bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local neurogenic regulation of rat hindlimb circulation: role of calcitonin gene‐related peptide in vasodilatation after skeletal muscle contraction
Authors: Yamada Masami , Ishikawa Tomohisa , Fujimori Akira , Goto Katsutoshi 
Published: January 2005

The mechanism of neurogenic regulation of skeletal muscle circulation was studied in the hindlimb of anaesthetized rats in vivo. Regional blood flow (RBF) of the hindlimb was recorded with a pulsed Doppler flow probe positioned in the iliac artery.
A short period (1 min) of sciatic nerve stimulation at 10 Hz caused a sustained increase in RBF (from 2.0±0.2 to 3.7±0.2 kHz at the peak), but no appreciable change in either MBP or HR, suggesting that the nerve stimulation produced local vasodilatation of the peripheral vasculature. The hyperaemic response reached a peak within 15 s and characteristically remained above the basal level for more than 5 min after the cessation of nerve stimulation. The response was regarded as a secondary response brought about by the contraction of skeletal muscles since (+)‐tubocurarine (0.73 μmol kg−1, i.a.) almost abolished it.
Lignocaine (43 μmol kg−1, i.a.) and capsaicin (0.33 μmol kg−1, i.a.) significantly suppressed the hyperaemic response to skeletal muscle contraction, suggesting that capsaicin‐sensitive sensory nerves contribute to the hyperaemia. In contrast, an inhibitor of NO synthase, Nω‐nitro‐L‐arginine methyl ester (1 μmol kg−1 min−1, i.v.), did not affect the hyperaemic response.
Serum levels of calcitonin gene‐related peptide (CGRP) in iliac venous effluent significantly increased from 51±4 to 77±5 fmol ml−1 during the hyperaemic response to skeletal muscle contraction. A bolus injection of CGRP (300 pmol kg−1, i.a.) induced a long‐lasting increase in RBF of the hindlimb. Moreover, CGRP(8–37) (100 nmol kg−1 min−1, i.v.), a specific CGRP1 receptor antagonist, significantly suppressed the hyperaemic response, especially the sustained phase of the response which was almost abolished by this antagonist.
These results suggest that CGRP, which is released from peripheral endings of capsaicin‐sensitive sensory nerves, partly mediates the hyperaemia evoked by skeletal muscle contraction of the rat hindlimb.

British Journal of Pharmacology (1997) 122, 703–709; doi:10.1038/sj.bjp.0701422
Augmentation of human neutrophil and alveolar macrophage LTB4 production by N‐acetylcysteine: role of hydrogen peroxide
Authors: Dent Gordon , Rabe Klaus F. , Magnussen Helgo 
Published: January 2005

The actions of N‐acetylcysteine (NAC) on hydrogen peroxide (H2O2) and leukotriene B4 (LTB4) production by human resting and stimulated peripheral blood neutrophils and alveolar macrophages were investigated.
At a concentration of 100 μM, NAC significantly (P<0.01) suppressed the accumulation of H2O2 in the incubation medium of resting and opsonized zymosan (OZ; 0.5 mg ml−1)‐ or N‐formylmethionyl‐leucyl‐phenylalanine (fMLP; 1 μM)‐stimulated neutrophils and of resting and OZ‐stimulated macrophages. At concentrations of 10 μM and above, NAC augmented significantly the level of LTB4 in the supernatants of OZ‐ and fMLP‐stimulated neutrophils (P<0.01 and P<0.05, respectively) and OZ‐stimulated macrophages (P<0.05 at 10 μM, P<0.01 at 100 μM NAC).
NAC (100 μM) caused a significant (P<0.01) reduction in the quantity of measurable H2O2 when incubated with exogenous H2O2 concentrations equivalent to those released from OZ‐stimulated neutrophils and macrophages. At no concentration did NAC affect quantitites of measurable LTB4 when incubated with exogenous LTB4.
Superoxide dismutase (SOD), which catalyzes the conversion of superoxide anion to H2O2 had no significant effect on LTB4 production by human neutrophils. In contrast, catalase, which catalyzes the conversion of H2O2 to H2O and O2, caused a pronounced, statistically significant (P<0.01) increase in the levels of LTB4 measured in the supernatants of OZ‐ and fMLP‐stimulated neutrophils.
H2O2 (12.5 μM and 25 μM, concentrations equivalent to those measured in the supernatants of activated neutrophils and alveolar macrophages, respectively) caused a small (13%) decrease in the quantity of measurable LTB4 (P=0.051 and P<0.05 at 12.5 μM and 25 μM, respectively) that was inhibited by NAC (100 μM) but not by catalase (400 u ml−1).
In conclusion, the anti‐oxidant drug, NAC, increases LTB4 production by human neutrophils and alveolar macrophages, probably through the elimination of cell‐derived H2O2. LTB4 undergoes a H2O2‐dependent oxidation that is inhibited by NAC but this is unlikely to account fully for the increased levels of LTB4, suggesting that NAC may increase LTB4 production by blocking the H2O2‐dependent inhibition of a synthetic enzyme, such as 5‐lipoxygenase.

British Journal of Pharmacology (1997) 122, 758–764; doi:10.1038/sj.bjp.0701428
Stimulation of intracellular chloride accumulation by noradrenaline and hence potentiation of its depolarization of rat arterial smooth muscle in vitro
Authors: Davis Julian P. L. , Harper Alexander A. , Chipperfield Alan R. 
Published: January 2005

Double‐barrelled ion‐selective microelectrodes were used to examine the effects of exogenous noradrenaline upon the membrane potential (Em) and intracellular chloride concentration ([Cl]i) of arterial smooth muscle from the saphenous branch of the femoral artery of the rat.
After treatment with 0.6 mM 6‐hydroxydopamine (to functionally denervate the tissue), exogenous noradrenaline (5 nM) caused repeatable depolarization of Em from −63.7±2.4 mV (s.d., n=18) to −53.8±3.4 mV (P<0.0001) and increases in [Cl]i from 31.0±0.5 mM to 42.5±2.2 mM (P<0.0001).
In the presence of 10 μM bumetanide (an inhibitor of (Na‐K‐Cl) cotransport), 5 nM noradrenaline caused a depolarization of Em of 3.0±3.2 mV, and a rise in [Cl]i of 4.5±2.5 mM.
In the presence of bumetanide and 1 mM acetazolamide (used as an inhibitor of a Na‐independent inward Cl pump), noradrenaline had no effect on Em or [Cl]i.
In the absence of extracellular chloride, the rise in apparent [Cl]i in response to 5 nM noradrenaline was abolished but there was a depolarization of 2.0±3.9 mV.
These results are consistent with the stimulation of (Na‐K‐Cl) cotransport and a Na‐independent Cl pump by exogenous noradrenaline and with the consequent increase in [Cl]i and shift in ECl potentiating the depolarization caused by noradrenaline. The possibility that modulation of [Cl]i may be a general mechanism of Em regulation is discussed.

British Journal of Pharmacology (1997) 122, 639–642; doi:10.1038/sj.bjp.0701431
Chemokine production by human vascular smooth muscle cells: modulation by IL‐13
Authors: Jordan Nicola J. , Watson Malcolm L. , Williams Robert J. , Roach Alan G. , Yoshimura Teizo , Westwick John 
Published: January 2005

The production of chemokines by vascular smooth muscle cells (SMC) is implicated in the pathogenesis of atherosclerosis, although the factors regulating chemokine production by these cells are incompletely characterized.
We describe the differential stimulation of interleukin‐(IL)‐8, monocyte chemoattractant protein (MCP)‐1 and regulated on activation normal T‐cell expressed and secreted (RANTES) synthesis following treatment of human vascular SMC with IL‐1α or tumour necrosis factor α (TNFα). Under basal conditions, cultured SMC release very low amounts of IL‐8, MCP‐1 and RANTES as assessed by specific ELISA. Concentration‐response studies with IL‐1α or TNFα revealed that each stimulus induced a similar amount of MCP‐1. In contrast approximately three fold more IL‐8 was induced by IL‐1α than by TNFα whereas significant RANTES production was induced only by TNFα. These findings point to a divergence in the regulation of synthesis of the different chemokines in response to IL‐1α or TNFα stimulation.
The T‐cell derived cytokines IL‐10 and IL‐13 were also found to have differential effects on chemokine production by SMC. IL‐13, but not IL‐10, significantly enhanced IL‐8 and MCP‐1 release in response to IL‐1α or TNFα. This increase in chemokine release appeared to be accounted for by increased mRNA expression.
These findings provide support for the concept that smooth muscle cells can have an active role in a local immune response via the production of chemokines which can be selectively modulated by T‐cell derived cytokines.

British Journal of Pharmacology (1997) 122, 749–757; doi:10.1038/sj.bjp.0701433
The role of the IsK protein in the specific pharmacological properties of the IKs channel complex
Authors: Busch A. E. , Busch G. L. , Ford E. , Suessbrich H. , Lang H.‐J. , Greger R. , Kunzelmann K. , Attali B. , Stühmer W. 
Published: January 2005

IKs channels are composed of IsK and KvLQT1 subunits and underly the slowly activating, voltage‐dependent IKs conductance in heart. Although it appears clear that the IsK protein affects both the biophysical properties and regulation of IKs channels, its role in channel pharmacology is unclear. In the present study we demonstrate that KvLQT1 homopolymeric K+ channels are inhibited by the IKs blockers 293B, azimilide and 17‐β‐oestradiol. However, IKs channels induced by the coexpression of IsK and KvLQT1 subunits have a 6–100 fold higher affinity for these blockers. Moreover, the IKs activators mefenamic acid and DIDS had little effect on KvLQT1 homopolymeric channels, although they dramatically enhanced steady‐state currents through heteropolymeric IKs channels by arresting them in an open state. In summary, the IsK protein modulates the effects of both blockers and activators of IKs channels. This finding is important for the action and specificity of these drugs as IsK protein expression in heart and other tissues is regulated during development and by hormones.British Journal of Pharmacology (1997) 122, 187–189; doi:10.1038/sj.bjp.0701434
Imbalance between the endothelial cell‐derived contracting factors prostacyclin and angiotensin II and nitric oxide/cyclic GMP in human primary varicosis
Authors: Schuller‐Petrovic Sanja , Siedler Susanne , Kern Thomas , Meinhart Johann , Schmidt Kurt , Brunner Friedrich 
Published: January 2005

The role of the endothelium in the vasomotor control of human veins in the lower extremity is little understood. We tested the hypothesis that the production of relaxing and contracting factors is altered in endothelial cells from varicose saphenous veins which may predispose to the decreased vessel tone observed in primary varicosis.
We determined the intracellular accumulation of guanosine 3′:5′‐cyclic monophosphate cyclic GMP; a measure of nitric oxide production) and the release of endothelin and prostacyclin (measured as its stable metabolite 6‐keto‐prostaglandin F1α) from cultured cells derived from the long saphenous veins of patients with primary varicosis (Varicose saphena group, n=27) or from patients undergoing coronary artery bypass surgery (Healthy saphena group, n=22). In addition, levels of endothelin, angiotensin II, bradykinin, cyclic GMP and cyclic AMP in plasma from patients with primary varicosis and healthy volunteers (n=8–11 in each group) were determined.
Although basal cyclic GMP levels were similar, more cyclic GMP accumulated in response to histamine (1–100 μmol l−1) in cells from varicose saphenous veins (0.75±0.1 pmol per well) than in cells from veins without varicosis (0.27±0.05 pmol per well). Furthermore, the relaxant potency of nitroprusside (1 nmol l−1–300 μmol l−1) in vitro was higher for varicose veins (mean EC50=5.9 μmol l−1; n=8) than healthy veins (mean EC50=20.0 μmol l−1; n=7).
The production of prostacyclin was significantly less in cells from varicose than healthy saphenous veins (66±8.7 and 121±20.1 nmol g−1 protein), but the production of endothelin was similar in both groups. Prostacyclin (3 nmol l−1–30 μmol l−1) consistently contracted rings of varicose saphenous vein in vitro with a mean EC50 value of 10–20 μmol l−1 (n=7); the maximum tension generated was ∼50% of that of a completely depolarizing solution of K+ (120 mmol l−1).
In plasma from patients with varicose veins, levels of cyclic GMP were higher than in healthy controls (9.2±0.03 and 7.2±0.02 nmol l−1), levels of angiotensin II were lower (81±11.5 and 147±21.7 pmol l−1), and levels of endothelin, cyclic AMP, and bradykinin were not different.
It is concluded that endothelial cells from diseased saphenous veins secrete less constrictor mediators than cells from healthy veins and that in diseased veins the nitric oxide/cyclic GMP system is up‐regulated which may shift the balance of vasoactive factors towards vasodilatation and contribute to the development of primary varicosis.

British Journal of Pharmacology (1997) 122, 772–778; doi:10.1038/sj.bjp.0701437
Muscarinic receptor subtypes controlling the cationic current in guinea‐pig ileal smooth muscle
Authors: Zholos Alexander V. , Bolton Thomas B. 
Published: January 2005

The effects of muscarinic antagonists on cationic current evoked by activating muscarinic receptors with the stable agonist carbachol were studied by use of patch‐clamp recording techniques in guinea‐pig single ileal smooth muscle cells.
Ascending concentrations of carbachol (3–300 μM) activated the cationic conductance in a concentration‐dependent manner with conductance at a maximally effective carbachol concentration (Gmax) of 27.4±1.4 nS and a mean −log EC50 of 5.12±0.03 (mean±s.e.mean) (n=114).
Muscarinic antagonists with higher affinity for the M2 receptor, methoctramine, himbacine and tripitramine, produced a parallel shift of the carbachol concentration‐effect curve to the right in a concentration‐dependent manner with pA2 values of 8.1, 8.0 and 9.1, respectively.
All M3 selective muscarinic antagonists tested, 4‐DAMP, p‐F‐HHSiD and zamifenacin, reduced the maximal response in a concentration‐dependent and non‐competitive manner. This effect could be observed even at concentrations which did not produce any increase in the EC50 for carbachol. At higher concentrations M3 antagonists shifted the agonist curve to the right, increasing the EC50, and depressed the maximum conductance response. Atropine, a non‐selective antagonist, produced both reduction in Gmax (M3 effect) and significant increase in the EC50 (M2 effect) in the same concentration range.
The depression of the conductance by 4‐DAMP, zamifenacin and atropine could not be explained by channel block as cationic current evoked by adding GTPγS to the pipette (without application of carbachol) was unaffected.
The results support the hypothesis that carbachol activates M2 muscarinic receptors so initiating the opening of cationic channels which cause depolarization; this effect is potentiated by an unknown mechanism when carbachol activates M3 receptors. As an increasing fraction of M3 receptors are blocked by an antagonist, the effects on cationic current of an increasing proportion of activated M2 receptors are disabled.

British Journal of Pharmacology (1997) 122, 885–893; doi:10.1038/sj.bjp.0701438
Cigarette smoke‐inhibition of neurogenic bronchoconstriction in guinea‐pigs in vivo: involvement of exogenous and endogenous nitric oxide
Authors: Emms Joanne C. , Rogers Duncan F. 
Published: January 2005

We investigated the effect of acute inhalation of cigarette smoke on subsequent non‐adrenergic, non‐cholinergic (NANC) neural bronchoconstriction in anaesthetized guinea‐pigs in vivo by use of pulmonary insufflation pressure (PIP) as an index of airway tone. The contribution of endogenous nitric oxide (NO) was investigated with the NO synthase inhibitor NG‐nitro‐L‐arginine methyl ester (L‐NAME). The contribution of plasma exudation to the response was investigated with Evans blue dye as a plasma marker.
Inhalation of 50 tidal volumes of cigarette smoke or air had no significant effect on baseline PIP. In the presence of propranolol and atropine (1 mg kg−1 each), electrical stimulation of the vagus nerves in animals given air 30 min previously induced a frequency‐dependent increase in PIP above sham stimulated controls (16 fold increase at 2.5 Hz, 24 fold increase at 10 Hz). In contrast, in smoke‐exposed animals, the increase in subsequent vagally‐induced PIP was markedly less than in the air controls (90% less at 2.5 Hz, 76% less at 10 Hz).
L‐NAME (10 mg kg−1), given 10 min before air or smoke, potentiated subsequent vagally‐induced (2.5 Hz) NANC bronchoconstriction by 338% in smoke‐exposed animals, but had no significant effect in air‐exposed animals. The inactive enantiomer D‐NAME (10 mg kg−1) had no effect, and the potentiation by L‐NAME was partially reversed by the NO‐precursor L‐arginine (100 mg kg−1). Vagal stimulation did not affect the magnitude of vagally‐induced bronchoconstriction 30 min later.
Cigarette smoke exposure reduced the magnitude of subsequent bronchoconstriction induced by neurokinin A (NKA) by 37% compared with the effect of NKA in air‐exposed animals. L‐NAME had no significant effect on the smoke‐induced inhibition of NKA‐induced bronchoconstriction.
Vagally‐induced plasma exudation in the main bronchi was greater in smoke‐exposed animals compared with air‐exposed animals (120% greater at 2.5 Hz, 82% greater at 10 Hz).
We conclude that cigarette smoke‐induced inhibition of subsequent NANC neurogenic bronchoconstriction is not associated with inhibition of airway plasma exudation and is mediated in part via exogenous smoke‐derived NO, or another bronchoprotective molecule, and by endogenous NO.

British Journal of Pharmacology (1997) 122, 779–785; doi:10.1038/sj.bjp.0701440
Aminoguanidine and the prevention of leukocyte dysfunction in diabetes mellitus: a direct vital microscopic study
Authors: Sannomiya Paulina , Oliveira Maria A. , Fortes Zuleica B. 
Published: January 2005

Defective leukocyte‐endothelial interactions are observed in experimental diabetes mellitus. The present study investigated the effect of aminoguanidine, an inhibitor of advanced glycation end products formation, on leukocyte‐endothelial interactions in alloxan‐induced diabetic rats.
In rats anaesthetized with sodium pentobarbitone, the internal spermatic fascia was exteriorized and the microcirculation was observed by a closed‐circuit TV coupled to a microscope. The number of leukocytes rolling along the venular endothelium and sticking to the vascular wall was determined after topical application of zymosan‐activated plasma (1 mg ml−1), as well as the number of adherent and migrated cells after an irritative stimulus (carrageenan 100 μg).
The diabetic state decreased the number of rolling, sticking and migrated leukocytes. Pretreatment of diabetic animals with aminoguanidine (250 mg kg−1 day−1, for 18 days) normalized these values. To be effective, aminoguanidine had to be administered chronically, starting treatment before induction of the diabetic state.
The preventive effect was unrelated to the number of circulating leukocytes, or to the hyperglycaemia or to the hyperosmolality secondary to hyperglycaemia.
A non‐dialyzed (>12,000‐Mr) material in plasma from diabetic, but not normal animals, decreased the number of rolling, sticking and migrated leukocytes in recipient rats. This effect was completely abolished by chronic treatment of diabetic plasma donors with aminoguanidine.
The results suggest that a protein modified by glycosylation (>12 kDa) is associated with leukocyte dysfunction in diabetes mellitus and that the ability of aminoguanidine to prevent such dysfunction is related to an inhibitory effect on advanced glycation end products formation.

British Journal of Pharmacology (1997) 122, 894–898; doi:10.1038/sj.bjp.0701448
Inhibition of trigeminal neurones after intravenous administration of naratriptan through an action at 5‐hydroxy‐tryptamine (5‐HT1B/1D) receptors
Authors: Goadsby Peter J. , Knight Yolande 
Published: January 2005

The observation that 5‐hydroxytryptamine (5‐HT) is effective in treating acute attacks of migraine when administered intravenously resulted in a research effort that led to the discovery of the 5‐HT1B/1D receptor agonist sumatriptan.
Clinical experience has shown sumatriptan to be an effective treatment with some limitations, such as relatively poor bioavailability, which naratriptan was developed to address. Increasing bioavailability has been achieved with greater lipophilicity and thus the potential for greater activity in the central nervous system.
In this study the increased access to central sites has been exploited in an attempt to characterize the pharmacology of those central receptors with the newer tools available. Trigeminovascular activation was examined in the model of superior sagittal sinus stimulation.
Cats were anaesthetized with α‐chloralose (60 mg kg−1, intraperitoneal), paralyzed (gallamine 6 mg kg−1, intravenously) and ventilated. The superior sagittal sinus was accessed and isolated for electrical stimulation (250 μs pulses, 0.3 Hz, 100 V) by a mid‐line circular craniotomy. The region of the dorsal surface of C2 spinal cord was exposed by a laminectomy and an electrode placed for recording evoked activity from sinus stimulation.
Stimulation of the superior sagittal sinus resulted in activation of cells in the dorsal horn of C2. Cells fired with a probability of 0.69±0.1 at a latency of 9.2±0.2 ms. Intravenous (i.v.) administration of naratriptan at clinically relevant doses (30 and 100 μg kg−1), inhibited neuronal activity in trigeminal neurones of the C2 dorsal horn, reducing probability of firing without affecting latency.
The effect of naratriptan could be reversed by administration of the selective 5‐HT1B/1D receptor antagonist GR127935 (100 μg kg−1, i.v.).
These data establish that naratriptan acts on central trigeminal neurones since sagittal sinus stimulation activates axons within the tentorial nerve and there are no inhibitory effects mediated within the trigeminal ganglion. Furthermore, given that this inhibition could be reversed by the relatively selective 5‐HT1B/1D receptor antagonist GR127935, it is highly likely that the anti‐migraine effects of drugs of this class with central nervous system access are mediated, at least in part, by 5‐HT1B/1D receptors within the trigeminal nucleus.

British Journal of Pharmacology (1997) 122, 918–922; doi:10.1038/sj.bjp.0701456
The role of cyclic AMP production, calcium channel activation and enzyme activities in the inhibition of testosterone secretion by amphetamine
Authors: Tsai Shiow‐Chwen , Chen Jiann‐Jong , Chiao Yu‐Chung , Lu Chien‐Chen , Lin Ho , Yeh Jiun‐Yih , Lo Ming‐Jae , Kau Mei‐Mei , Wang Shyi‐Wu , Wang Paulus S. 
Published: January 2005

The aim of this study was to investigate the mechanism by which amphetamine exerts its inhibitory effect on testicular interstitial cells of male rats.
Administration of amphetamine (10−12–10−6 M) in vitro resulted in a dose‐dependent inhibition of both basal and human chorionic gonadotropin (hCG, 0.05 iu ml−1)‐stimulated release of testosterone.
Amphetamine (10−9 M) enhanced the basal and hCG‐increased levels of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) accumulation in vitro (P<0.05) in rat testicular interstitial cells.
Administration of SQ22536, an adenylyl cyclase inhibitor, decreased the basal release (P<0.05) of testosterone in vitro and abolished the inhibitory effect of amphetamine.
Nifedipine (10−6 M) alone decreased the secretion of testosterone (P<0.01) but it failed to modify the inhibitory action of amphetamine (10−10–10−6 M).
Amphetamine (10−10–10−6 M) significantly (P<0.05 or P<0.01) decreased the activities of 3β‐hydroxysteroid dehydrogenase (3β‐HSD), P450c17, and 17‐ketosteroid reductase (17‐KSR) as indicated by thin‐layer chromatography (t.l.c.).
These results suggest that increased cyclic AMP production, decreased Ca2+ channel activity and decreased activities of 3β‐HSD, P450c17, and 17‐KSR are involved in the inhibition of testosterone production induced by the administration of amphetamine.

British Journal of Pharmacology (1997) 122, 949–955; doi:10.1038/sj.bjp.0701463