bluuebunny/crossref_metadata_2025_split huggingface dataset:
Feedback control of arterial smooth muscle tone: the role of prostacyclin
Authors: Hadházy P. , Magyar K. 
Published: July 2012

Indomethacin potentiated noradrenaline (NA)‐induced contractions of rabbit isolated mesenteric arteries. Mechanical removal of the endothelium did not influence its potentiating effect.
Prostacyclin (PGI2) synthesis was stimulated by NA (0.1‐1.0 μmol 1−1) and inhibited by indomethacin in a concentration‐dependent manner.
There was a positive correlation between the indomethacin‐induced inhibition of PGI2 formation and the indomethacin‐evoked potentiation of contractile responses to NA.
These results suggest that endogenous PGI2 plays a part in the feedback control of vascular smooth muscle tone.
Effect of exogenous 5, 8, 11, 14, 17‐eicosapentaenoic acid on cardiac anaphylaxis
Authors: Juan H. , Peskar B.A. , Simmet Th. 
Published: July 2012

The effects of infusions of eicosapentaenoic acid (EPA) (6 × 10−8 mol min−1 and 15 × 10−8 mol min−1) on the coronary constriction and the release of immunoreactive sulphidopeptide‐leukotrienes (SP‐LT), thromboxane B2(TXB2) and 6‐keto‐prostaglandin F1α(PGF1α) from perfused anaphylactic guinea‐pig hearts were investigated.
EPA dose‐dependently inhibited the profound early coronary flow reduction after antigen injection. The less pronounced late phase of anaphylactic coronary flow reduction was, however, not significantly affected. EPA (15 × 10−8 mol min−1) significantly shortened the average duration of antigen‐induced arrhythmias.
EPA dose‐dependently decreased release of immunoreactive TXB2 and 6‐keto‐PGF1α from anaphylactic guinea‐pig hearts.
Release of immunoreactive SP‐LT was dose‐dependently increased after antigen challenge in the presence of EPA. Inhibition of the release of SP‐LT by the lipoxygenase inhibitor esculetin (1 × 10−7 mol min−1) was accompanied by a significant attenuation of flow reduction during the late phase of anaphylactic vasoconstriction.
Reversed phase h.p.l.c. of perfusates from anaphylactic guinea‐pig hearts revealed immunoreactivity comigrating with authentic leukotriene C4 (LTC4), LTD4 and LTE4. In perfusates from hearts treated with EPA infusions, additional immunoreactivity was detected comigrating with LTC5, LTD5 and LTE5. In addition to immunoreactivity migrating with LTB4, as observed in control heart perfusates, in perfusates from EPA‐treated hearts, a second peak was observed, which coincides with the retention time described for LTB5.
Exogenous LTC5 (1 × 10−12 mol min−1 and 20 × 10−12 mol min−1) induced dose‐dependent reductions of coronary flow and was found to be a slightly weaker constrictor than LTC4, but no significant differences were observed. Coronary vasoconstriction elicited by infusion of exogenous LTC4 (20 × 10−12 mol min−1) was dose‐dependently inhibited by infusions of EPA. However, the negative inotropic effect of LTC4 remained unaffected.
Thus, in the isolated anaphylactic heart of the guinea‐pig exogenous EPA was effectively metabolized via the 5‐lipoxygenase pathway whereas the cyclo‐oxygenase pathway of polyunsaturated fatty acid metabolism was found to be inhibited. The results are in agreement with the suggestion that cyclo‐oxygenase products are mediators of the early phase of the anaphylactic coronary constriction, while vasoconstrictor SP‐LT are involved in the later phase. However, in spite of enhanced release of SP‐LT, EPA infusion did not result in increased coronary constriction. Considering the fact that EPA antagonizes LTC4‐induced coronary constriction, it seems possible, that EPA might act as a functional antagonist of vasoconstrictor eicosanoids including EPA‐derived SP‐LT.
Failure of prostaglandin E2 and its 16,16‐dimethyl analogue to prevent the gastric mucosal damage induced by Paf
Authors: Steel Graham , Wallace John L. , Whittle Brendan J.R. 
Published: July 2012

Intravenous and orally administered prostaglandin E2 (PGE2) and 16,16‐dimethyl PGE2 (dm PGE2) protect the rat gastric mucosa from injury induced by oral administration of acidified 40% ethanol. The effects of pretreatment with these prostaglandins on platelet activating factor (Paf)‐induced gastric damage has now been investigated in the rat.
A 10 min infusion of Paf (50 or 100 ng kg−1 min−1, i.v.) resulted in dose‐related vasocongestion of the gastric mucosa.
Intravenous pretreatment with dmPGE2 (20 μg kg−1) failed to prevent the gastric damage induced by the higher dose of Paf. Pretreatment with PGE2 (10–100 μg kg−1) or dmPGE2 (1–20 μg kg−1), either orally or intravenously, also failed to prevent the gastric vasocongestion induced by the lower dose of Paf. On the contrary, significant augmentation of Paf‐induced damage was observed with several of the doses of PGE2 and dmPGE2.
These studies demonstrate that the protective properties of PGE2 and dmPGE2 in the gastric mucosa do not extend to damage induced by Paf.
Crystal‐induced inflammation in the rat subcutaneous air‐pouch
Authors: Brooks P.M. , Burton D. , Forrest M.J. 
Published: July 2012

Monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals initiated acute inflammatory reactions characterized by increased plasma extravasation and polymorphonuclear leukocyte (PMNL) accumulation in the rat subcutaneous air‐pouch.
Pretreatment of rats with colchicine (1 mg kg−1, s.c.) inhibited PMNL accumulation induced by either crystal type but had a greater inhibitory effect on MSU‐induced plasma extravasation compared with that induced by CPPD crystals.
Colchicine (1 mg kg−1, s.c.) did not reduce histamine‐induced plasma extravasation in the air‐pouch.
The lipoxygenase product of arachidonic acid metabolism, leukotriene B4 (LTB4), was detected in MSU‐induced exudates but not in CPPD‐induced exudates.
Pretreatment of rats with colchicine (1 mg kg−1, s.c.) inhibited LTB4 production in MSU‐induced exudates.
Inhibition of IgE‐dependent histamine release from human dispersed lung mast cells by anti‐allergic drugs and salbutamol
Authors: Church Martin K. , Hiroi Jun 
Published: July 2012

The ability of the anti‐allergic drugs, sodium cromoglycate (SCG), lodoxamide, traxanox, RU31156 and the β‐adrenoceptor agonist sulbutamol to inhibit IgE‐dependent histamine and prostaglandin D2 (PGD2) release was assessed using human dispersed lung mast cells.
The anti‐allergic drugs were weak inhibitors of histamine release, high concentrations (100–1000 μm) producing < 35% inhibition. Salbutamol produced 39% inhibition at 10 μm.
The efficacy of both SCG and salbutamol was inversely related to the concentration of anti‐IgE used for challenge and to the degree of histamine release.
Rapid tachyphylaxis was observed with all anti‐allergic drugs but not with salbutamol.
Cross‐tachyphylaxis was observed between SCG and the other anti‐allergic drugs, suggesting a common mechanism of action. No cross‐tachyphylaxis was observed between SCG and salbutamol.
SCG was significantly (P < 0.001) more effective in inhibiting PGD2 than it was histamine release. Preferential inhibition of PGD2 compared with histamine release was less marked (P < 0.05) with salbutamol and not significant with the other anti‐allergic drugs.
Mast cells dispersed by enzymatic digestion of human lung released more histamine on immunological challenge than mechanically dispersed cells obtained by fine chopping of tissue. Enzyme treatment of mechanically dispersed cells removed this difference. Enzymatically and mechanically dispersed cells responded similarly to the inhibitory effects of SCG and salbutamol.
Our results suggest that salbutamol is a more effective inhibitor of mediator release from human lung mast cells than anti‐allergic drugs. However, with the low levels of mediator release achieved during an allergic reaction in man in vivo, both salbutamol and SCG are likely to be effective inhibitors of both preformed and newly generated mediators.
Influence of derivation on the lipophilicity and inhibitory actions of cardiac glycosides on myocardial Na+‐K+‐ATPase
Authors: Dzimiri Nduna , Fricke Uwe , Klaus Wolfgang 
Published: July 2012

Lipophilicity and inhibitory actions on guinea‐pig heart Na+‐K+‐ATPase of twenty‐six digitalis and six strophanthus glycosides comprising the aglycones, mono‐, bis‐, tris‐sugar, alkylated (acylated) tris‐sugar, acyl steroid derivatives and three cardanolides were investigated.
Their octanol/water partition coefficients (P), reversed phase thin layer (r.t.l.c.) and reversed phase high performance liquid chromatography (r.h.p.l.c.) were determined and the viability of these methods as a measure of the lipophilicity of the cardiotonic steroids evaluated.
The influence of lipophilicity and so also structural changes on the inhibitory effects of the cardiac glycosides on myocardial Na+‐K+‐ATPase was then examined.
It is concluded that (a) r.t.l.c. and r.h.p.l.c. are just as effective as the conventional shake‐flask method for estimation of the lipophilicity of cardiac glycosides and (b) the inhibitory potencies of cardiotonic steroids on the myocardial Na+‐K+‐ATPase increase with growing lipophilicity. The relationship between these two parameters is, however, governed by the influence of substitution or derivation of structural components on their inhibitory potencies on the myocardial Na+‐K+‐ATPase.
Failure of allopurinol and a spin trapping agent N‐t‐butyl‐α‐phenyl nitrone to modify significantly ischaemia and reperfusion‐induced arrhythmias
Authors: Parratt James R. , Wainwright Cherry L. 
Published: July 2012

The possible role of free radicals in the genesis of occlusion and reperfusion‐induced arrhythmias was studied by determining the effects of the xanthine oxidase inhibitor allopurinol (400 mg p.o. 24 h before experimentation + 25 mg kg−1 i.v.) and the free radical scavenger N‐t‐butyl‐α‐phenyl nitrone (PBN; 50 mg kg−1 i.v.) on these arrhythmias in chloralose anaesthetized greyhounds.
Neither of the drugs had any major effects on haemodynamic variables, although allopurinol caused a significant increase in heart rate.
The mean number of extrasystoles observed during ischaemia in dogs given allopurinol or PBN was not significantly different from those seen in controls. Further, the incidence of ventricular fibrillation during either occlusion or reperfusion was unchanged by either drug and there was thus no improvement in survival.
These results suggest that, in this model of myocardial ischaemia and reperfusion, free radicals may not play a major role in the genesis of life‐threatening arrhythmias.
Circulating [Met]enkephalin and catecholamine responses to acute hypotension and hypertension in anaesthetized greyhounds
Authors: Mason D.F.J. , Medbak S. , Rees Lesley H. 
Published: July 2012

The effects of either hypotension induced by sodium nitroprusside or hexamethonium or hypertension produced by angiotensin II or noradrenaline on the circulating levels of methionine enkephalin ([Met]enkephalin)‐like immunoreactivity (MLI), adrenaline and noradrenaline in anaesthetized greyhounds were examined.
Nitroprusside infusions (200 and 400 μg min−1) induced a fall in blood pressure accompanied by significant rises in plasma MLI and catecholamine concentrations.
Concomitant administration of a high dose of naloxone did not alter the fall in blood pressure produced by nitroprusside but was associated with greater rises in circulating MLI and catecholamines when compared to nitroprusside alone, suggesting that [Met]enkephalin is not involved in the hypotensive action of nitroprusside.
Intravenous hexamethonium (2.5 mg kg−1) provoked a fall in blood pressure which was not associated with any changes in plasma MLI. However, it produced a fall in plasma noradrenaline and a rise in plasma adrenaline. Thus it appears that neural mechanisms are required, at least in part, for the release of MLI.
Angiotensin II (1.25 μg kg−1 min−1) and noradrenaline (8 μg kg−1 min−1) infusions produced an elevation in blood pressure without altering the circulating MLI levels.
Study of the molecular forms of circulating MLI, before and during hypotension, revealed that the large molecular weight enkephalin‐containing peptides with approximate molecular sizes of 18kD and 8kD were the predominant forms both in the basal and stimulated states.
It is concluded that circulating [Met]enkephalin is not involved in the tonic control of blood pressure but it may modulate catecholamine release following hypotension as part of the stress response.
Inhibition of cholesteryl ester deposition in macrophages by calcium entry blockers: an effect dissociable from calcium entry blockade
Authors: Daugherty Alan , Rateri Debra L. , Schonfeld Gustav , Sobel Burton E. 
Published: July 2012

The effects of calcium entry blockers on stimulated cholesteryl [3H]‐oleate deposition in cultured macrophages were characterized in order to elucidate mechanisms underlying possible antiatheros‐clerotic effects. Stimulation of intracellular cholesteryl [3H]‐oleate deposition was initiated by incubation of macrophages with β‐very low density lipoproteins (β‐VLDL).
Nifedipine (Class I) markedly reduced cholesteryl [3H]‐oleate deposition at all concentrations tested. However, Bay K 8644, a dihydropyridine which is known to stimulate calcium entry, also reduced cholesteryl [3H]‐oleate deposition with a similar potency to nifedipine.
The effects of three Class II calcium entry blockers were evaluated: verapamil, methoxyverapamil, and diltiazem. Verapamil inhibited cholesteryl [3H]‐oleate deposition in a concentration‐dependent manner. Similarly, methoxyverapamil reduced cholesteryl [3H]‐oleate deposition in a concentration‐dependent manner although the reduction was not as great as that produced by verapamil. In contrast, diltiazem at any concentration tested did not inhibit cholesteryl [3H]‐oleate deposition.
Flunarizine (a Class III calcium entry blocker) produced a modest stimulation of cholesteryl [3H]‐oleate deposition at the lowest concentration used (10−7 m) but marked depression at the highest concentration (10−5 m).
The results indicate calcium entry blockers may exert protective effects on the development of atherosclerosis in animal models of diet‐induced hyperlipidaemia by inhibiting intracellular cholesteryl ester deposition, but this effect may not be related to their calcium entry‐blocking effects.
Cytoprotective effects of disodium cromoglycate on rat stomach mucosa
Authors: Goossens J. , Van Reempts J. , Van Wauwe J.P. 
Published: July 2012

The cytoprotective effects of the anti‐asthmatic drug, disodium cromoglycate (DSCG), on gastric mucosal necrosis induced by ethanol in rats were studied. Subcutaneous, but not oral, DSCG prevented the formation of gastric lesions and this effect was dose‐dependent between 1.25 and 40 mg kg−1, with an ED50 value of 6.8 mg kg−1. Maximal cytoprotection occurred 15–30 min after DSCG treatment.
Histological examination revealed that DSCG effectively protected the gastric mucosa against ethanol‐induced vascular congestion, haemorrhage, epithelial desquamation and mucosal oedema.
Enhanced production of endogenous prostaglandins, which are known cytoprotective compounds, could not explain the mucosal protection. At a dose of 40 mg kg−1, DSCG did not change prostaglandin E2 or 6‐keto‐prostaglandin F1α concentrations in gastric mucosal tissue, although its cytoprotective activity was partially inhibited by prior treatment of the animals with indomethacin.
GABAergic modulation of a substance P‐mediated reflex of slow time course in the isolated rat spinal cord
Authors: Akagi Hiroyuki , Yanagisawa Mitsuhiko 
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) and other drugs which interact with GABA receptors were studied on a reflex of slow time course in the spinal cord preparation isolated from the neonatal rat.
A single shock to a dorsal root (L3‐L5) elicited a stereotyped series of reflexes, consisting of fast and slow components, recorded from the contralateral ventral root of the corresponding segment. The slow component, i.e. the contralateral slow ventral root potential (v.r.p.) had a time‐to‐peak of 2–5 s and lasted 20–30 s.
Bath‐application of GABA (5–20 μm) or muscimol (0.05‐0.5 μm) caused a decrease in the amplitude of the contralateral slow v.r.p. without producing any change in the d.c. potential recorded from the ventral root. The monosynaptic reflex recorded from the ipsilateral ventral root was not changed by the drugs at these concentrations.
Diazepam (0.1−1 μm) potentiated the depolarizing response of the dorsal root to GABA and markedly depressed the contralateral slow v.r.p. Neither the d.c. potential of the ventral root nor the dorsal root was changed by diazepam. The monosynaptic reflex was also unaffected by the drug.
Bicuculline (1 μm) suppressed the GABA‐induced depolarization recorded from the dorsal root whilst it markedly potentiated the contralateral slow v.r.p.
Baclofen at concentrations from 0.01 to 0.1 μm reduced the contralateral slow v.r.p. The inhibitory action of baclofen on the contralateral slow v.r.p. was more marked than on the monosynaptic reflex.
The depolarization of the ventral root induced by a brief application of substance P (SP) was depressed by muscimol, diazepam and baclofen, whereas the depolarization was potentiated by bicuculline.
The present results suggest that an intraspinal GABAergic inhibitory mechanism plays a role in the modulation of certain slow spinal reflexes. They also support the hypothesis that SP released from certain primary afferent fibres is a neurotransmitter involved in the contralateral slow v.r.p.
Identification of 13,14‐dihydro‐15‐oxo‐prostaglandin F2α in the circulation during infusions of bradykinin and prostaglandin E2 in man
Authors: Barrow S.E. , Cockcroft J. , Dollery C.T. , Hickling N.E. , Ritter J.M. 
Published: July 2012

Bradykinin, prostaglandin E2 (PGE2), PGD2 and vehicle (saline) were each administered intravenously on separate occasions to 6 healthy men for a period of 60 min.
13,14‐Dihydro‐15‐oxo‐PGF2α was identified in plasma samples obtained during intravenous infusions of bradykinin and PGE2 but not during infusions of PGD2 or saline.
The structure of this metabolite was verified by comparison of three different derivatives with authentic standards, using gas chromatography/electron capture mass spectrometry.
Bradykinin increased plasma concentrations of 13,14‐dihydro‐15‐oxo‐PGF2α from baseline values in the range < 5–10 pg ml−1 to 28–403 pg ml−1. PGE2 increased plasma concentrations of 13,14‐dihydro‐15‐oxo‐PGF2α from baseline values in the range < 5–17 pg ml−1 to 160–603 pg ml−1. Neither PGD2 nor the vehicle affected 13,14‐dihydro‐15‐oxo‐PGF2α concentrations.
We conclude that bradykinin‐stimulated 13,14‐dihydro‐15‐oxo‐PGF2α may be derived from PGE2 or PGF2α. The possibility that these prostaglandins are synthesized by stimulation of microvascular endothelium during bradykinin infusion is discussed.
The effects of intraperitoneal administration of antagonists and development of morphine tolerance on the antinociception induced by stimulating the anterior pretectal nucleus of the rat
Authors: Rees H. , Prado W.A. , Rawlings S. , Roberts M.H.T. 
Published: July 2012

The effects of intraperitoneal administration of antagonists to morphine, 5‐hydroxytryptamine (5‐HT), noradrenaline and dopamine have been studied on the antinociceptive effects of electrical stimulation of the anterior pretectal nucleus (APtN) of the rat.
A 15 s period of 35 μA sine wave stimulation of APtN significantly increased the latency of the tail flick reflex to noxious heat for periods up to 1 h.
Naloxone (0.25‐1.0 mg kg−1) attenuated the effects of APtN stimulation in a dose‐dependent manner. In rats made tolerant to morphine by daily administration of morphine, the antinociceptive effects of APtN stimulation were significantly reduced.
The 5‐HT receptor antagonists methysergide (5 mg kg−1) and ketanserin (1 mg kg−1), the dopamine receptor antagonist haloperidol (1 mg kg−1) and the β‐adrenoceptor antagonist propranolol (1 mg kg−1) had little effect on the antinociceptive effects of stimulating the APtN.
α‐Adrenoceptor antagonists caused a dose‐dependent antagonism of the response. The order of potency was; idazoxan > prazosin > phenoxybenzamine, the respective ED50 for each drug being 0.08: 0.45: 1.5 mg kg−1.
It is concluded that antagonism at opioid receptors and α‐adrenoceptors but not β‐adrenoceptors, dopamine or 5‐HT receptors reduces the antinociceptive effects of APtN stimulation. This differs from the reported effects of these antagonists on the antinociception caused by stimulating other sites in the brain.
Calcitonin gene‐related peptide (CGRP) is a potent non‐endothelium‐dependent inhibitor of coronary vasomotor tone
Authors: Greenberg Barry , Rhoden Kerry , Barnes Peter 
Published: July 2012

Ring segments of bovine left circumflex coronary artery were pre‐contracted with 5‐hydroxytryptamine or phenylephrine and then exposed to increasing concentrations of calcitonin gene‐related peptide (CGRP) and other drugs.
CGRP administration resulted in dose‐dependent inhibition of induced tone. Maximal relaxation to CGRP was 89 ± 5% and the concentration required to achieve 50% maximal relaxation (EC50) was 2.11 ± 1.35 × 10−9 m.
CGRP‐induced relaxation was not affected by removal of endothelial cells nor was it significantly altered by incubation of coronary vessels with atropine, propranolol, phentolamine (all 10−6 m) or indomethacin (10−5 m).
From these data we conclude that CGRP is a potent inhibitor of coronary artery vasomotor tone which appears to act directly on vascular smooth muscle rather than through the release of a secondary mediator. These data support the possibility that CGRP may play a role in non‐adrenergic, non‐cholinergic regulation of coronary artery tone.
Inhibition of adrenomedullary catecholamine release by propranolol isomers and clonidine involving mechanisms unrelated to adrenoceptors
Authors: Orts Alfredo , Orellana Carmen , Cantó Tomás , Ceña Valentín , González‐García Carmen , García Antonio G. 
Published: July 2012

Transmural electrical stimulation (10 Hz, 40 V, 1 ms for 60 s) increased total catecholamine secretion from perfused cat adrenal glands; this respnse was enhanced by neostigmine and inhibited by mecamylamine, suggesting that release of acetylcholine from splanchnic nerve terminals was stimulating nicotinic receptors and enhancing catecholamine secretion.
Isoprenaline, (‐)‐propranolol and (+)‐propranolol (10−7‐10−5 m) inhibited the electrically‐evoked secretory response by 40–70%; similar reductions were obtained with clonidine and yohimbine. Neither, (+)‐propranolol nor (‐)‐propranolol inhibited K‐evoked secretion from cat adrenals; in contrast, nimodipine potently inhibited it (IC50 = 24 nm).
Either, racemic propranolol or the (+)‐ or (‐)‐isomers (1–10 μm) equally inhibited [3H]‐noradrenaline release evoked by nicotine or acetylcholine from cultured bovine adrenal chromaffin cells; clonidine (10 μm) inhibited secretion by 50% and yohimbine or isoprenaline did not affect it.
The results indicate that adrenomedullary catecholamine release evoked by splanchnic nerve stimulation is not modulated by α‐or β‐adrenoceptors and suggest that propranolol may inhibit secretion by blocking ion fluxes through the acetylcholine receptor ionophore. Clonidine may inhibit secretion by this same mechanism, and/or by interfering with some intracellular event in the secretory mechanism.
New synthetic antagonists of bradykinin
Authors: Schachter M. , Uchida Y. , Longridge D.J. , Labedz T. , Whalley E.T. , Vavrek R.J. , Stewart J.M. 
Published: July 2012

A new synthetic bradykinin analogue was found to be an antagonist of bradykinin‐induced vascular permeability in rabbit skin. It was effective in equimolar concentrations.
These analogues also antagonized the action of bradykinin in contracting the guinea‐pig isolated ileum. The mean pA2 values of five different antagonists ranged from 5.3–6.4 respectively, on this preparation.
Our observations, together with those of others suggest that these antagonists act on the same receptor types, viz., B2, in rabbit blood vessels and in smooth muscle of guinea‐pig ileum.
Our results support the view that the way is now promising for the synthesis of potent specific antagonists of bradykinin for experimental and therapeutic use.