bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anticonvulsant effects of some calcium entry blockers in DBA/2 mice
Authors: De Sarro G.B. , Meldrum B.S. , Nisticó G. 
Published: July 2012

The behavioural and anticonvulsant effects of several drugs acting by various mechanisms on calcium‐channels or affecting intracellular Ca2+ concentrations were studied after both systemic and intracerebroventricular administration in DBA/2 mice, a strain genetically susceptible to sound‐induced seizures.
The anticonvulsant effects were evaluated on seizures evoked by means of auditory stimulation (109 dB) in animals placed singly under a perspex dome.
Flunarizine and dihydropyridine derivatives, belonging to class I of calcium entry blockers, administered intraperitoneally, were the most potent compounds.
Diltiazem, a benzothiazepine derivative belonging to class III, and HA 1004, a calcium antagonist, acting by inhibiting Ca2+ mobilization from intracellular stores, injected intraperitoneally, were 3–7.6 fold and 5.8–10.7 fold less potent than flunarizine respectively.
Verapamil and methoxyverapamil, two phenylalkylamine derivatives, given intraperitoneally, were completely ineffective in preventing sound‐induced seizures in DBA/2 mice. In addition, high doses of verapamil and its methoxyderivative occasionally produced spontaneous tonic‐clonic seizures.
After intracerebroventricular administration of the hydrosoluble calcium entry blockers, belonging to different classes, the anticonvulsant effects were similar to those observed after systemic administration.
The systemic administration of Bay K 8644, a dihydropyridine analogue, having the ability to stimulate calcium entry into cells produced a dose‐dependent increase in clonic and tonic convulsions and other neurological side effects.
The present results strongly support the idea that some Ca2+ antagonists may be useful in human epilepsy.
Lysophosphatidylcholine‐induced arrhythmias and its accumulation in the rat perfused heart
Authors: Man Ricky Y.K. 
Published: July 2012

The tissue level of lysophosphatidylcholine (LPC) was determined in rat hearts perfused with a solution containing 5 μm LPC. The relationship between LPC accumulation and the severity of arrhythmias produced was examined.
The accumulation of LPC was dependent on the perfusion time and this accumulation was associated with the occurrence of severe arrhythmias. A positive correlation between the tissue LPC content and the arrhythmia score was found (P < 0.01).
No consistent alteration in total phospholipid, phosphatidylcholine or cholesterol content was found. This suggests that LPC‐induced arrhythmias are not associated with alterations of major lipid components in the heart.
When severe arrhythmias occurred in the presence of LPC in the rat perfused heart, less than 2% of total tissue phospholipid was in the form of LPC.
The positive correlation between LPC accumulation and the occurrence of arrhythmias suggests a cause and effect relationship of LPC with cardiac arrhythmias in the rat perfused heart. However, in the ischaemic heart, other biochemical factors can contribute, to different degrees, to ischaemia‐induced cardiac arrhythmias.
A study of the actions of P1‐purinoceptor agonists and antagonists in the mouse vas deferens in vitro
Authors: Blakeley A.G.H. , Dunn P.M. , Petersen S.A. 
Published: July 2012

We have examined the effects of purinoceptor agonists and antagonists on the mechanical ‘twitch’ response, excitatory junction potential (e.j.p.) amplitude and [3H]‐noradrenaline overflow in the mouse vas deferens.
The agonist profile for inhibition of the mechanical response was N6‐([R]‐2‐phenylisopropyl)adenosine (l‐PIA) ⋍ N6‐cyclohexyladenosine (CHA) > 5′ N‐ethylcarboxamidoadenosine (NECA) > 2‐chloroadenosine (2ClA) ⋍ N6‐([S]‐2‐phenylisopropyl)adenosine (d‐PIA).
The P1‐purinoceptor agonists inhibited the e.j.p. with an agonist profile of CHA > l‐PIA NECA > 2ClA.
2ClA inhibited [3H]‐noradrenaline overflow with an EC50 of 1.2 μm which was not significantly different from the values for inhibition of the e.j.p. and the mechanical response.
The inhibitory action of 2ClA on the mechanical response was antagonized by 5 μm 8‐phenyltheophylline (8‐PT). However, neither blockade of P1‐purinoceptors by 8‐PT nor increasing the rate of degradation of endogenous adenosine by addition of adenosine deaminase had any effect on the mechanical response per se. 8‐PT (5 μm) also failed to alter the e.j.p. amplitude or [3H]‐noradrenaline overflow.
These results indicate that there are P1‐purinoceptors present on sympathetic nerve terminals of the mouse vas deferens which are more like A1‐ than A2‐receptors, but may be better classified as being of the A3‐subtype (Ribeiro & Sebastiao, 1986). These receptors are not normally involved in the feedback regulation of transmitter release in this tissue.
Hypoglycaemic and hypoketonaemic effects of single and repeated oral doses of methyl palmoxirate (methyl 2‐tetradecylglycidate) in streptozotocin/alloxan‐induced diabetic dogs
Authors: Tuman Robert W. , Tutwiler Gene F. , Joseph John M. , Wallace Nathaniel H. 
Published: July 2012

The hypoglycaemic and hypoketonaemic effects of orally administered methyl palmoxirate were studied in streptozotocin/alloxan‐induced diabetic dogs.
Single oral 50 mg doses (≅7.5 mg kg−1) of methyl palmoxirate produced statistically significant reductions of plasma glucose (32 ± 6% maximum reduction from baseline) and ketones (74 ± 12% maximum reduction from baseline), with the peak effect on plasma ketones (3.5 h) preceding that for plasma glucose (6.0 h).
Lower doses (0.7‐2.0 mg kg−1 daily) of methyl palmoxirate given repeatedly for seven days produced reductions of blood glucose and ketones equivalent to those produced with the higher single dose. Maximal reductions of plasma ketones were generally observed following the first dose of drug, whereas significant lowering of plasma glucose required several days of continuous dosing.
Repeated daily doses of methyl palmoxirate markedly reduced the overnight fasting ketone levels but not glucose levels of diabetic dogs.
In conclusion, administration of the fatty acid oxidation inhibitor methyl palmoxirate, in the absence of concomitant insulin therapy, was able to lower the plasma glucose and ketone levels of insulin‐deficient streptozotocin/alloxan diabetic dogs. Only the plasma ketones were decreased to normal by this treatment.
An investigation of the pharmacological response to vitamin K1 in the rabbit
Authors: Winn M.J. , Cholerton S. , Park B.K. 
Published: July 2012

The relationship between pharmacological response and disposition of a dose of vitamin K1 (10 mg kg−1, i.v.) in normal rabbits and in rabbits treated with the coumarin anticoagulant brodifacoum, has been studied.
High performance liquid chromatography (h.p.l.c.) with electrochemical detection (EC) was used to determine concentrations of vitamin K1 in plasma, whole liver homogenate, and liver microsomes.
After intravenous administration of vitamin plasma concentrations of the vitamin declined in a tri‐exponential fashion. There were no differences between the two groups over the first 24 h of the experiment. However, between 24 h and the end of the study, plasma concentrations of vitamin K1 in the presence of brodifacoum were significantly (P ≤ 0.05) below those of vehicle‐treated rabbits.
Seventy‐two hours after administration of vitamin K1, plasma concentrations of the vitamin were not different from normal.
Three hours after administration of vitamin K1, the concentrations of the vitamin in whole liver were 46.6 ± 4.3 μg g−1 in the presence of brodifacoum, and 32.8 ± 6.4 μg g−1 in the absence of brodifacoum; and were significantly (P ≤ 0.05) greater than normal (127.7 μ 44.3 ng g−1). Likewise, microsomal concentrations of vitamin K1 (4.00 ± 2.38 μg mg−1 protein, and 2.65 ± 1.01 μg mg−1 protein, in the presence and absence of brodifacoum, respectively) were significantly (P ≤ 0.01) greater than normal (16.0 ± 3.5 ng mg−1 protein).
In conclusion, there appears to be no direct effect of coumarins on clearance of vitamin K1 from either plasma or liver; the need for large doses of vitamin K1 during coumarin poisoning is due to a greatly increased requirement for the vitamin.
Pharmacological modulation of Paf‐induced rat pleurisy and its role in inflammation by zymosan
Authors: Martins Marco A. , e Silva Patricia M.R. , Neto Hugo C. Castro Faria , Bozza Patricia T. , Dias Paulo M.F.L. , Lima Marcia C.R. , Cordeiro Renato S.B. , Vargaftig B. Boris 
Published: July 2012

The intrapleural injection of Paf‐acether into rats caused, at 30 min, a marked exudation accompanied by a reduction in the pleural leucocyte count. At 6 h, the exudate volume had decreased and a significant increase in the total leucocyte count, particularly eosinophils was noted.
Two Paf‐acether antagonists, WEB 2086 and 48740 RP abrogated the pleural leucopenia observed 30 min after Paf‐acether administration, whereas the exudation was inhibited only by the former. Pleurisy was also reduced by about 60% with dexamethasone, by about 45% with BW 755C or LY 171883, a mixed cyclo‐oxygenase/lipoxygenase inhibitor and a peptido‐leukotriene antagonist respectively, and by about 30% with indomethacin, flurbiprofen or piroxicam.
Repeated daily intrapleural injections of Paf‐acether led to a state of progressive desensitization to Paf‐acether itself, whereas responsiveness to 5‐hydroxytryptamine was maintained. In addition, the Paf‐induced auto‐desensitization was largely inhibited by WEB 2086.
Pleurisy induced by zymosan, but not by carrageenin, was significantly reduced in Paf‐acether‐desensitized animals. These results were consistent with those obtained with WEB 2086 which supressed zymosan‐induced but not carrageenin‐induced pleurisy.
This study suggests that Paf‐acether‐induced pleurisy in the rat may be mediated by lipoxygenase arachidonic acid metabolites and that pleurisy induced by zymosan, but not by carrageenin, is largely dependent upon Paf‐acether.
Effects of the bradykinin antagonist B4310 on smooth muscles and blood pressure in the rat, and its enzymatic degradation
Authors: Griesbacher Thomas , Lembeck Fred , Saria Alois 
Published: July 2012

Six competitive bradykinin (Bk) antagonists were tested for their agonistic properties on the rat uterus. Five of these peptides showed agonistic effects only at concentrations at least two orders of magnitude higher than those of bradykinin.
The antagonistic potency of Lys‐Lys‐3‐Hyp‐5,8‐Thi‐7‐DPhe‐Bk (B4310) in the rat uterus (pA2 = 7.24) and in the rat duodenum (pA2 = 7.31) was very similar to that determined in an earlier study for the antagonism of the bradykinin‐induced stimulation of the trigeminal nerve in the rabbit iris sphincter muscle preparation (pA2 = 7.59).
The fall in mean arterial blood pressure induced by i.a. injections of bradykinin was greatly reduced during an i.a. infusion of B4310, but not 10 min thereafter, which indicates a rapid inactivation of B4310 in vivo. Bacitracin possibly interferes with the enzymatic cleavage of B4310 but seems to have no effect on the degradation of bradykinin.
An i.a. infusion of captopril greatly enhanced the potency of bradykinin in inducing a fall in arterial blood pressure, confirming the important role of angiotensin converting enzyme in the cleavage of bradykinin. However, the design of this experiment did not allow conclusions about the effect of captopril on the degradation of B4310.
B4310 incubated with rat lung tissue disappeared from the incubation medium within a few minutes, i.e. as fast as bradykinin, which explains its short duration of action in vivo. Captopril partially inhibited the cleavage of both bradykinin and B4310.
The present results show that the bradykinin antagonists available at present are useful tools for the investigation of the biological role of bradykinin. However, the susceptibility to enzymatic degradation may limit their usefulness in animal experiments or in clinical studies.
N‐methylhydroxylamine inhibits and M&B 22948 potentiates relaxations of the mouse anococcygeus to non‐adrenergic, non‐cholinergic field stimulation and to nitrovasodilator drugs
Authors: Gibson A. , Mirzazadeh S. 
Published: July 2012

The effects of N‐methylhydroxylamine (NMH) and of M&B 22948 on relaxations of the mouse anococcygeus to non‐adrenergic, non‐cholinergic (NANC) field stimulation and to a number of smooth muscle relaxant drugs were investigated.
Relaxations to NANC field stimulation (10 Hz; 60s train) were reversibly blocked by NMH (1–5 mm), which also caused weak, transient reductions of carbachol (50 μm)‐induced tone. N,N‐dimethylhydroxylamine (2 mm) and hydroxylamine (5 μm) reduced tone to the same extent as NMH, but neither produced any inhibition of NANC relaxations.
M&B 22948 10 μm, which by itself reduced tone by 12%, potentiated submaximal but not maximal relaxations to NANC field stimulation; overall the log frequency‐response curve was displaced to the left by a factor of 2.
Sodium nitroprusside (0.01–1 μm), hydroxylamine (0.5–100 μm), and nitric oxide (2–200 μm) all relaxed carbachol‐induced tone; relaxations to submaximal concentrations of these nitro‐vasodilators were reduced in the presence of 2 mm NMH, and potentiated in the presence of 10 μm M&B 22948.
Neither NMH (2 mm) nor M&B 22948 (10 μm) affected relaxations induced by submaximal concentrations of vasoactive intestinal peptide (VIP; 1 μm), papaverine (10 μm), 3‐isobutyl‐1‐methylxanthine (10 μm), or 8‐bromo‐cyclic guanosine monophosphate (100 μm); relaxations to adenosine 5′‐triphosphate (ATP, 2 mm) were unaffected by M&B 22948, but were potentiated by NMH.
The selective inhibition by NMH, and potentiation by M&B 22948, of NANC and nitrovasodilator‐induced relaxations of the mouse anococcygeus suggests that the NANC transmitter is neither VIP nor ATP, but resembles the nitrovasodilator drugs in its mode of action. The NANC transmission system is therefore similar to that recently described in the bovine retractor penis.
Factors inducing endothelium‐dependent relaxation in the guinea‐pig basilar artery as estimated from the actions of haemoglobin
Authors: Nishiye E. , Nakao K. , Itoh T. , Kuriyama H. 
Published: July 2012

Factors inducing dilatation of guinea‐pig basilar artery were investigated in intact and endothelium‐denuded tissues by measurement of isometric tension and by electrophysiological methods.
The amplitudes of contractions induced by 9,11,epithio‐11,12‐methanothromboxane A2 (STA2) and by high K+ were enhanced by haemoglobin (oxyhaemoglobin, Hb) in a concentration‐dependent fashion (above 1 μm). For the high K+‐induced contraction, the initial tonic component was enhanced to a greater extent than the secondary phasic component. Mechanical responses evoked by STA2 and by high K+ were greater in endothelium‐denuded tissues, but Hb (below 10 μm) had no effect on them.
Hb (10 μm) had no effect on the contractile proteins as estimated from the actions of Hb on Ca2+‐induced contractions in skinned muscle tissues. Further, Hb had no effect on the release of Ca2+ from intracellular stores but it accelerated the Ca2+ accumulation into the sarcoplasmic reticulum as judged from the caffeine‐ or STA2‐induced contraction generated in intact tissues.
Acetylcholine (ACh) relaxed tissues that were precontracted by STA2 but Hb prevented this relaxation, in a concentration‐dependent fashion. The ACh‐induced relaxation was sustained for over 10 min in the absence of Hb, but following application of Hb, ACh caused only a transient relaxation.
STA2 (up to 100 nm) did not modify the resting membrane potential of smooth muscle cells of the basilar artery. ACh (10 μm) caused transient hyperpolarization which was only slightly inhibited by Hb (10 μm) whether or not STA2 was present. The hyperpolarization induced by ACh required the presence of endothelial cells.
A23187 (0.01–1 μm) relaxed tissues which were precontracted by STA2, in a concentration‐dependent fashion but had no effect on the membrane potential.
These results suggest that in guinea‐pig basilar artery, ACh induces relaxation of tissues that were precontracted by STA2 by causing release of both endothelium‐derived relaxing (EDRF) and endothelial dependent hyperpolarizing factor (EDHF) (sustained and initial transient relaxation, respectively), but via different mechanisms. Hb inhibits the former and to a lesser extent, the latter. Since A23187 produced relaxation of pre‐contracted tissue but caused no detectable change in the membrane potential, this agent may release EDRF but not EDHF.
Prostanoid‐induced contraction of human bronchial smooth muscle is mediated by TP‐receptors
Authors: Coleman R.A. , Sheldrick R.L.G. 
Published: July 2012

A range of naturally‐occurring prostaglandins sulprostone, 16,16‐dimethyl prostaglandin E2 (DME2) and the thromboxane A2 (TXA2)‐mimetic, 11α,9α‐epoxymethano prostaglandin H2 (U‐46619) have been tested for contractile agonist activity on human isolated bronchial smooth muscle.
Prostaglandin D2 (PGD2), PGF2α, 9α,11β‐PGF2 (11β‐PGF2) and U‐46619 all caused concentration‐related contractions. U46619 was at least 300 fold more potent than the other prostanoids with a mean EC50 of 12 nm. Sulprostone caused contraction only at the highest concentration tested (30 μm). PGE2 and PGI2 caused relaxations at low concentrations, and only caused contractile responses at high concentrations (≥ 10 μm). In contrast, DME2 caused small contractions at low concentrations but relaxation at the highest concentration tested (30 μm).
The rank order of contractile agonist potency was: U‐46619 > 11β‐PGF2 > PGF2α > PGD2 > PGE2 > PGI2 > sulprostone > DME2.
The TP‐receptor blocking drug, AH23848 (1 μm) antagonized the contractile effects of U‐46619, PGD2, PGF2α and 11β‐PGF2, but had no effect against contractions to carbachol. In a single experiment, a pA2 of 8.3 (slope = 1.2) was obtained for AH23848 against U‐46619.
In most preparations, administration of AH23848 (1 μm) to human bronchus resulted in small, transient contractile responses.
The results obtained with both the agonists and the antagonist, AH23848 are therefore consistent with prostanoid‐induced contractions of human bronchial smooth muscle being mediated by TP‐receptors.
S‐nitrosothiols as vasodilators: implications regarding tolerance to nitric oxide‐containing vasodilators
Authors: Henry Peter J. , Drummer Olaf H. , Horowitz John D. 
Published: July 2012

The formation of an S‐nitrosothiol compound, S‐nitroso‐N‐acetylcysteine (SNAC) has recently been proposed to mediate the augmentation of the anti‐aggregatory and haemodynamic effects of glyceryl trinitrate observed in the presence of N‐acetylcysteine. This study investigated the effects on an isolated coronary artery preparation of acute and prolonged exposure to S‐nitrosothiol compounds and nitric oxide (NO).
Single doses of NO and of the S‐nitrosothiol compounds, SNAC and S‐nitroso‐N‐acetylpenicillamine (SNAP), induced rapid, but transient, relaxations in U46619‐contracted bovine isolated coronary artery rings. Peak relaxation responses to SNAP and NO were attenuated in the presence of N‐acetylcysteine, cysteine, ascorbic acid and methylene blue. The duration of the relaxation responses to SNAC was two to three times longer than those to SNAP and NO. In the presence of N‐acetylcysteine (but not cysteine, ascorbic acid or methylene blue) the duration of the relaxation responses to SNAP and NO (but not to SNAC) was markedly increased. H.p.l.c. assay confirmed that, in the presence of N‐acetylcysteine, SNAP and, to a lesser degree, NO were converted to the relatively more stable and longer acting vasodilator, SNAC.
When compared to control rings, coronary artery rings superfused with glyceryl trinitrate were subsequently markedly less responsive to the vasodilator actions of glyceryl trinitrate, whereas responsiveness to SNAC or NO was only marginally reduced. On the other hand, coronary artery rings superfused with SNAC or NO were subsequently less responsive to glyceryl trinitrate, SNAC and NO. Thus prolonged vascular exposure to SNAC or NO induced a form of tolerance different from that induced with glyceryl trinitrate and which is possibly associated with impaired guanylate cyclase activity.
Coronary artery rings superfused with NO were markedly less responsive to glyceryl trinitrate and NO, whereas responses to the endothelium‐dependent vasodilator A23187 and to theophylline were not significantly attenuated.
It is concluded that formation of the more stable vasodilator SNAC occurs on incubation of N‐acetylcysteine with SNAP or NO. While coronary artery responsiveness to SNAC and NO is virtually unchanged in the presence of glyceryl trinitrate‐induced tolerance, after prolonged exposure to SNAC or NO tolerance may develop to these vasodilators with cross‐tolerance to glyceryl trinitrate but not A23187. Thus, formation or therapeutic utilization of SNAC may acutely circumvent the problem of glyceryl trinitrate‐induced tolerance but, during prolonged vascular exposure to SNAC, attenuation of vascular responsiveness may occur to a wide range of vasodilators.
Endothelium‐dependent relaxation and hyperpolarization of canine coronary artery smooth muscles in relation to the electrogenic Na‐K pump
Authors: Chen Guifa , Hashitani Hikaru , Suzuki Hikaru 
Published: July 2012

In the smooth muscle cells of canine coronary artery, acetylcholine (ACh) produced a transient, endothelium‐dependent hyperpolarization of the membrane. A similar hyperpolarization was also elicited by exposure to Krebs solution after incubation of the artery in K‐free solution for 30 min.
A hyperpolarization of reproducible amplitude was generated when ACh was applied at intervals greater than 30 min. Repetitive application of ACh at 15 min intervals caused a successive reduction in the amplitude of hyperpolarization.
The reduction in the amplitude of relaxation during five successive applications of ACh at 15 min intervals was less than 10% of the first relaxation.
The ACh‐induced hyperpolarization was blocked by atropine but not by ouabain, whereas the K‐free induced hyperpolarization was blocked by ouabain. In low Na (Li‐substituted) solution, ACh still induced a hyperpolarization but the K‐free induced hyperpolarization was absent.
In coronary artery precontracted by high‐K solution, ACh produced an endothelium‐dependent relaxation, without membrane hyperpolarization. The associated relaxation was resistant to ouabain but sensitive to atropine.
It is concluded that in the canine coronary artery, the electrogenic Na‐K pump does not contribute to the endothelium‐dependent hyperpolarization or relaxation. The results are consistent with the release of two different inhibitory factors from the vascular endothelium.