSM [Ca2+]i, NO dilates the microvessels in a calcium‐independent manner.

British Journal of Pharmacology (1999) 128, 124–134; doi:10.1038/sj.bjp.0702775