bluuebunny/crossref_metadata_2025 huggingface dataset:
Carbenoxolone and deglycyrrhized liquorice have little or no effect on prostanoid synthesis by rat gastric mucosa ex vivo
Authors: Bennett Alan , Melhuish Pauline B. , Stamford Ian F.
Published: July 2012

Rats were given either carbenoxolone 50 mg kg−1, deglycyrrhized liquorice 1 g kg−1 or vehicle by gastric tube. The doses were repeated 16 h later, and the stomachs removed after another 2 h.

The amounts of prostaglandin E (PGE), 6‐keto‐PGF1α and thromboxane B2, measured by radioimmunoassay in extracts of the gastric corpus and antrum mucosa, were similar in the treated animals and the controls.

We conclude that in rats, carbenoxolone and deglycyrrhized liquorice may exert their anti‐ulcer effect by a non‐prostaglandin mechanism. This contrasts with the mechanism thought to occur in man with carbenoxolone.
A comparison of 5‐hydroxytryptamine receptors mediating contraction in rabbit aorta and dog saphenous vein: evidence for different receptor types obtained by use of selective agonists and antagonists
Authors: Feniuk W. , Humphrey P.P.A. , Perren M.J. , Watts A.D.
Published: July 2012

Using recently available selective agonists and antagonists we have examined further our postulate (Apperley et al., 1980) that 5‐hydroxytryptamine (5‐HT) mediates contraction of dog saphenous vein via a different 5‐HT receptor type from that in the rabbit aorta.

In the rabbit isolated aorta, ketanserin and spiperone were potent, specific, competitively‐acting antagonists of the contractile effects of 5‐HT.

In contrast, in the dog isolated saphenous vein neither ketanserin nor spiperone caused any rightward displacement of concentration‐response curves to 5‐HT although the maximum response was reduced by about 10%.

In the rabbit aorta 5‐carboxamidotryptamine (5‐CONH2‐T) was a weak agonist whilst the 5‐N,N‐dimethyl and 5‐N‐ethyl derivatives were even weaker or inactive. The contractile effect of 5‐CONH2‐T in the rabbit aorta was potently and competitively antagonized by ketanserin.

In contrast, in the dog saphenous vein 5‐CONH2‐T and its 5‐N,N‐dimethyl and 5‐N‐ethyl derivatives were all potent agonists. The contractile effect of 5‐CONH2‐T was not markedly affected by ketanserin.

The profile of action of ketanserin and spiperone in the rabbit aorta is consistent with the view that 5‐HT2 receptors mediate contraction in this preparation. However, the 5‐HT receptor mediating contraction in the dog saphenous vein appears to be ‘5‐HT1‐like’, sharing a number of characteristics with the 5‐HT1 recognition site identified from [3H]‐5‐HT ligand binding studies in brain tissue. tissue.
Evidence for two mechanisms of depolarization associated with α1‐adrenoceptor activation in the rat anococcygeus muscle
Authors: Byrne N.G. , Large W.A.
Published: July 2012

Membrane potential responses in the rat isolated anococcygeus to bath‐applied noradrenaline and field stimulation have been investigated by use of intracellular microelectrode and combined extracellular electrical and mechanical (sucrose gap) recording techniques. Intracellular recordings were made usually from tissues immobilized with hypertonic Krebs solution.

Bath‐application of noradrenaline produced depolarizations which consisted of two components; an initial ‘fast’ phase which peaked within 1–2 s and which was followed by a ‘slow’ sustained depolarization. Both components were concentration‐dependent.

Noradrenaline could also evoke oscillations in membrane potential which, unlike the ‘fast’ component of depolarization, were prevented by conditioning hyperpolarization of the membrane and were evoked by direct membrane depolarization with externally applied current pulses. Thus, the oscillations are voltage‐dependent phenomena.

Replacement of the external NaCl of the Krebs solution with an equimolar amount of Na benzenesulphonate abolished the noradrenaline‐evoked ‘fast’ depolarization while the ‘slow’ phase was unaffected. This suggests that two mechanisms of depolarization are activated in this muscle by the bath‐application of noradrenaline. The adrenergic excitatory junction potential was also abolished in Na benzenesulphonate.

Prazosin reduced both the ‘fast’ and ‘slow’ components of depolarization produced by noradrenaline indicating their mediation by α1‐adrenoceptors.

The membrane potential (‐ 29 mV) at the maximum amplitude of the ‘fast’ depolarization was similar to the equilibrium potential (‐ 27 mV) for the depolarization evoked by ionophoretically applied noradrenaline and which was obtained by extrapolation from the relationship between amplitude of the ionophoretic response and membrane potential displacement in the partition chamber. These results suggest that the ‘fast’ depolarization and the ionophoretic response are due to an increased membrane conductance, possibly to chloride.
The effects of the dihydropyridine Bay K 8644 in guinea‐pig isolated trachealis
Authors: Allen S.L. , Foster R.W. , Small R.C. , Towart R.
Published: July 2012

In trachea bathed by Krebs solution containing indomethacin 0.8 μmol 1−1, Bay K 8644 (0.01‐1 μmol 1−1) evoked mild spasm. Peak tension was achieved after 10 min and was generally less than 20% of an acetylcholine (ACh) maximum. The effect of Bay K 8644 was not potentiated by addition of 2.5 mmol 1−1 potassium chloride (KCl) to the Krebs solution.

Bay K 8644 (1 μmol 1−1) caused a small potentiation of KCl and tetraethylammonium (TEA). In contrast it did not modify the actions of ACh or histamine.

Bay K 8644 (1 μmol 1−1) caused a small potentiation of the effect of calcium chloride (CaCl2) tested in trachea bathed by a K+‐rich, Ca2+‐free, MOPS‐buffered physiological salt solution.

Organic inhibitors of calcium influx such as nifedipine (0.1 μmol 1−1), verapamil (1 μmol 1−1) or diltiazem (10 μmol 1−1) each caused marked depression of concentration‐effect curves to KCl. Bay K 8644 (0.01‐1 μmol 1−1) provided concentration‐dependent protection against this effect in all three cases.

Estimation of calcium influx by the lanthanum technique revealed that Bay K 8644 (1 μmol 1−1) was able to promote the cellular influx of Ca2+.

Intracellular electrophysiological recording showed that Bay K8644 (1 μmol 1−1) caused no change in the resting membrane potential of trachealis cells and no change in the properties of the spontaneous electrical slow waves. However, Bay K 8644 was able to delay the slow wave suppression evoked by 1 μmol 1−1 nifedipine.

The ability of Bay K 8644 to promote Ca2+ influx and its ability to protect against the effects of several structurally‐unrelated inhibitors of Ca2+ influx are consistent with Bay K 8644 acting as an agonist at the dihydropyridine receptor associated with the voltage‐operated Ca2+ channel (VOC) of trachealis muscle. By this action it potentiates those spasmogens (KCl, TEA) which act by permitting Ca2+ influx through VOCs. In contrast it has no effect on those spasmogens (ACh, histamine) which principally act to liberate Ca2+ from intracellular sites of sequestration.
Potassium changes the relationship between receptor occupancy and the inotropic effect of cardiac glycosides in guinea‐pig myocardium
Authors: Bachmaier A. , Ebner F. , Reiter M.
Published: July 2012

K+ (2.4–15.6 mmol l−1) antagonized the positive inotropic effect of dihydro‐ouabain. The concentration‐effect curves became steeper with the shift to higher concentrations of the glycoside. At 1.2 mmol l−1 Ca2+, an increase in K+ from 2.4 to 12 mmol l−1 required tenfold higher concentrations of dihydro‐ouabain to produce equal inotropic effects. This factor was reduced to four at 3.2 mmol l−1 Ca2+. The same change in K+ concentration, at 1.2 mmol l−1 Ca2+, diminished the inotropic effect of ouabain on rested‐state contractions by a factor of six.

The positive inotropic effect of Ca2+ was also antagonized by K+ (1.2–12 mmol l−1). Reduction of Na+ from 140 to 70 mmol l−1 abolished the antagonistic action of K+ (1.2–8.0 mmol l−1) Moreover the inotropic effect of Ca2+ was enhanced.

Reduction of Na+, from 140 to 70 mmol l−1, antagonized the positive inotropic effect of dihydro‐ouabain more at low (2.4 mmol l−1) than at high (8.0 mmol l−1) K+. Accordingly, the extent of the dihydro‐ouabain‐K+ antagonism was reduced.

When the K+ concentration was increased from 2.4 to 12 mmol l−1, [3H]‐ouabain binding was reduced by a factor of three. This is less than the reduction in the inotropic effectiveness of ouabain or dihydro‐ouabain.

Reduction of stimulation frequency from 1 to 0.1215 Hz did not significantly alter the antagonistic effect of K+. Diminution of of the action potential was observed only at K+ concentrations greater than 5.9 mmol 1−1, whereas the resting membrane potential was continuously depolarized over the entire range of K+ concentrations.

The results support the view that the reduction in receptor affinity cannot be the sole cause of the antagonism between the glycoside and K+. Impairment of passive Na+ influx during diastole, due to the K+‐dependent depolarization of the resting membrane potential, contributed to about one half of the glycoside‐K+ antagonism.
The effect of hypoxia on neuroeffector transmission in the bovine retractor penis and rat anococcygeus muscles
Authors: Bowman Anne , McGrath J.C.
Published: July 2012

The effects of reducing the Po2 of the bathing fluid were studiedon non‐adrenergic non‐cholinergic (NANC) transmission in isolated preparations of the bovine retractor penis muscle, the rat anococcygeus muscle, the guinea‐pig taenia caeci and the guinea‐pig urinary bladder.

Hypoxia rapidly and reversibly impaired NANC transmission in the bovine retractor penis and rat anococcygeus muscles but did not affect transmission in the guinea‐pig taenia caeci or bladder, suggesting that different NANC mechanisms are involved.

Although neurally‐evoked relaxation of the bovine retractor penis was impaired by hypoxia, relaxations produced by vasoactive intestinal peptide, prostaglandin E1, sodium nitroprusside or an inhibitory factor isolated from the bovine retractor penis were unaffected. Since the inhibitory factor is similar to, and may actually be the NANC transmitter, the results suggest that the site of action of hypoxia in impairing transmission is prejunctional at the inhibitory nerve endings.
An unusual effect of γ‐aminobutyric acid on synaptic transmission of frog tectal neurones in vitro
Authors: Nistri A. , Sivilotti Lucia
Published: July 2012

Bath‐applied γ‐aminobutyric acid (GABA) enhanced, in a dose‐dependent fashion, the amplitude of optic nerve‐evoked monosynaptic excitatory responses of the frog optic tectum superfused in vitro at 7°C.

Muscimol was more potent than GABA in eliciting similar effects.

GABA‐induced responses were antagonized by picrotoxin and were insensitive to bicuculline or strychnine.

Raising the bath temperature to 20°C reduced the potency of GABA on these preparations.

No significant effect of GABA on the compound action potential of the whole optic nerve was found.

These data indicate that GABA can amplify visual inputs to the tectum through bicuculline‐insensitive mechanisms.
Evidence that oxmetidine inhibits transmembrane calcium flux in cardiac and vascular tissue
Authors: Gristwood R.W. , Jim K.F. , Macia R.A. , Matthews W.D. , Morl C.J. , Owen D.A.A.
Published: July 2012

Oxmetidine, at concentrations in excess of 1 times 10−6M, caused concentration‐dependent negative inotropic and chronotropic responses in guinea‐pig isolated heart preparations.

Oxmetidine, at concentrations in excess of 1 times 10−5M, caused negative inotropic responses in guinea‐pig papillary muscle preparations. The negative inotropic responses to oxmetidine were associated with shortening of the plateau phase of the action potential.

Verapamil and nifedipine caused similar shortening of the plateau phase of the action potential at equivalent negative inotropic concentrations indicating that oxmetidine may also act as a calcium antagonist.

In preparations partially depolarized by raising extracellular K+ concentration, oxmetidine also exhibited negative inotropic activity and reduced the calcium‐dependent action potential. However, unlike verapamil and nifedipine, oxmetidine did not show voltage‐dependent activity.

Oxmetidine, at concentrations in excess of 1 times 10−5M, inhibited Ca2+‐dependent contractions of dog saphenous vein preparations and inhibited 45Ca2+‐uptake into veins depolarized by high extracellular K+.

In vivo, these calcium antagonist actions of oxmetidine were demonstrated by vasodilatation, reduction in blood pressure, bradycardia and reduced cardiac output in anaesthetized cats.

Oxmetidine, at concentrations of 1 times 10−5M and above, shows properties consistent with inhibition of transmembrane Ca2+ flux. This action can be distinguished from other calcium antagonists as the effects of oxmetidine are not voltage‐dependent.
Acceleration of recovery of gastric epithelial integrity by 16,16‐dimethyl prostaglandin E2
Authors: Wallace John L. , Whittle Brendan J.R.
Published: July 2012

The effects of pretreatment with 16,16‐dimethyl prostaglandin E2 (DmPGE2) on the recovery of gastric mucosal ‘barrier’ parameters after ethanol‐induced damage were studied using an ex vivo chamber preparation in the rat.

DmPGE2 (4–40 μg kg−1) significantly reduced the extent of haemorrhagic damage to the gastric mucosa induced by the topical application of 50% ethanol followed by 0.05 M hydrochloric acid.

The lowest dose of DmPGE2 tested (4 μg kg−1) had no effect on the ethanol‐induced changes in transmucosal potential difference (PD) or K+ efflux. However, DmPGE2 at doses at 20 or 40 μg kg−1 significantly reduced the changes in these indices of epithelial integrity.

The recovery of PD and K+ efflux to control levels after ethanol‐injury was accelerated by DmPGE2.

With the two higher doses of DmPGE2 (20 and 40 μg kg−1) there was a significantly (P < 0.001) lower level of epithelial discontinuity, measured histologically, in samples taken at the end of the experiment.

These results suggest that at the higher doses, DmPGE2 confers some protection to the gastric epithelium as well as accelerating the recovery of epithelial integrity after damage induced by ethanol.
Dietary and pharmacological alterations in endogenous angiotensin II: effect on noradrenaline pressor responsiveness in the rat
Authors: Jones Donald R. , Penner S. Brian , Smyth Donald D.
Published: July 2012

Rats were placed on either a low sodium intake (low sodium diet 0.025% dry weight, tap water for drinking) or a high sodium intake (normal sodium diet 0.45% dry weight, 0.9% saline for drinking) for 10 days. The pressor‐response curve to angiotensin II in rats previously on a high sodium intake was shifted to the left of that found in rats previously on a low sodium intake.

Suppression of endogenous angiotensin II formation with captopril (0.3 mg kg−1) or acute volume repletion (3% body wt per 30 min) resulted in a significant parallel shift of the pressor‐response curve for angiotensin II to the left in the low salt group. In the high salt group captopril produced a similar but smaller parallel shift of the dose‐response curve to the left.

Similar manipulation of endogenous angiotensin II concentrations with high and low salt intake plus captopril treatment or acute volume repletion, produced no alterations in the pressor response for noradrenaline.

The attenuated in vivo response to angiotensin II in the low salt intake group may be explained in part by the suppressed vascular sensitivity to angiotensin II in this group, as measured in the isolated perfused kidney of the rat. In kidneys from rats previously on a low sodium intake, an enhanced maximal vasoconstrictor response to noradrenaline was observed as compared to kidneys from high sodium intake rats.

These results indicate that, whereas alterations in endogenous angiotensin II concentrations within physiological limits affects the response to exogenous angiotensin, there is little if any effect on the pressor response to noradrenaline.
The effects of nisoldipine (Bay K 5552) on cardiovascular performance and regional blood flow in pentobarbital ‐ anaesthetized pigs with or without β‐adrenoceptor blockade
Authors: Duncker D.J. , Hartog J.M. , Hugenholtz P.G. , Saxena P.R. , Verdouw P.D.
Published: July 2012

The effects of the 1,4‐dihydropyridine derivative nisoldipine, infused intravenously (i.v.) at 3 different rates (0.25, 0.5 and 1.0 μg kg−1 min−1), were studied in anaesthetized pigs on cardiovascular performance with or without β‐adrenoceptor blockade produced by propranolol.

Nisoldipine caused dose‐dependent decreases in arterial blood pressure (30%), systemic vascular resistance (30%) and left ventricular filling pressure (15%), but raised heart rate (25%) and LV dP/dt max (20%). Cardiac output was not significantly affected.

Transmural myocardial blood flow and vascular conductances increased dose‐dependently after nisoldipine. The elevation in blood flow to the left ventricle favoured epicardial layers. Endocardial blood flow showed small increases as the changes in conductance of the endocardial layer more than compensated for the loss in perfusion pressure. The endo‐epi blood flow ratio decreased from 1.16 ± 0.05 to 0.70 ±0.01. Myocardial O2‐consumption was unaltered as the decrease in arterial‐coronary venous O2‐content difference (30%) was balanced by the increase in transmural blood flow.

Nisoldipine increased blood flow to skeletal muscle (500%), stomach (50%) and adrenals (25%), but decreased that to the liver (50%), spleen (25%) and kidneys (25%). No changes were noticed in the small intestine, skin and brain. In spite of differential effects on blood flow, vascular conductance in all organs and tissues, with the exception of the liver, increased.

After β‐adrenoceptor blockade the responses of mean arterial blood pressure, cardiac output and systemic vascular resistance to nisoldipine remained virtually unchanged, but the elevations in heart rate and LV dP/dt max were abolished, as was the decrease in left ventricular filling pressure.

A higher dose of nisoldipine was required after β‐adrenoceptor blockade to elicit significant vasodilatation in the epi‐ and endocardial layers. However, the reduction in endo‐epi blood flow ratio by nisoldipine was not affected by propranolol. Myocardial O2‐consumption tended to decrease as the diminution in the arterial‐coronary venous O2‐content difference (30%) slightly exceeded the increase of left ventricular blood flow (30%).

Except for the brain and liver, effects of nisoldipine on regional vascular conductances were attenuated after β‐adrenoceptor blockade.
Propylbenzilylcholine mustard is selective for rat heart muscarinic receptors having a low affinity for agonists
Authors: Christophe Jean , De Neef Philippe , Robberecht Patrick , Waelbroeck Magali
Published: July 2012

Propylbenzilylcholine mustard (PrBCM), an irreversible muscarinic antagonist, inactivated receptors with a low affinity for agonists faster than those with a high affinity in rat heart membranes. This result was obtained using either: (a) a low ionic strength buffer (allowing heterogeneity among antagonist binding sites, (b) the same buffer enriched with GTP, or (c) a high ionic strength buffer (where antagonists showed similar binding characteristics to all receptors).

These data suggest either that PrBCM is a ‘selective’ antagonist which detects conformational differences between low and high affinity receptors, or that the agonist affinity of cardiac muscarinic receptors is determined, in part, by the relative concentrations of receptor and GTP binding protein.
Pharmacokinetics and antiarrhythmic activity of ajmaline in rats subjected to coronary artery occlusion
Authors: Hashimoto Yukiya , Hori Ryohei , Okumura Katsuhiko , Yasuhara Masato
Published: July 2012

The pharmacokinetics and the antiarrhythmic action of intravenous ajmaline were investigated in anaesthetized rats subjected to coronary artery occlusion.

Ajmaline (0.125‐2 mg kg−1, i.v. given just after occlusion) suppressed arrhythmias in a dose‐dependent manner, judged by the reduction of premature ventricular complexes. The incidence of malignant arrhythmias (ventricular tachycardia and fibrillation) was preferentially suppressed at the higher doses of ajmaline (1 and 2 mg kg−1).

Coronary occlusion induced a change in pharmacokinetics of ajmaline (2 mg kg−1) and its total body blood clearance was significantly decreased from 56.6 ml min−1 kg−1 in sham‐operated rats to 43.1 ml min−1 kg−1 in rats after coronary occlusion.

Ajmaline exhibited a significantly increased negative dromotropic action (increased PQ interval) in rats after coronary occlusion compared with that in sham‐operated rats. The difference seems to be due to the pharmacokinetic change since the concentration‐effect relationship was similar in the two groups of rats.

We suggest that the measurement of drug levels is important in the assessment of antiarrhythmic agents.
How is ventilation maintained in the presence of the muscle relaxant, dantrolene sodium? A study in the anaesthetized rat
Authors: Farquhar Ruth , Leslie G.C. , Part N.J.
Published: July 2012

The effects of intravenous injection of the muscle relaxant dantrolene sodium on ventilation, integrated EMG of external intercostal muscles and motor unit discharge in these muscles were measured in anaesthetized rats.

Dantrolene sodium was administered in a carrier solution at pH 10. The carrier was not responsible for the effects seen on dantrolene sodium infusion.

Dantrolene sodium (5 mg kg−1 body weight) reduced inspired ventilation (V̇1) on average from 308 ± 106 ml min−1 (s.d., n = 8) in the control period to 247 ± 118 ml min−1 (n = 8) after dantrolene sodium. Expired ventilation was reduced likewise from 214 ± 132 ml min−1 (n = 8) to 229 ± 109 ml min−1 (n = 8). These changes are significant at P < 0.05.

The integrated EMG was increased by 40.0 ± 29.3% (n = 9), a change significant at P < 0.001.

Dantrolene sodium not only decreased the mean interspike interval of individual motor units by 16.2 ± 11.1 % (n = 13), a change significant at P < 0.001, but also increased the duration of the burst of activity of each individual motor unit on average by 36.2 ± 52.4% (n = 13), a change significant at P < 0.05.

The recruitment of additional motor units was also effected by dantrolene sodium. These units did not behave in any noticeably different manner from units previously active.

It is concluded that the nervous system compensates for the effect of dantrolene sodium only to a limited extent by increasing the frequency of discharge of active motor units. Recruitment of additional motor units and increased burst duration play at least as important a role.
Action of dopamine on the exocrine pancreatic secretion of the intact dog
Authors: Delcenserie R. , Devaux M.A. , Sarles H.
Published: July 2012

The effects of dopamine and domperidone, a dopamine antagonist, have been studied on the exocrine secretion of the dog pancreas. The purpose of this study was to see if dopamine acted on enzyme secretion and if its action was merely ‘pharmacological’ or had a physiological role.

Conscious Beagle dogs, fitted with Thomas cannulae were studied following infusions of dopamine 125–1000 μg kg−1 h−1.

During dopamine infusion, a secretory peak lasting 10 min was observed. This was followed by a stable plateau which was approximately 1/3 of the peak. The pattern of water, bicarbonate and protein secretion was similar. The maximum effect was obtained with 500 μg kg−1 h−1 dopamine.

The stimulatory action of dopamine was blocked by domperidone, without any detected effect on the central nervous system, but not by propranolol or phenoxybenzamine. Domperidone 10 μg kg−1 almost completely suppressed the secretory response to the maximally effective dose of dopamine. This inhibition was not competitive. Atropine decreased the secretory response to dopamine.

The protein response was not observed when dopamine was infused against a background infusion of secretin. This suggests that the effect of dopamine on protein secretion could be due to a wash‐out phenomenon.

The maximally effective dose of domperidone, 10 μg kg−1, did not modify the pancreatic response to a solid meal.

Thus, in the non‐anaesthetized dog, the effect of dopamine on water and bicarbonate secretion has been confirmed. It is concluded that dopamine had no detectable action on protein secretion and that the physiological role of dopamine with respect to pancreatic secretion is still questionable.
Hypersensitivity to methoxamine in atria isolated from streptozotocin‐induced diabetic rats
Authors: Canga Liliana , Sterin‐Borda Leonor
Published: July 2012

The reactivity to methoxamine (Met) of atria isolated from the hearts of normal and from acutely streptozotocin‐diabetic rats has been studied.

Met (1 × 10−6 M) increased the tension of both normal and diabetic atria, but in diabetic atria, the dose‐response curve to Met was shifted to the left and the efficacy of Met was enhanced.

Inhibitors of α‐adrenoceptors blocked, in a competitive manner, the positive inotropic effect induced by Met in both types of atrial preparations.

Inhibitors of the cyclo‐oxygenase pathway for arachidonic acid metabolism blocked the atrial response to Met in non‐diabetic as well as in diabetic atria. The inhibition of prostacyclin synthetase prevented the effect of Met in normal atria, while blockers of thromboxane generation inhibited it in diabetic ones.

Agents that inhibit the activity of lipoxygenase(s) significantly reduced the positive inotropic action induced by Met in diabetic atria but failed to modify it in non‐diabetic preparations.

These results show that diabetic atria are more sensitive to Met than normal atria. In diabetes the response to α‐adrenoceptor stimulation could be mediated by oxidative products generated via thromboxane synthetase and lipoxygenase(s) activities; whereas in normal preparations the action of Met may involve the release of prostacyclin.
Non involvement of γ‐aminobutyric acid in catechol‐induced seizures
Authors: Dewhurst D.G.
Published: July 2012

The effects of certain anticonvulsant agents, namely, vaproate, diazepam and phenobarbitone were investigated on catechol‐induced spontaneous and evoked convulsions, in anaesthetized rats and mice.

Valproate and diazepam significantly reduced the intensity of spontaneous convulsions and the frequency of occurrence of the longer‐latency components (M2 and M3) of the evoked muscle response.

Phenobarbitone significantly reduced spontaneous convulsions and the M3 component of the evoked muscle response.

None of the drugs affected the short latency M1 component indicating a supra‐spinal site of action of these drugs.

Agents which modify γ‐aminobutyric acid (GABA)‐mediated transmission were without effect on the frequency of occurrence of M1, M2 or M3.

The results suggest that the convulsant action of catechol is not dependent on antagonism of GABA‐mediated inhibition.
Similarity and dissimilarity of the vasoconstrictor effects of Bay K 8644 on coronary, femoral, mesenteric and renal circulations of dogs
Authors: Ishii Kuniaki , Sato Yoshinori , Taira Norio
Published: July 2012

The effect of the dihydropyridine calcium agonist Bay K 8644 on the coronary, femoral, mesenteric and renal circulations was investigated and compared with that of noradrenaline in pentobarbitone‐anaesthetized dogs.

The left anterior descending coronary, femoral, cranial mesenteric and renal arteries were cannulated and their arterial beds perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 (0.1–300 nmol) and noradrenaline (0.1–300 nmol) were injected intra‐arterially.

Bay K 8644 decreased blood flow (vasoconstriction) in all 4 arterial beds. A maximum decrease was attained at 100 nmol and a further increase in dose did not appear to result in a further decrease in blood flow.

At maximum effects blood flow decreased to about 35% of the basal value in coronary, 30% in femoral, 20% in renal and 15% in mesenteric circulation.

Normalized ED50 values (ED50 divided by basal flow) of Bay K 8644 were 0.07 ± 0.02 nmol in the femoral, 0.08 ± 0.01 nmol in the coronary, 0.16 ± 0.06 nmol in the mesenteric and 0.55 ± 0.19 nmol in the renal circulation.

At 100 nmol, the values for the half‐duration of Bay K 8644 vasoconstrictor effects were about 196 s in the renal, 78 s in the mesenteric, 84 s in the femoral and 21 s in the coronary circulation.

Noradrenaline produced a dose‐dependent decrease in blood flow in femoral, mesenteric and renal circulations, and was about 2 times in femoral, 4 times in mesenteric and 9 times in renal circulation more potent than Bay K 8644.

Bay K 8644 produced slight increases in the maximum rate of rise of left ventricular pressure and intraluminal pressure of the ileum. However, the increases did not appear to impede blood flow.

Bay K 8644 produced slightly but significantly greater femoral vasoconstriction in normal dogs than in reserpine‐pretreated dogs.

From these results it was concluded that differences in potency, effectiveness and duration of the vasoconstrictor effects of Bay K 8644 between the 4 arterial beds probably derive from differences in characteristics of the smooth muscle of resistance vessels there. In arterial beds where α‐adrenoceptors are dominant, potentiation of the vasoconstrictor effect of endogenous catecholamines by Bay K 8644 seems to contribute to its vasoconstrictor effect.
The effect of ionic strength on cardiac muscarinic receptors
Authors: Burgen A.S.V.
Published: July 2012

The binding of N‐methylscopolamine (NMS) and carbachol to muscarinic receptors in the rat heart has been measured as a function of ionic strength (μ).

The binding of NMS was reduced by 3.69 fold for a 10 fold increase in ionic strength.

The binding of carbachol was affected in two ways. Firstly, the proportions of the subsites were changed. Above μ = 0.5 M, the superhigh (SH) subsite was converted into the low(L) subsite and above μ = 0.8 M, the high (H) subsite was also converted into the L subsite. Therefore, at high ionic strength, no agonist‐determined subsites can be detected. In addition, increase in ionic strength reduced the binding of carbachol to all subsites and to a much greater extent than for NMS.
Membrane and contractile properties of the dog ciliary muscle
Authors: Ito Yushi , Yoshitomi Takeshi
Published: July 2012

Membrane properties and excitation‐contraction coupling mechanisms of the dog ciliary muscle were investigated by use of microelectrode and isometric tension recording methods.

The mean resting membrane potential of the smooth muscle cell was − 59.6 ± 1.6 mV and the membrane was electrically quiescent. With applications of inward and outward current pulses, by the partition stimulating method (pulse duration, 1.0 s), electrotonic potentials, but not action potentials (spike) were evoked even in the presence of tetraethylammonium (TEA, 10 mM).

The space and time constants calculated from the current‐voltage relationship observed at various distances from the stimulating electrode were 0.43 ± 0.07 mm (± s.d. n = 5) and 82.5 ± 10.6 ms (± s.d. n = 4), respectively.

Electrical field stimulation of short duration (50–300 μ s) evoked excitatory junction potentials (e.j.ps) followed by twitch contraction, both of which were potentiated by neostigmine (10−7 M) and abolished by tetrodotoxin (TTX, 10−7 M) or atropine (10−6 M). However, e.j.ps of amplitude over 3–5 mV did not evoke action potentials.

Excess [K]o solution dose‐dependently depolarized the membrane (the maximum slope of the depolarizations produced by a tenfold increase in [K]o plotted on a log scale was 52.5 mV) and evoked contractions. Atropine (10−6 M) had no effect on the [K]o‐induced membrane depolarization, however, it greatly reduced the amplitude of [K]o‐induced contraction.

Nisoldipine (5 × 10−7 M) had no effect on the contraction evoked by field stimulation, however, this agent suppressed the [K]o‐induced contraction to 78.3 ± 6.8% of the control value. Combined application of nisoldipine and atropine completely inhibited the [K]o‐induced contraction.

Although the membrane depolarization evoked by carbachol (> 10−7 M) was small (10 mV depolarization at 10−5 M), the contraction evoked by 10−5 M carbachol was larger than that evoked by 118 mM [K]o (185 ± 50%, n = 9).

Ca‐free 3 mM EGTA‐containing solution did not alter the resting tension, but greatly reduced the carbachol‐induced contraction (to 8.6 ± 2.3% of the control value).

The present results indicate that the membrane of dog ciliary muscle behaves as an electrical syncytium, and that the contractile responses occur mainly through activation of the receptor‐operated Ca channels and partly through activation of voltage‐dependent Ca channels.
Chronic caffeine treatment reduces caffeine but not adenosine effects on cortical acetylcholine release
Authors: Corradetti R. , Pedata Felicita , Pepeu G. , Vannucchi Maria Giuliana
Published: July 2012

The effects of both adenosine and caffeine on the release of acetylcholine (ACh) were investigated in slices of cerebral cortex taken from rats pretreated for 30 days with caffeine (100 mg kg−1 daily, dissolved in their drinking water) at rest and during electrical stimulation at frequencies of 0.2, 1 and 5 Hz. The effect of this treatment on adenosine binding sites was also investigated in cortical membranes using N‐cyclohexyl‐(3H]‐adenosine ([3H]‐CHA) as a ligand.

The chronic caffeine treatment did not change animal growth patterns. Spontaneous exploratory activity appeared to be increased at the 3rd day but was unchanged at the 30th day when compared with controls.

Caffeine‐treatment increased the number of high affinity binding sites for [3H]‐CHA by 64% over the control values. Low affinity binding site density and affinity constants were unaffected.

Adenosine 30 μM added to the superfusion fluid decreased electrically stimulated ACh release both in rats drinking tap water and rats drinking caffeine.

In rats drinking tap water, caffeine added to the superfusion fluid at a concentration of 50 μM enhanced ACh release, while at 0.5 mM it decreased ACh output from the slices. Both effects were abolished by pretreatment with caffeine in vivo.

The results indicate that prolonged consumption of high doses of caffeine causes changes in the responsiveness of cholinergic neurones to caffeine. The change is not shared by adenosine, through whose recognition sites caffeine is believed to act. It is therefore possible that the adaptive changes following repeated caffeine administration involve either only the coupler‐transducer mechanism activated by the antagonist, or effects unrelated to receptors.
Functional studies on human veins after storage at − 190°C
Authors: Müller‐Schweinitzer E. , Tapparelli C. , Victorzon M.
Published: July 2012

Human saphenous veins were immersed in foetal calf serum containing 1.8 M dimethylsulphoxide, slowly frozen to −70°C and stored in liquid nitrogen (− 190°C).

Comparative in vitro studies on helical strips from unfrozen and frozen and thawed veins revealed that after thawing of frozen stored veins the contractile force development was unchanged, and the evidence suggested that the monoamine oxidase activity was unimpaired.

There was a good correlation between the pD2 values of various 5‐hydroxytryptamine receptor agonists and the blocking activities of various antagonists tested against 5‐hydroxytryptamine (5‐HT) and noradrenaline on unfrozen and frozen and thawed veins.

It is suggested that cryopreservation is a useful technique for storing human veins for pharmacological studies.
Characterization of the effects of (±)‐meptazinol, its individual enantiomers and N‐methyl meptazinol on food consumption in the rat
Authors: Jackson Helen C. , Sewell R.D.E.
Published: July 2012

Both (±)‐meptazinol (2 mg kg−1) and levorphanol (1 mg kg−1) produced hyperphagia over a 4 h period after intraperitoneal injection in free feeding rats during the daylight phase.

The individual (+)‐ and (−)‐enantiomers of meptazinol (2 mg kg−1 i.p.) induced comparable increases in cumulative food intake.

N‐methyl meptazinol (2–10 mg kg−1 i.p.), the quaternary analogue of meptazinol, produced no modification of food intake though it increased food consumption when injected intracerebroventricularly (10–100 μg per animal).

Meptazinol and levorphanol hyperphagia was abolished by 1 mg kg−1 doses (i.p.) of the opioid antagonists naltrexone, naloxonazine and (−)‐Mr 1452 but not by its (+)‐enantiomer Mr 1453 which is not effective as an opioid antagonist.

Intracerebroventricular administration of the δ‐opioid receptor antagonist ICI 154,129 (10 μg per animal) suppressed meptazinol but not levorphanol hyperphagia.

It was concluded that meptazinol produces centrally mediated stereospecifically reversible hyperphagia through a μ‐opioid receptor mechanism common to levorphanol, and also through δ‐opioid receptor mechanism(s).
Antiarrhythmic effects of DPI 201‐106
Authors: Scholtysik Günter , Williams Frances M.
Published: July 2012

The cardiotonic agent DPI 201‐106 (4‐[3‐(4‐diphenylmethyl‐1‐piperazinyl‐2‐hydroxypropyl]‐1H‐ indole‐2‐carbonitrile) which modifies the sarcolemmal Na+ channel gating system and has electrophysiological properties of class III antiarrhythmics was investigated for local anaesthetic and antiarrhythmic activity.

The compound action potential amplitude of cat cervical vagus nerves in vitro was decreased by DPI 201‐106 in a concentration‐dependent manner, the IC50 being 1.82 × 10−5 M. This was paralleled by a slowing in conduction velocity and demonstrates local anaesthetic effects.

Ventricular fibrillation which occurs in response to coronary artery reperfusion in rats was prevented by intravenous infusions of 0.3 mg kg−1 min−1 of DPI 201‐106.

The arrhythmogenic intravenous doses of aconitine in rats were increased following pretreatment with DPI 201‐106 in a dose‐dependent manner.

DPI 201‐106 did not protect against ouabain‐induced arrhythmias in guinea‐pigs.

The results demonstrate that DPI 201‐106 has local anaesthetic effects and is a potential antiarrhythmic.
The haemodynamic and metabolic effects of tolmesoxide with special reference to impaired myocardial function
Authors: Mackenzie John E. , Marshall Richard J. , Parratt James R.
Published: July 2012

The haemodynamic, metabolic and regional blood flow effects of the vasodilator, tolmesoxide (1 mg kg−1 min−1 for 20 min by intravenous infusion) were examined in two groups of greyhound dogs anaesthetized with α‐chloralose and mechanically ventilated. One group of dogs was thoracotomized and subjected to acute coronary artery occlusion. In these dogs tolmesoxide was infused 2.5 h after occlusion when there was evidence of impaired myocardial function.

Tolmesoxide administration resulted in marked systemic hypotension which was associated with myocardial stimulation (increase in heart rate and LVdP/dtmax). These effects were less marked in thoracotomized dogs subjected to coronary artery occlusion. Cardiac stimulation was attenuated by pretreatment with the β‐adrenoceptor antagonist, atenolol.

Peripheral resistance and left ventricular end‐diastolic pressure (LVEDP) were reduced by tolmesoxide. In spite of the systemic hypotension, the marked reduction in LVEDP resulted in an enhanced subendocardial driving pressure and an increased blood flow to ischaemic regions of the left ventricular wall as measured with Xe133 clearance. Blood flow to normal regions of the left ventricular wall was also increased by tolmesoxide.

A metabolic and respiratory acidosis may have contributed to the haemodynamic effects of tolmesoxide. Plasma renin levels were significantly elevated by the drug.

Tolmesoxide administration thus resulted in cardiac stimulation, reduced both pre‐load and after‐load, yet maintained coronary and pulmonary perfusion. This haemodynamic profile of tolmesoxide would explain the beneficial effects obtained with this drug in the treatment of cardiac failure.
Kadsurenone distinguishes between different platelet activating factor receptor subtypes on macrophages and polymorphonuclear leucocytes
Authors: Lambrecht Günter , Parnham Michael J.
Published: July 2012

The effects of the antagonist kadsurenone on the platelet activating factor (Paf)‐induced chemiluminescence of guinea‐pig peritoneal macrophages and on pig peripheral blood leucocyte aggregation were compared. Linearity and slopes of unity of the Schild plots confirmed the competitive nature of the antagonism by kadsurenone. pA2 values indicated a 91 fold lower affinity of kadsurenone for leucocyte Paf receptors than for those in macrophages. It is concluded that these two types of Paf receptors are not identical and are provisionally designated Paf1 and Paf2 receptors, respectively.
Electrophysiological effects of amoxapine in untreated and in amoxapine‐pretreated rat atria
Authors: Delgado C. , Manzanares J. , Tamargo J. , Valenzuela C.
Published: July 2012

The effects of amoxapine (10−7 − 10−4 M) have been studied in rat atrial fibres obtained from untreated animals and animals pretreated for 28 days with amoxapine (10 mg kg−1, i.p.).

In untreated atria amoxapine reduced atrial rate, contractile force and df/dtmax, prolonged the sinus node recovery time and decreased atrial excitability.

Amoxapine also decreased amplitude and Vmax of the upstroke, prolonged the duration of the action potential (APD) and effective refractory period (ERP) and reduced the resting membrane potential.

During the treatment with amoxapine behavioural and cardiovascular adverse effects, including hypotension, tachycardia and prolongation of the Q‐Tc, were observed. However, with the exception of the ERP which was significantly prolonged in pretreated atria, pretreatment with amoxapine did not modify the control values of the measured parameters compared to those obtained in untreated atria.

Further addition of amoxapine produced similar changes in both pretreated and untreated atria. However, in contrast to untreated atria, in pretreated atria the prolongation of the ERP produced by amoxapine exceeded the prolongation of the APD and thus, the ERP/APD ratio increased. The decrease in atrial excitability was also more marked in pretreated than in untreated atria.

Amoxapine inhibited the slow action potentials and contractions induced by isoprenaline in K‐depolarized atria.

It is concluded that the electrophysiological effects of amoxapine on rat atrial fibres are similar to those described for other tricyclic antidepressants. Possible explanations for the lower cardiodepressant activity of amoxapine are discussed.
Effect of prostaglandin D2 on histamine‐induced weals in human skin
Authors: Barnes Vanessa F. , Heavey Dennis J.
Published: July 2012

The effect of prostaglandin D2 (PGD2) on weal response to intradermal injection of histamine was examined in normal volunteers.

Co‐injection of variable amounts of PGD2 with a fixed dose of histamine (2.5 nmol) was made so that the molar ratio of histamine: PGD2 covered the range 15 to 1215. There was no significant effect of PGD2 on weal area.

PGD2, present at a 50 times lower concentration than histamine, had no effect on either the dose‐response curves for the histamine‐induced weal area or the forearm weal volume response to 2.5 nmol histamine.

It is concluded that PGD2, when present at the relative amounts found in vitro and in vivo, has no effect on the weal response to histamine in man.
Central β‐adrenoceptors can modulate 5‐hydroxytryptamine‐induced tremor in rats
Authors: Hallberg Heléne
Published: July 2012

The effects of two β2‐adrenoceptor agonists with different lipophilicities were studied on tremor induced by L‐5‐hydroxytryptophan (L‐5‐HTP) in pargyline‐ and carbidopa‐pretreated rats.

Tremor was recorded and analysed by an objective method based on accelerometry.

Clenbuterol, a lipophilic β2‐selective agonist, dose‐dependently enhanced tremor intensity, whereas the hydrophilic β2‐agonist terbutaline had no effect.

The clenbuterol‐induced enhancement of tremor was completely abolished by the β2‐selective antagonist ICI 118,551 but unchanged by the β1‐selective antagonist metoprolol.

The results suggest that centrally located β2‐adrenoceptors can mediate a modulation of 5‐hydroxytryptamine‐induced tremor in rats.
High affinity binding of [3H]‐tyramine in the central nervous system
Authors: Vaccari Andrea
Published: July 2012

Optimum assay conditions for the association of [3H]‐para‐tyramine ([3H]‐pTA) with rat brain membranes were characterized, and a saturable, reversible, drug‐specific, and high affinity binding mechanism for this trace amine was revealed.

The binding capacity (Bmax) for [3H]‐pTA in the corpus striatum was approximately 30 times higher than that in the cerebellum, with similar dissociation constants (KD).

The binding process of [3H]‐pTA involved the dopamine system, inasmuch as (a) highest binding capacity was associated with dopamine‐rich regions; (b) dopamine and pTA equally displaced specifically bound [3H]‐pTA; (c) there was a severe loss in striatal binding capacity for [3H]‐pTA and, reportedly, for [3H]‐dopamine, following unilateral nigrostriatal lesion; (d) acute in vivo reserpine treatment markedly decreased the density of [3H]‐pTA and, reportedly, of [3H]‐dopamine binding sites.

In competition experiments [3H]‐pTA binding sites, though displaying nanomolar affinity for dopamine, revealed micromolar affinities for the dopamine agonists apomorphine and pergolide, and for several dopamine antagonists, while having very high affinity for reserpine, a marker for the catecholamine transporter in synaptic vesicles.

The binding process of [3H]‐pTA was both energy‐dependent (ouabain‐sensitive), and ATP‐Mg2+‐insensitive; furthermore, the potencies of various drugs in competing for [3H]‐pTA binding to rat striatal membranes correlated well (r = 0.96) with their reported potencies in inhibiting [3H]‐dopamine uptake into striatal synaptosomes.

It is concluded that [3H]‐pTA binds at a site located on/within synaptic vesicles where it is involved in the transport mechanism of dopamine.
Tetrodotoxin‐sensitive, K+‐induced relaxation of guinea‐pig isolated trachealis in the presence of Ca2+‐entry blocking drugs, Ca2+‐free solution and after polyamine exposure
Authors: Chideckel Elliott W. , Fedan Jeffrey S. , Mike Pamela
Published: July 2012

We have previously observed a paradoxical relaxant effect of K+ on guinea‐pig isolated trachealis after exposure to polyamines. The purpose of the present study was to evaluate whether the relaxation involved a reduction in the entry of extracellular Ca2+. We therefore investigated the effect of K+ in the presence of Ca2+‐entry blocking drugs and in the presence of Ca2+‐free solution.

In the presence of nifedipine (10−5 M), verapamil (10−5 M) or diltiazem (10−5 M), K+ (30 mM) induced relaxation of the trachealis muscle. The relaxation to K+ was not blocked by ouabain (10−6 M), propranolol (10−6 M), or indomethacin (10−6 M).

A relaxation in response to K+ was also observed in Ca2+‐free solution, (with tone induced by methacholine), an effect not blocked by propranolol or ouabain.

Tetraethylammonium (30 mM) (TEA), which ordinarily evokes contractile responses, induced trachealis relaxation in the presence of verapamil or nifedipine. The relaxation was unaltered by ouabain or propranolol.

Tetrodotoxin (10−6 M) (TTX) blocked 65% of the K+‐induced relaxation in the presence of nifedipine and 100% of K+‐induced relaxation either in a Ca2+‐free solution or after polyamine exposure. TTX was without effect on TEA‐induced relaxation after Ca2+‐entry blocking drugs.

Atropine (10−6 M) or hexamethonium (10−6 M) did not affect K+‐induced relaxation after polyamine exposure.

The concentration‐response curve for K+‐induced contraction in normal modified Krebs‐Henseleit solution was shifted to the left by TTX.

It is concluded: (a) K+ has a direct effect on the trachealis causing contraction and an indirect effect, mediated by neurotransmitter release, causing relaxation. This latter effect is exposed when the direct effect is inhibited by Ca2+‐entry blocking drugs, Ca2+‐free solution or polyamine exposure; the indirect effect is non‐adrenergic, non‐cholinergic and not via ganglionic transmission; (b) the TEA‐induced relaxation and a component of the K+‐induced relaxation after Ca2+ blocking drugs cannot be explained by neurotransmitter release; (c) polyamines may act as naturally occurring Ca2+ antagonists.