bluuebunny/crossref_metadata_2025 huggingface dataset:
Histamine‐induced inhibition of leukotriene biosynthesis in human neutrophils: involvement of the H2 receptor and cAMP
Authors: Flamand Nicolas , Plante Hendrick , Picard Serge , Laviolette Michel , Borgeat Pierre
Published: February 2004

Histamine is generally regarded as a pro‐inflammatory mediator in diseases such as allergy and asthma. A growing number of studies, however, suggest that this autacoid is also involved in the downregulation of human polymorphonuclear leukocyte (PMN) functions and inflammatory responses through activation of the Gs‐coupled histamine H2 receptor.

We report here that histamine inhibits thapsigargin‐ and ligand (PAF and fMLP)‐induced leukotriene (LT) biosynthesis in human PMN in a dose‐dependent manner.

The suppressive effect of histamine on LT biosynthesis was abrogated by the histamine H2 receptor antagonists cimetidine, ranitidine, and tiotidine. In contrast, the histamine H1, H3, and H4 receptor antagonists used in this study were ineffective in counteracting the inhibitory effect of histamine on the biosynthesis of LT in activated human PMN.

The inhibition of LT biosynthesis by histamine was characterized by decreased arachidonic acid release and 5‐lipoxygenase translocation to the nuclear membrane.

Incubation of PMN with the cAMP‐dependent protein kinase (PKA) inhibitor N‐[2‐(p‐bromocinnamylamino)ethyl]‐5‐isoquinoline‐sulfonamide prevented the inhibitory effect of histamine on LT biosynthesis, suggesting an important role for PKA in this effect of histamine on LT biosynthesis in PMN.

These data provide the first evidences that, similarly to adenosine and prostaglandin E2, histamine is a potent suppressor of LT biosynthesis, and support the concept that histamine may play a dual role in the regulation of inflammation.

British Journal of Pharmacology (2004) 141, 552–561. doi:10.1038/sj.bjp.0705654
Effects of chlorpromazine on excitation–contraction coupling events in fast‐twitch skeletal muscle fibres of the rat
Authors: Wagner R , Fink R H A , Stephenson D G
Published: February 2004

Single mechanically skinned fibres from the rat extensor digitorum longus muscle, which allow access to intracellular compartments, were used to examine the effects of 0.5–100 μM chlorpromazine hydrochloride (CPZ) on the major steps of the excitation–contraction (E–C) coupling to elucidate the involvement of skeletal muscle in the neuroleptic malignant syndrome (NMS).

At 1 μM, CPZ caused a 20–30% increase in the force response induced by t‐system depolarisation and a marked increase in the rate of caffeine‐induced SR Ca2+ release. At [CPZ]2.5 μM, there was an initial increase followed by a marked decrease of the t‐system depolarisation‐induced force responses, while the potentiating effect on the caffeine‐induced SR Ca2+ release remained. These effects were reversible.

CPZ had no effect on the maximum Ca2+‐activated force, but caused reversible, concentration‐dependent increases in the Ca2+ sensitivity of the contractile apparatus at [CPZ] 10 μM, with a 50% predicted shift of 0.11 pCa (−log [Ca2+]) units at 82.3 μM CPZ.

CPZ did not alter the rate of SR‐Ca2+ loading at 1 and 10 μM, but reversibly reduced it by ∼40% at 100 μM by reducing the SR Ca2+ pump. Nevertheless, the SR Ca2+ content was greater when fibres became unresponsive to t‐system‐induced depolarisation in the presence than in the absence of 100 μM CPZ.

The results show that CPZ has concentration‐dependent stimulatory and inhibitory effects on various steps of the E–C coupling, which can explain the involvement of skeletal muscle in NMS and reconcile previous divergent data on CPZ effects on muscle.

British Journal of Pharmacology (2004) 141, 624–633. doi:10.1038/sj.bjp.0705655
Studies on the mechanisms of action of picrotoxin, quercetin and pregnanolone at the GABAρ1 receptor
Authors: Goutman Juan D , Calvo Daniel J
Published: February 2004

The mechanisms of action of antagonists of the γ‐aminobutyric acid C (GABAC) receptor picrotoxin, quercetin and pregnanolone were studied.

Ionic currents (chloride), mediated through human homomeric GABAρ1 receptors expressed in Xenopus oocytes, were recorded by two‐electrode voltage clamp.

Dose–response (D–R) curves and kinetic measurements of GABAρ1 currents were carried out in the presence or absence of antagonists. Use‐dependent actions were also evaluated.

Picrotoxin, quercetin and pregnanolone exerted noncompetitive actions.

IC50 values measured at the EC50 for GABA (1 μM) were as follows: picrotoxin 0.6±0.1 μM (Hill coefficient n=1.0±0.2); quercetin 4.4±0.4 μM (n=1.5±0.2); pregnanolone 2.1±0.5 μM (n=0.8±0.1).

These antagonists produced changes only in the slope of the linear current–voltage relationships, which was indicative of voltage‐independent effects.

The effect of picrotoxin on GABAρ1 currents was use‐dependent, strongly relied on agonist concentration and showed a slow onset and offset. The mechanism was compatible with an allosteric inhibition and receptor activation was a prerequisite for antagonism.

The effect of quercetin was use‐independent, showed relatively fast onset and offset, and resulted in a slowed time course of the GABA‐evoked currents.

The effect of pregnanolone was use‐independent, presented fast onset and a very slow washout, and did not affect current activation.

All the antagonists accelerated the time course of deactivation of the GABAρ1 currents.

British Journal of Pharmacology (2004) 141, 717–727. doi:10.1038/sj.bjp.0705657
Sildenafil (Viagra) reduces arrhythmia severity during ischaemia 24 h after oral administration in dogs
Authors: Nagy Orsolya , Hajnal Ágnes , Parratt James R , Végh Ágnes
Published: February 2004

Sildenafil (Viagra) prolongs repolarisation in cardiac muscle, an effect that could lead to ventricular fibrillation (VF). Sildenafil (2 mg kg−1) was given by mouth to 12 mongrel dogs and, 24 h later, these dogs were anaesthetised, thoracotomised and subjected to a 25 min occlusion of the anterior descending coronary artery. Haemodynamic parameters were similar in this and the control group, but there were fewer and less serious ventricular arrhythmias during occlusion in the sildenafil group (VF 17 vs 60%; ventricular premature beats 140±52 vs 437±127% and episodes of ventricular tachycardia 4.0±3.2 vs 19.3±7.7%, all P<0.05). However, reperfusion VF and indices of ischaemia severity (epicardial ST‐segment mapping, inhomogeneity) were not modified by the drug. Sildenafil increased the QT interval, especially during ischaemia. Our conclusion is that ischaemia‐induced ventricular arrhythmias are reduced by sildenafil, but this protection is less pronounced than that following cardiac pacing or exercise.

British Journal of Pharmacology (2004) 141, 549–551. doi:10.1038/sj.bjp.0705658
Regional haemodynamic effects of cyclosporine A, tacrolimus and sirolimus in conscious rats
Authors: Gardiner S M , March J E , Kemp P A , Fallgren B , Bennett T
Published: February 2004

The observation that the immunosuppressants, cyclosporine A (CsA) and tacrolimus, have pressor effects, but sirolimus does not, has led to an hypothesis that generalised sympathoexcitation, resulting from inhibition of calcineurin by CsA and tacrolimus underlies their pressor effects, because sirolimus does not inhibit calcineurin. It is unknown if sirolimus has haemodynamic actions not accompanied by a pressor effect, and whether or not the pressor effects of CsA and tacrolimus are accompanied by similar haemodynamic changes. Therefore, the first aim of our studies was to investigate these possibilities in conscious, chronically‐instrumented, male, Sprague‐Dawley rats.

CsA (5.9 mg kg−1 bolus i.v.) caused rapid‐onset, prolonged hypertension, tachycardia and mesenteric vasoconstriction. There was a slower onset renal vasoconstriction, but no significant change in hindquarters vascular conductance; all the effects of CsA were significantly greater than those of vehicle. CsA given by infusion (over 30 min or 2 h) caused changes qualitatively similar to those above. Repeated administration of CsA over 4 days did not enhance its cardiovascular effects.

Pretreatment with the angiotensin (AT1) receptor antagonist, losartan, and the endothelin (ETA and ETB) receptor antagonist, SB 209670, reduced the pressor and mesenteric vasoconstrictor effects of CsA. Additional administration of the α‐adrenoceptor antagonist, phentolamine, completely inhibited the cardiovascular effects of CsA.

Tacrolimus (450 μg kg−1 bolus i.v.) caused similar peak pressor and tachycardic effects to CsA, but these were much slower in onset, and were maximal when there were no significant regional vasoconstrictions, indicating that the pressor effect was probably due to a rise in cardiac output. However, although propranolol reversed the tachycardic effect of tacrolimus, it did not influence the pressor response.

Sirolimus (450 μg kg−1 bolus i.v.) had no tachycardic action, and only a modest, transient pressor effect, accompanied by equally brief reductions in renal, mesenteric, and hindquarters vascular conductances.

The differences between the regional haemodynamic profiles of equipressor doses of CsA and tacrolimus, and the finding that sirolimus has significant cardiovascular actions, indicate that generalised sympathoexcitation, resulting from calcineurin inhibition (with CsA and tacrolimus), is unlikely to be the sole explanation of their pressor effects.

British Journal of Pharmacology (2004) 141, 634–643. doi:10.1038/sj.bjp.0705659
Donepezil modulates nicotinic receptors of substantia nigra dopaminergic neurones
Authors: Angelantonio Silvia Di , Bernardi Giorgio , Mercuri Nicola B
Published: February 2004

The effects of donepezil, one of the most common cholinesterase inhibitors used for treatment of Alzheimer's disease, were studied on nicotinic receptors (nAChRs)‐mediated postsynaptic currents, in dopaminergic neurons of the substantia nigra pars compacta, using the patch‐clamp recording technique in slice preparations.

Donepezil (10–100 μM) selectively and reversibly depressed nicotine currents, induced by brief puffer pulses, through a glass micropipette positioned above the slice.

The peak amplitude fading of the responses generated by repeated test applications of low doses of nicotine was accelerated by donepezil, while it slowed the recovery of nicotine currents after a large, desensitising, dose of the same agonist.

Donepezil depressed even maximal responses to nicotine, revealing a noncompetitive mechanism of action; moreover, the inhibition of nAChRs was voltage and time independent.

Pretreatment with vesamicol or methamidophos did not prevent the reduction of nicotine‐induced currents. The data indicated direct effect on nAChR, independent from the activity of donepezil as cholinesterase inhibitor.

British Journal of Pharmacology (2004) 141, 644–652. doi:10.1038/sj.bjp.0705660
Role of cyclic GMP on inhibition by nitric oxide donors of human eosinophil chemotaxis in vitro
Authors: Thomazzi Sara M , Moreira Juliana , Marcondes Sisi , Nucci Gilberto De , Antunes Edson
Published: February 2004

This study was designed to investigate the effects of the nitric oxide (NO) donors sodium nitroprusside (SNP), 3‐morpholinosydnonimine (SIN‐1) and S‐nitroso‐N‐acetylpenicillamine (SNAP) on N‐formyl‐L‐methionyl‐L‐leucyl‐phenylalanine (fMLP, 1 × 10−7 M)‐induced human eosinophil chemotaxis, cyclic guanosine‐3′,5′‐monophosphate (cGMP) levels, protein nitration and cytotoxicity.

Human eosinophils were exposed to SNP, SIN‐1 and SNAP (0.001–1.0 mM) for either short (10 min) or prolonged (90 min) time periods. Exposition of eosinophils with these NO donors significantly inhibited the eosinophil chemotaxis irrespective of whether cells were exposed to these agents for 10 or 90 min. No marked differences were detected among them regarding the profile of chemotaxis inhibition.

Exposition of eosinophils to SNP, SIN‐1 and SNAP (0.001–1.0 mM) markedly elevated the cGMP levels above basal levels, but the 90‐min exposition resulted in significantly higher levels compared with the 10‐min protocols (5.3±0.6 and 2.6±0.2 nM 1.5 × 106 cells−1, respectively). The cGMP levels achieved with SNAP were greater than SNP and SIN‐1.

The NO donors did not induce cell toxicity in any experimental condition used. Additionally, eosinophils exposed to SNP, SIN‐1 and SNAP (1.0 mM each) either for 10 or 90 min did not show any tyrosine nitration in conditions where a strong nitration of bovine serum albumin was observed.

Our findings show that inhibitory effects of fMLP‐induced human eosinophil chemotaxis by NO donors at short or prolonged exposition time were accompanied by significant elevations of cGMP levels. However, additional elevations of cGMP levels do not change the functional profile (chemotaxis inhibition) of stimulated eosinophils.

British Journal of Pharmacology (2004) 141, 653–660. doi:10.1038/sj.bjp.0705661
Neuroprotective effects of M826, a reversible caspase‐3 inhibitor, in the rat malonate model of Huntington's disease
Authors: Toulmond Sylvie , Tang Keith , Bureau Yves , Ashdown Helen , Degen Sarah , O'Donnell Ruth , Tam John , Han Yongxin , Colucci John , Giroux André , Zhu Yanxia , Boucher Mathieu , Pikounis Bill , Xanthoudakis Steven , Roy Sophie , Rigby Michael , Zamboni Robert , Robertson George S , Ng Gordon Y K , Nicholson Donald W , Flückiger Jean‐Pierre
Published: February 2004

Caspases, key enzymes in the apoptosis pathway, have been detected in the brain of HD patients and in animal models of the disease. In the present study, we investigated the neuroprotective properties of a new, reversible, caspase‐3‐specific inhibitor, M826 (3‐({(2S)‐2‐[5‐tert‐butyl‐3‐{[(4‐methyl‐1,2,5‐oxadiazol‐3‐yl)methyl]amino}‐2‐oxopyrazin‐1(2H)‐yl]butanoyl}amino)‐5‐[hexyl(methyl)amino]‐4‐oxopentanoic acid), in a rat malonate model of HD.

Pharmacokinetic and autoradiography studies after intrastriatal (i.str.) injection of 1.5 nmol of M826 or its tritiated analogue [3H]M826 indicated that the compound diffused within the entire striatum. The elimination half‐life (T1/2) of M826 in the rat striatum was 3 h.

I.str. injection of 1.5 nmol of M826 10 min after malonate infusion induced a significant reduction (66%) in the number of neurones expressing active caspase‐3 in the ipsilateral striatum.

Inhibition of active caspase‐3 translated into a significant but moderate reduction (39%) of the lesion volume, and of cell death (24%), 24 h after injury. The efficacy of M826 at inhibiting cell death was comparable to that of the noncompetitive NMDA receptor antagonist MK801.

These data provide in vivo proof‐of‐concept of the neuroprotective effects of reversible caspase‐3 inhibitors in a model of malonate‐induced striatal injury in the adult rat.

British Journal of Pharmacology (2004) 141, 689–697. doi:10.1038/sj.bjp.0705662
Endothelins contribute towards nociception induced by antigen in ovalbumin‐sensitised mice
Authors: Piovezan Anna P , D'Orléans‐Juste Pedro , Frighetto Monica , Souza Glória E P , Henriques Maria G M O , Rae Giles A
Published: February 2004

The contribution of endogenous endothelins to nociceptive responses elicited by ovalbumin (OVA) in the hind‐paw of mice sensitised to this antigen (50 μg OVA+5 mg Al(OH)3, s.c., 14 days beforehand) was investigated.

Sensitised mice exhibited greater nocifensive responsiveness to intraplantar (i.pl.) OVA (total licking time over first 30 min: 85.2±14.6 s at 0.3 μg; 152.6±35.6 s at 1 μg) than nonsensitised animals (29.3±7.4 s at 1 μg). Nocifensive responses of sensitised mice to 0.3 μg OVA were inhibited by morphine (3 mg kg−1, s.c.) or local depletion of mast cells (four daily i.pl. injections of compound 48/80).

Pretreatment with i.v. bosentan (mixed ETA/ETB receptor antagonist; 52 μmol kg−1) or A‐122722.5 (selective ETA receptor antagonist; 6 μmol kg−1) reduced OVA‐induced licking from 124.8±20.6 s to 45.7±13.0 s and 64.2±12.1 s, respectively, whereas A‐192621.1 (selective ETB receptor antagonist; 25 μmol kg−1) enhanced them to 259.2±39.6 s.

Local i.pl. pretreatment with BQ‐123 or BQ‐788 (selective ETA or ETB receptor antagonists, respectively, each at 3 nmol) reduced OVA‐induced licking (from 106.2±15.2 to 57.0±9.4 s and from 118.6±10.5 to 76.8±14.7 s, respectively). Sarafotoxin S6c (selective ETB receptor agonist, 30 pmol, i.pl., 30 min after OVA) induced nocifensive responses in OVA‐sensitised, but not in nonsensitised, animals.

Compound 48/80 (0.3 μg, i.pl.) induced nocifensive responses per se and potentiated those induced by i.pl. capsaicin (0.1 μg). Treatment with BQ‐123 (3 nmol, i.pl.) reduced only the hyperalgesic effect of compound 48/80, whereas BQ‐788 (3 nmol) was ineffective.

Thus, immune‐mediated Type I hypersensitivity reactions elicit mast cell‐ and endothelin‐dependent nociception in the mouse hind‐paw, which are mediated locally by both ETA and ETB receptors. The nocifensive response to antigen is amenable to blockade by systemic treatment with dual ETA/ETB or selective ETA receptor antagonists, but is sharply potentiated by systemic selective ETB receptor antagonist treatment. The apparently distinct roles played by ETB receptors in this phenomenon at local and other sites remain to be characterised.

British Journal of Pharmacology (2004) 141, 755–763. doi:10.1038/sj.bjp.0705663
Cyclosporin A enhances colchicine‐induced apoptosis in rat cerebellar granule neurons
Authors: Canudas Anna Maria , Jordà Elvira G , Verdaguer Ester , Jiménez Andrés , Sureda Francesc Xavier , Rimbau Víctor , Camins Antoni , Pallàs Mercè
Published: February 2004

Cyclosporin A (CsA, 1–50 μM), an immunosuppressive drug with known neurotoxic effects, did not decrease the viability of primary cultures of rat cerebellar granule neurons (CGN) or induce apoptotic features. However, CsA specifically enhanced the cytotoxicity and apoptosis induced by colchicine (1 μM).

Flavopiridol, an inhibitor of cyclin‐dependent kinases (CDKs), prevented the neurotoxic effects of colchicine plus CsA. At 0.1–5 μM, it also showed antiapoptotic effects, as revealed by propidium iodide staining, flow cytometry and counting of cell nuclei.

Roscovitine (25–50 μM), a selective cdk1, 2 and 5 inhibitor, showed an antiapoptotic effect against colchicine‐ and colchicine plus CsA‐induced apoptosis.

CsA increased the expression of cdk5 and cdk5/p25 mediated by colchicine, a CDK involved in neuronal apoptosis. After treatment of CGN with colchicine plus CsA, the changes in the p25/p35 ratio pointed to cdk5 activation.

Immunohistochemical results showed a nuclear localization of cdk5 after neurotoxic treatment, which was prevented by cdk inhibitors. Thus, we propose a new mechanism of modulation of CsA neurotoxicity mediated by cdk5.

British Journal of Pharmacology (2004) 141, 661–669. doi:10.1038/sj.bjp.0705664
Noradrenaline inhibits pacemaker currents through stimulation of β1‐adrenoceptors in cultured interstitial cells of Cajal from murine small intestine
Authors: Jun Jae Yeoul , Choi Seok , Yeum Cheol Ho , Chang In Youb , Park Chan Kuk , Kim Man Yoo , Kong In Deok , So Insuk , Kim Ki Whan , You Ho Jin
Published: February 2004

Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous inward currents (pacemaker currents) responsible for the production of slow waves in gastrointestinal smooth muscle. The effects of noradrenaline on the pacemaker currents in cultured ICCs from murine small intestine were investigated by using whole‐cell patch‐clamp techniques at 30°C.

Under current clamping, ICCs had a mean resting membrane potential of −58±5 mV and produced electrical slow waves. Under voltage clamping, ICCs produced pacemaker currents with a mean amplitude of −410±57 pA and a mean frequency of 16±2 cycles min−1.

Under voltage clamping, noradrenaline inhibited the amplitude and frequency of pacemaker currents and increased resting currents in the outward direction in a dose‐dependent manner. These effects were reduced by intracellular GDPβS.

Noradrenaline‐induced effects were blocked by propranolol (β‐adrenoceptor antagonist). However, neither prazosin (α1‐adrenoceptor antagonist) nor yohimbine (α2‐adrenoceptor antagonist) blocked the noradrenaline‐induced effects. Phenylephrine (α1‐adrenoceptor agonist) had no effect on the pacemaker currents, whereas isoprenaline (β‐adrenoceptor agonist) mimicked the effect of noradrenaline. Atenolol (β1‐adrenoceptor antagonist) blocked the noradrenaline‐induced effects, but butoxamine (β2‐adrenoceptor antagonist) did not. In addition, BRL37344 (β3‐adrenoceptor agonist) had no effect on pacemaker currents.

9‐(Tetrahydro‐2‐furanyl)‐9H‐purine‐6‐amine (SQ‐22536; adenylate cyclase inhibitor) and a myristoylated protein kinase A inhibitor did not inhibit the noradrenaline‐induced effects and 8‐bromo‐cAMP had no effects on pacemaker currents. 8‐Bromo‐cGMP and SNAP inhibited pacemaker currents and these effects of SNAP were blocked by 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ; a guanylate cyclase inhibitor). However, ODQ did not block the noradrenaline‐induced effects.

Neither tetraethylammonium (a voltage‐dependent K+ channel blocker), apamin (a Ca2+‐dependent K+ channel blocker) nor glibenclamide (an ATP‐sensitive K+ channel blocker) blocked the noradrenaline‐induced effects.

The results suggest that noradrenaline‐induced stimulation of β1‐adrenoceptors in the ICCs inhibits pacemaker currents, and that this is mediated by the activation of G‐protein. Neither adenylate cyclase, guanylate cyclase nor a K+ channel‐dependent pathway are involved in this effect of noradrenaline.

British Journal of Pharmacology (2004) 141, 670–677. doi:10.1038/sj.bjp.0705665
Predicting the distribution of four species of raptors (Aves: Accipitridae) in southern Spain: statistical models work better than existing maps
Authors: Bustamante Javier , Seoane Javier
Published: February 2004

Aim  To test the effectiveness of statistical models based on explanatory environmental variables vs. existing distribution information (maps and breeding atlas), for predicting the distribution of four species of raptors (family Accipitridae): common buzzard Buteo buteo (Linnaeus, 1758), short‐toed eagle Circaetus gallicus (Gmelin, 1788), booted eagle Hieraaetus pennatus (Gmelin, 1788) and black kite Milvus migrans (Boddaert, 1783).

Location  Andalusia, southern Spain.

Methods  Generalized linear models of 10 × 10 km squares surveyed for the presence/absence of the species by road census. Statistical models use as predictors variables derived from topography, vegetation and land‐use, and the geographical coordinates (to take account of possible spatial trends). Predictions from the models are compared with current distribution maps from the national breeding atlas and leading reference works.

Results  The maps derived from statistical models for all four species were more predictive than the previously published range maps and the recent national breeding atlas. The best models incorporated both topographic and vegetation and land‐use variables. Further, in three of the four species the inclusion of spatial coordinates to account for neighbourhood effects improved these models. Models for the common buzzard and black kite were highly predictive and easy to interpret from an ecological point of view, while models for short‐toed eagle and, particularly, booted eagle were not so easy to interpret, but still predicted better than previous distribution information.

Main conclusions  It is possible to build accurate predictive models for raptor distribution with a limited field survey using as predictors environmental variables derived from digital maps. These models integrated in a geographical information system produced distribution maps that were more accurate than previously published ones for the study species in the study area. Our study is an example of a methodology that could be used for many taxa and areas to improve unreliable distribution information.
King John and the Historians
Authors: Hollister C. Warren
Published: February 2004

King John Lackland was surely one of the most enigmatic figures ever to rule England. The dramatic ambivalence of his personality, the passions that he stirred among his own contemporaries, the very magnitude of his failures, have made him an object of endless fascination to historians and biographers. Whose interests would not be piqued by the man who was recently described by a distinguished scholar as “cruel and ruthless, violent and passionate, greedy and self-indulgent, genial and repellant, arbitrary and judicious, clever and capable, original and inquisitive”?

As one might expect, King John has received a great deal of scholarly attention. Nearly every historian who touches on any aspect of his reign feels compelled to offer his own judgment of John's puzzling character, his effectiveness, even his personal morality. The present century has seen, in addition to numerous specialized studies of various facets of John's reign, no less than three major biographies of that indefatigable but luckless king. The first of these, by Miss Kate Norgate, was published in 1902 and reflects the traditional viewpoint of the late nineteenth century. The second, Sidney Painter's work of 1949, stresses the monarch's relations with his baronial and administrative subordinates and presents a more genial and sophisticated interpretation of John himself. Hopes for a promised companion volume dealing with military and naval institutions and the development of the common law under John have been shattered by Painter's untimely death.
Thomas More: on the Margins of Modernity
Authors: Hexter J. H.
Published: February 2004

Once upon a time men who read and wrote about Sir Thomas More, the author of Utopia and Henry VIII's Lord Chancellor, were convinced that he was a modern man, by which in some measure they seem to have meant their kind of man. This conviction became fully standardized in the eighteenth and nineteenth centuries. Those, however, who saw him as a modern man — Lord Acton, Bishop Creighton, Principal Lindsay, Sir Sidney Lee — could not help but view More with impatience. For in their eyes he reneged on his modernity. He did not in the end stand firm for free thought, or for toleration, or for emancipation from the bondage of medieval bigotry and superstition. And although Karl Kautsky was sure that at the horizon Sir Thomas had seen the red light of the Marxist dawn, More did not even throw himself into the struggle for socialism. Instead he approved of the execution of men who were burnt at the stake because they rejected the spiritual control of the medieval church; and in the end he died a martyr for the unity which through the centuries that orthodox and persecuting Church had imposed on Europe.
John Milton's Movement toward Deism
Authors: Frank Joseph
Published: February 2004

In the sixteenth line of his Essay on Man Alexander Pope announced that his purpose was to “vindicate the ways of God to man.” John Milton waited until the twenty-sixth line of Paradise Lost to state that his aim was to “justify the ways of God to men.” It would be pedantic to inquire why Pope used the singular noun for the human race, Milton the plural. But it might be instructive to investigate why Milton chose to justify the ways of God, and Pope, two generations later, to vindicate them — especially since both words scan equally well. Moreover, even though Pope may have picked his verb to convey a hint of self-parody, Samuel Johnson two generations after Pope misquoted Paradise Lost when he wrote in his “Life of John Milton” that the epic's purpose was “to vindicate the ways of God to man.”

But before one proceeds down any such semantic-theological path he should be aware of two dangers. The first is the general warning that scholars who look for needles in haystacks almost always find them. The second is the specific caution that the word “justify” is a shaky foundation on which to build a case: its designations and connotations were — and still are — many-sided, and Milton may not have used it with any sense of defensiveness, even though today the word “vindicate” has a more positive, more assured ring. Yet despite these dangers, the path is inviting and the destination very possibly significant.
Milton and the Protestant Ethic
Authors: Haller William
Published: February 2004

Mr. Frank's engaging argument is convincing up to a point. Milton was indeed a protestant of the protestants and in true protestant fashion kept pressing on in his thinking to ever more extreme conclusions which seemed to him of the very essence of rationality. Such a course pointed in one direction logically enough to the reduction of the many divagations of protestant doctrine to a religion of common sense free of dilemmas and miracles. But such a conclusion would seem more natural to minds seeking a repose that ever is the same from the uncharted liberties taken by protestant revolutionaries than to a poet whose devotion to protestant individualism was as unflagging as Milton's. Mr. Frank seems to me more convincing when he says that “perhaps the Milton who wrote Paradise Lost, Paradise Regained and Samson Agonistes was more than an incipient deist, that he was what can be called a total Protestant.” But before one can say whether or to what degree Milton was even an incipient deist, surely one must consider what it amounted to in his case to be a “total” protestant, for not all total protestants turned out to be deists. In considering that question, since it was by way of their Pauline-Augustinian-Calvinistic theology that English protestants, not excepting Milton, arrived at their protestant ethic, it seems to me impossible to limit the term protestant as Mr. Frank suggests to its “ethical rather than theological signification.”
The Earl of Arlington and the Treaty of Dover
Authors: Lee Maurice D.
Published: February 2004

Henry Bennet, Earl of Arlington, like most other Restoration politicians, has suffered from a bad press. He has always been spoken of slightingly by what J. P. Kenyon calls the “bed-spring and chamber-pot” school of Restoration historians; and for once the serious scholars have agreed with the romancers. David Ogg, for instance, says of Arlington, “He had the gift for making the right friends and discarding them at the right moment; but as he lacked courage, he never rose to real greatness among the bad men of Charles's Court. … Always civil and obliging, his chief talent was that of anticipating and fostering what he thought to be the secret wishes of his royal master.” Arlington's biographer, Miss Violet Barbour, says nothing quite so harsh as that, but her implied opinion is clearly not very high. Of modern historians only Keith Feiling, in his work on British foreign policy from 1660 to 1672, is at all favorable. Most of Arlington's British contemporaries took an equally critical view of him. The attacks of Burnet and Clarendon are well known. Here is what the Duke of Buckingham, Arlington's great rival in the Cabal, had to say in his poem, “Advice to a Painter To Draw my L. A-----ton, Grand Minister of State”:

First draw an arrant fop, from top to toe

Whose very looks at first dash shew him so:

Two goggle-eyes, so clear, tho' very dead,

That one may see, thro' them, quite thro' his Head.

Let every nod of his, and subtle wink

Declare the fool would talk, but cannot think.

Let him all other fools so far surpasse

That fools themselves point at him for an ass.

Whether all this denigration is entirely deserved is open to serious doubt. Foreign observers had no such low opinion of Arlington. When he became secretary of state in 1662, the Venetian resident described him as "a man of wit and ability, affable and courteous, possessing several languages, . . . and competent for his position from his knowledge of the interests of foreign princes." And nine years later another Venetian resident called him "tried and prudent."
Party, Purpose, and Pattern: Sir Lewis Namier and His Critics
Authors: Price Jacob M.
Published: February 2004

The recent death of Professor Sir Lewis Namier (19 August 1960) provides an occasion to assess, albeit most tentatively, if not the man (I did not know him well), then at least his contribution to the writing of English history. The need for such an assessment is a little ironic, for Sir Lewis, for all his renown, has left a somewhat indistinct after-image among historians in this country. Ever since the appearance in 1929 of his great work on theStructure of Politics at the Accession of George III, his name has been a fixture in bibliographies and in the knowingness of knowing graduate student and cannier undergraduate. Yet few in this country have read his work through – that is, his monumental works on eighteenth century politics on which most of theestimeof hissuccès d'estimehas been built. Many more are familiar with the lectures, reviews and critical works on modern German and diplomatic history to which he devoted much of his productive effort between 1933 and 1953. Though these last are works of some importance, the ultimate reputation of Namier as a scholar must rest on his eighteenth century work — in fact upon his publications of 1929 and 1930. It is this work and some of the methodological questions it raises which are under discussion here.
“The White Man's Grave:” Image and Reality, 1780-1850
Authors: Curtin P. D.
Published: February 2004

There is a “black legend” about the climate of tropical countries, that lives on in spite of the knowledge geographers, meteorologists, and specialists in tropical medicine have gained over the past half century. With all the recent publicity given to West Africa, most people in the Western world carry a half-conscious image of “The White Man's Grave”. It is usually elaborated with such elements as “primitive tribes”, burning heat, fever-laden swamps, swarming insects, and miles of trackless jungle. Above all, West Africa is thought of as a place where white men cannot work. Only Africans can work there, and Europeans “go out” for brief periods at a considerable risk to their lives. Most of this image is, of course, quite false. Maximum temperatures on the West African coast would be moderate summer heat in the American mid-West. Insects are generally less annoying than they are in the United States. The forest is by no means trackless, but the home of sedentary agricultural people who have for centuries periodically cut it down to burn a place for their farms. Neither physical capacity for work nor immunity to disease is significantly different between Europeans and Africans on racial grounds.

Still, the image was not made up from imagination alone. In its British version, it was based on facts — facts misunderstood in Africa, reported “at home”, and repeated over several generations. Both the facts and the image have a part in shaping West African relations with Great Britain, and both the facts and the image have changed through time in significant ways. The early nineteenth century represents a crucial phase in these changes. British traders had been on the Guinea coast for two centuries before 1783, but the loss of the American War and the thirteen colonies brought a new phase in Anglo-African relations.
The Toryness of English Conservatism
Authors: Glickman Harvey
Published: February 2004

It has often been observed that the agreement underlying British politics today extends beyond the constitution to issues of public policy. To the historic consensus on “the rules of the game” the British have added a stalemate on “the welfare state.” Common sense dictates that electoral demands have shaped the terms of political debate, so that the Conservatives, whose interests obviously are served by lower taxation and less government interference in the affairs of business, have had to bow to the pressures for collectivism built up during World War II and institutionalized by five years of rule under a Labour Government. By the same token the Labour Party has had to re-evaluate its policies of government direction and control of social and economic affairs in the face of decided satisfaction recently with the Conservative operation of the welfare machinery.

Sole emphasis on electioneering, however, can overlook simultaneous and related developments on the ideological plane. For the community this can be observed in the gradual acceptance of Keynesian economics. The fact that government action can achieve and maintain full employment helped broaden and define the area of effective policy for both parties in Britain. More important for our purposes here is the inherent collectivism of British Conservatism — its “Toryness” — which permitted its adaptation to modern welfare policy and helped build the framework for that policy in the in ter-war years. It is my contention that British Conservatism exhibits its doctrinal element through its Tory tradition and that it is this tradition of the organic society, paternalism and authority, that served to interpret the demands of Conservative interests. The Tory tradition helps explain not only the collectivist similarity of the two main parties, it also contributes to an understanding of the endurance of Conservatism.
On the Road from Constance to 1688: The Political Thought of John Major and George Buchanan
Authors: Oakley Francis
Published: February 2004

It was Harold J. Laski who said “the road from Constance to 1688 is a direct one,” and he did so when speaking of the constitutional theories enunciated by the Conciliar thinkers and put into practice at the Council of Constance. These closely related theories had their roots deep in the corporative thinking of the medieval canon lawyers but sprang into prominence during the years after 1378, when the Western Church was divided first into two and then into three “obediences” under the sway of rival claimants to the Papacy. Basic to all the Conciliar theories was the central insistence that the final authority in the Church lay not with the Pope but with the whole body of the faithful and that the Pope possessed, therefore, not an absolute but merely a ministerial authority delegated to him for the good of the Church. This belief made it possible to appeal from the obduracy of the rival pontiffs to the decision of the faithful as expressed through their representatives assembled in a General Council of the whole Church, and such a possibility was actualized at the Councils of Pisa (1409) and Basel (1431-1449) and, most strikingly of all, at Constance (1414-1418). There it found expression, not only in the judgment and deposition of popes, but also in the promulgation of the decree Sacrosancta (1415), which declared:

This sacred synod of Constance, forming a General Council … represents the Catholic Church and has immediate power from Christ which anyone, of whatsoever status and condition, even if holding the Papal dignity, is bound to obey in matters pertaining to the Faith, extirpation of the schism and reformation of the said Church in head and members.
The Restoration of the Scottish Episcopacy, 1660-1661
Authors: Davies Godfrey , Paul H. Hardacre
Published: February 2004

The reign of Charles II was described by Wodrow as “one of the blackest periods,” and by the late Hume Brown as “the most pitiful chapter” of Scottish history, The former attributed Charles's tyranny to the influence of popery; Hume Brown thought it stemmed from his desire to maintain his prerogative and to fill his purse. Doubtless the latter was more nearly correct. Nevertheless, a re-examination of the events of 1660-61 in the light of certain new materials suggests that the restoration of Scottish episcopacy was accomplished only after much hesitation by the King and his principal advisers, who were far less sanguine of success than the firebrands in Edinburgh. The interdependence of Scottish and English developments was also probably more important than has hitherto been supposed. In this paper the Erastian character of the restoration in Scotland has rendered necessary the inclusion of certain political questions, but its main purpose is to elucidate the ecclesiastical settlement.

The extravagant rejoicings at the restoration of monarchy afford ample proof of Scotland's relief at the prospect of the dissolution of the union with England. The nation eagerly looked forward to the withdrawal of the English forces, the end of the cess, and the re-establishment of the old government by King, Council, and Parliament. The King's return seemed so desirable that no one thought to impose any conditions as the price of his restoration, and no Declaration of Breda was issued for Scotland.

Popular enthusiasm temporarily concealed the deep divisions between the Protesters (or Remonstrants) and the Resolutioners, the two principal parties in both church and state.
The Idea of Party in the Writing of Later Stuart History
Authors: Walcott Robert
Published: February 2004

The most familiar view of party, and one held almost universally for a century and a half, sees a continuity in party history from the Whigs and Tories of Charles II's reign to the Liberals and Conservatives of Victoria's. This view received its classic expression at the hands of Macaulay, and with him it was a verdict arrived at before he even began The History of England and more than thirty years before he finished with it. In an election speech at Edinburgh in 1839 he proudly traced his Whig ancestry back to the Roundheads of the time of Charles I. In the opening section of the History he was more specific and selected a certain day in October of 1641 for the birth of the modern party system. “From that day,” he wrote, “dates the corporate existence of the two parties which have ever since alternately governed the country.”

Macaulay was not the first historian to reach such a conclusion. Writing some twenty years earlier the Catholic John Lingard, in dealing with the 1678-1681 crisis over Exclusion of the Duke of York, wrote that “it was during this period that the appellations of Whig and Tory became permanently affixed to the two great political parties which for a century and a half [1680-1830] have divided the nation.” Even before the turn of the nineteenth century the same idea had been suggested by Thomas Somerville in his History of England which appeared in 1792.
Henry Pelham and the Duke of Newcastle
Authors: Barnes Donald Grove
Published: February 2004

In most histories of Great Britain in the eighteenth century the ministry of Henry Pelham, 1743 to 1754, is accorded small space. For example, Basil Williams' The Whig Supremacy, in the Oxford History of England, devotes only slightly more than thirty pages to these eleven years. No full-scale biography of Pelham has appeared since Archdeacon Coxe's enormous two-volume work in 1829, and this, as Macaulay wrote of a similar work, was the product of the author's scissors and paste pot rather than of his pen. Much has been done on phases of the career of Newcastle, but no complete biography has been attempted. It has been suggested that the enormous mass of material in the Newcastle and Hardwicke papers available in the Manuscript Room of the British Museum has scared off possible biographers. This, however, is not the only explanation. At one time I gave serious consideration to devoting several years to a full biography of the Duke; but in the end it was the quality of Newcastle and not the quantity of the material which deterred me.

The neglect of Pelham, however, is more puzzling; and appears to be a case of unsalutary neglect. Possibly the best explanation lies in the Pittolatry (if the term is allowable) of the great majority of both English and American historians writing on this period. Usually Pelham is not even ranked as a John the Baptist to William Pitt, but rather is treated in the same relationship to him as the older interpretation of the Old Regime in France is to the French Revolution and the Unreformed House of Commons to the Reform Bill of 1832.
The Reputation of Edmund Burke
Authors: Copeland Thomas W.
Published: February 2004

Of the many books which have been written about Edmund Burke, very few compare in importance with a book which was never written. Burke's “official biography” was first promised by his literary executors four years after his death; it was to be the final volume in their edition of his Works. When contemporaries realised, as they soon did, that the bringing out of the Works was going to take many years, some guessed that the biography might be postponed indefinitely. Sir James Mackintosh late in 1806, having remarked of Burke that “perhaps a fit biographer is more important to his just fame than ever such a person was before to a great man,” added a sharp comment:

Ten years have almost passed since Mr. Burke's death. This is by no means a long time to employ in writing his life; but it is too long to elapse before it is begun. I hope this is not the case with Dr. Lawrence.

Alas! it was exactly the case. When Dr. French Laurence, the most energetic of Burke's literary executors, died in 1809, he had seen through the press four volumes of the octavo edition of the Works but no portion of the promised biography. He had collected biographical materials, which are still among Burke's papers, but nothing was thrown into form. His collaborator and successor, Dr. Walker King, went on collecting materials, and renewed the promise of a biography, but he too put off its execution until his other tasks could be accomplished.
Across the Western Sea (1783-1845)
Authors: Kraus Michael
Published: February 2004

In ancient Greece the priests of Apollo asserted that freedom of movement was one of the essentials of human freedom. Many hundreds of years later, toward the end of the eighteenth century, people in the Atlantic world again talked of emigration as one of man's natural rights. It was in northern and western Europe that easier mobility was first achieved within the various states. The next step was to use that mobility to leap local boundaries to reach the lands across the western sea. From the “unsettlement of Europe” (Lewis Mumford's phrase) came the settlement of America.

Americans and those who wished to become Americans felt at home in the geographical realm conceived by Oscar Wilde. “A map of the world that does not include Utopia,” he said, “is not even worth glancing at, for it leaves out the one country at which Humanity is always landing. Progress is the realization of Utopias.” It was the belief that Utopias were being realized in America that caused millions to leave Europe for homes overseas.

I

A Scottish observer, Alexander Irvine, inquiring into the causes and effects of emigration from his native land (1802), remarked that there were “few emigrations from despotic countries,” as “their inhabitants bore their chains in tranquility”; “despotism has made them afraid to think.” Nevertheless, though proud of the freedom his countrymen enjoyed, Irvine was critical of their irrational expectations in setting forth to America. There were few individuals or none in the Highlands, he said, “who have not some expectation of being some time great or affluent.