bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of platelet agonists on airway reactivity and intrathoracic platelet accumulation
Authors: Robertson D.N. , Page C.P.
Published: July 2012

Intravenous infusion of platelet activating factor (Paf), adenosine diphosphate (ADP), collagen and the thromboxane‐mimetic U46619 induced a dose‐related accumulation of 111indium‐labelled platelets into the thoracic region of anaesthetized guinea‐pigs.

Intravenous infusion of Paf increased the reactivity of the airways to the spasmogen histamine. Such changes were not observed following treatment with ADP, collagen or U46619.

Paf‐induced bronchial hyperreactivity is not secondary to pulmonary platelet recruitment, changes in basal lung function or cardiovascular changes.

Paf‐induced bronchial hyperreactivity is not dependent upon the endogenous generation of ADP or thromboxane.
The influence of atherosclerosis on the mechanical responses of human isolated coronary arteries to substance P, isoprenaline and noradrenaline
Authors: Berkenboom Guy , Depierreux Michel , Fontaine Jeanine
Published: July 2012

The responses to substance P, isoprenaline and noradrenaline were observed on human isolated coronary arteries removed from 30 human hearts, and were classified according to the age of the hearts, the presence or absence of cardiac failure and the degree of atherosclerosis.

The endothelium‐dependent vasodilator, substance P (0.1 μm), relaxed rings precontracted with prostaglandin F2α, (PGF2α, 1 μm) when they were devoid of atherosclerosis. The presence of moderate or severe lesions of atherosclerosis abolished this response. There was no difference in the response, related to either the age of the hearts or to the presence or absence of cardiac failure.

The dose‐response curves to isoprenaline (an endothelium‐independent vasodilator) were also markedly altered by the presence of atherosclerotic lesions, while aging and the presence of cardiac failure did not alter the maximal relaxation. These last 2 factors induced only a rightward shift of the dose‐response curves.

On severely atherosclerotic rings, β‐adrenoceptor‐mediated responses were so altered that the effect of noradrenaline was wholly vasoconstrictor (via α‐adrenoceptors). This response was not modified after pretreatment with atenolol (10 μm).

It is concluded that atherosclerosis in human coronary arteries, induces alterations in the responses to substance P and to β‐adrenoceptor agonists. The β‐adrenoceptor‐mediated relaxations seem more influenced by the presence of atherosclerosis than they are by aging or by the down‐regulation induced by cardiac failure. Conversely, the α‐adrenoceptor responses appear to be well preserved.
Procoagulant activity of platelet arachidonic acid metabolites
Authors: Barrowcliffe T.W. , Edwards S.J. , Gray Elaine , Kerry P.J.
Published: July 2012

Arachidonate metabolites have been extracted from indomethacin‐treated human platelets after incubation with arachidonic acid.

After separation from platelet phospholipids, the extracts promoted the generation of large amounts of thrombin in normal plasma, but not in plasma devoid of lipoproteins.

The procoagulant activity was associated with a minor component of the mixture, which was active at concentrations below 10 μg ml−1.

The activity was similar to that of autoxidised arachidonic acid previously described.

Platelet arachidonic acid metabolites could play a role in the coagulation system.
Antisecretory and antiulcer effect of the H2‐receptor antagonist famotidine in the rat: comparison with ranitidine
Authors: Scarpignato Carmelo , Tramacere Roberto , Zappia Luciana
Published: July 2012

The effects of the new H2‐receptor antagonist famotidine, administered orally, on gastric secretion and emptying as well as on experimentally‐induced gastric and duodenal ulcers were studied in the rat. Ranitidine was used as a reference compound.

Both compounds inhibited acid secretion in a dose‐dependent manner. Calculated ED50 values were 0.80 and 6.84 mg kg−1 for famotidine and ranitidine, respectively. However, the duration of the antisecretory action was the same for both drugs.

The effect of the two drugs, administered at equiactive antisecretory doses, on gastric emptying was different. Ranitidine significantly accelerated the emptying rate whereas famotidine had no effect.

Famotidine reduced, in a dose‐dependent manner, ulcer incidence in stomachs of dimaprit‐treated rats and in duodena of cysteamine‐treated animals with a potency respectively 2 and 7 times higher than that of ranitidine.

Famotidine is therefore an effective antisecretory and untiulcer compound. Its potency, but not its efficacy, is higher than that of ranitidine. Moreover, the duration of the antisecretory action is virtually the same for both drugs.
Protein kinase C activation and α2‐autoreceptor‐modulated release of noradrenaline
Authors: Allgaier Clemens , Hertting Georg , Huang Hua Yu , Jackisch Rolf
Published: July 2012

Effects of phorbol esters on the evoked noradrenaline release were studied in slices of the rabbit hippocampus, labelled with [3H]‐noradrenaline, superfused continuously with a medium containing the reuptake inhibitor cocaine and stimulated electrically for 2 min (stimulation parameters: 2 ms, 24 mA, 5 V cm−1, 3 or 0.3 Hz).

The electrically‐evoked overflow of [3H]‐noradrenaline in the slices was increased in a concentration‐dependent manner by the protein kinase C (PKC) activators 12‐O‐tetradecanoylphorbol 13‐acetate (TPA) and 4β‐phorbol 12,13‐dibutyrate (4β‐PDB). Phorbol esters, which do not activate PKC, 4‐O‐methyl‐TPA and 4α‐PDB, showed no effect on neurotransmitter release. The effect of 4β‐PDB was abolished in the presence of tetrodotoxin and in the absence of calcium. The PKC inhibitor polymyxin B inhibited the evoked noradrenaline release.

In the presence of 4β‐PDB the inhibitory effects of the α2‐adrenoceptor agonist clonidine or the facilitatory effects of the α2‐adrenoceptor antagonist yohimbine seemed to be modified only by changes in the concentration of noradrenaline in the synaptic region. At a stimulation frequency of 3 Hz the inhibitory action of clonidine was reduced whereas the facilitatory effect of the yohimbine was even slightly enhanced by the phorbol ester. At 0.3 Hz and in the presence of 4β‐PDB the effect of clonidine remained and that of yohimbine was strongly enhanced.

Pretreatment of the slices with islet‐activating protein or N‐ethylmaleimide significantly reduced the enhancement of noradrenaline release caused by 4β‐PDB. It is possible that a regulatory N‐protein is involved in steps following PKC activation.

These results suggest that PKC participates in the mechanism of action‐potential‐induced noradrenaline release from noradrenergic nerve terminals of the rabbit hippocampus and that effects on the autoinhibitory feedback system were not responsible for the 4β‐PDB‐induced increase of neurotransmitter release.
Airways hyperreactivity and bronchoconstriction induced by vanadate in the guinea‐pig
Authors: Nayler Ross A. , Mitchell Howard W.
Published: July 2012

The characteristics of vanadate‐induced bronchoconstriction and airways hyperreactivity were observed in spontaneously breathing anaesthetized guinea‐pigs by measurement of airways resistance (Raw) and dynamic lung compliance (Cdyn). Vanadate (0.3–3 mg kg−1 i. v. over 25 min) increased Raw and decreased Cdyn in a reversible, dose‐related manner. This action (1 mg kg−1 vanadate) was not inhibited by atropine (1 mg kg−1 i.v.), propranolol (1 mg kg−1 i.v.) or bilateral vagotomy, suggesting a direct effect on the airways smooth muscle.

An aerosol of vanadate (10% w/v in H2O) for 3 min decreased Cdyn by 19.5% (P < 0.05, n = 6) but caused no change in Raw.

Histamine (3 μg kg−1 i.v.) caused a bronchoconstriction which was enhanced by vanadate in a dose‐related manner. This hyperreactivity (after 1 mg kg−1 i.v. vanadate) was unchanged after propranolol or bilateral vagotomy, but was partly blocked by atropine (enhancement by vanadate of the Cdyn change to histamine was diminished, P < 0.02, n = 3).

Bronchoconstrictor responses to acetylcholine (6 μg kg−1 i.v.) and 5‐hydroxytryptamine (6 μg kg−1 i.v.) were also enhanced by vanadate (1 mg kg−1 i.v.). Hyperreactivity after vanadate to the three bronchoconstrictors tested continued during vanadate infusion and was reversed 45 min after cessation of infusion.

Histamine (3 μg kg−1 i.v.) caused a transient tachypnoea which was also enhanced by vanadate (0.3–3 mg kg−1 i.v.), in a dose‐related manner, in association with the increased reactivity of the airways (r = 0.66, n = 11).

It is concluded that vanadate‐induced airways hyperreactivity is non‐vagal (efferent) and largely non‐cholinergic in origin and appears to involve an action of vanadate within the lung itself.
The effect of enkephalins and of β‐endorphin on the hypertensive response to physostigmine in the rat
Authors: Varagić V.M. , Stojanović Vedrana
Published: July 2012

Intracarotid injection of [Leu]enkephalin and [Met]enkephalin produced a dose‐dependent biphasic change in blood pressure of the rat consisting of an initial shortlasting fall followed by a longlasting increase of blood pressure. Naloxone consistently depressed or abolished the effects of enkephalins on blood pressure.

Intracarotid injection of β‐endorphin only occasionally produced a hypotension, or did not produce any change in the blood pressure of the rat.

All three opioids ([Leu]enkephalin, [Met]enkephalin and β‐endorphin) significantly depressed or abolished the hypertensive response to intravenous injection of physostigmine. This depressive action of opioids was easily reversed by naloxone.

It is concluded that opioids depress the central cholinergic link implicated in the hypertensive response to physostigmine most probably by inhibiting acetylcholine and/or noradrenaline release in the structures relevant for the action of physostigmine on blood pressure of the rat. This interaction is realized through the activation of opioid receptor(s).
Influence of thyroid status on responses of rat isolated pulmonary artery, vas deferens and trachea to smooth muscle relaxant drugs
Authors: O'Donnell Stella R. , Wanstall Janet C. , Mustafa Mariana B.H.
Published: July 2012

Responses to relaxant drugs have been examined on isolated KCl‐contracted smooth muscle preparations from rats in which thyroid status was changed by prior treatment with either thyroxine (T4) for 1 week (preparations of pulmonary artery, trachea and vas deferens) or methimazole for 10–12 weeks (pulmonary artery preparations).

On pulmonary artery preparations, T4 treatment caused a significant increase in the magnitude of the relaxant responses to noradrenaline and isoprenaline but not those to adrenaline. The potency of noradrenaline was increased 5.6 fold but that of isoprenaline and adrenaline was unchanged. This resulted in a change in the relative potencies from adrenaline > noradrenaline (controls) to noradrenaline = adrenaline (T4‐treated). Methimazole treatment caused a significant reduction in the magnitude of the responses to noradrenaline and in its potency (2.8 fold). Isoprenaline and procaterol were unaffected.

On pulmonary artery preparations, T4 treatment did not affect the magnitude of the responses to forskolin, sodium nitrite or isobutylmethylxanthine (IBMX) or their potency. In vitro treatment with the monoamine oxidase (MAO) inhibitors, iproniazid or pargyline, did not potentiate responses to either noradrenaline or isoprenaline. Therefore, it was concluded that the T4‐induced changes in the magnitude of the responses to noradrenaline and isoprenaline and in the potency of noradrenaline were unlikely to be due to reduced activity of cyclic nucleotide phosphodiesterase(s) or MAO.

On preparations of vas deferens and trachea, T4 treatment had no effect on the magnitude of the responses to noradrenaline, isoprenaline, adrenaline or procaterol. On preparations of trachea, but not vas deferens, T4 treatment significantly increased the potency of noradrenaline (2.9 fold) but not that of isoprenaline, adrenaline or procaterol.

We concluded that, on pulmonary artery T4 treatment of rats increased, while methimazole treatment reduced, the magnitude of the responses to, and/or the potency of, the β‐adrenoceptor agonists, noradrenaline and isoprenaline, by a mechanism which is specifically associated with the β‐adrenoceptors, and which is probably selective for the β1‐subtype. T4 treatment caused no change in responses of vas deferens to β‐adrenoceptor agonists. On trachea the only change was a small increase in the potency of noradrenaline. The differences in the effects of T4 treatment on β‐adrenoceptor‐mediated responses of rat pulmonary artery, vas deferens and trachea may be due to the differences in the β‐adrenoceptor populations of these three tissue types and/or differences in the effects of thyroid hormones on vascular compared with non‐vascular smooth muscle.
Characterization and autoradiographic localization of β‐adrenoceptor subtypes in human cardiac tissues
Authors: Buxton B.F. , Jones C.R. , Molenaar P. , Summers R.J.
Published: July 2012

Receptor autoradiography using (—)‐[125I]‐cyanopindolol (CYP) was used to study the distribution of β‐adrenoceptor subtypes in human right atrial appendage, left atrial free wall, left ventricular papillary muscle and pericardium.

The binding of (—)‐[125I]‐CYP to slide‐mounted tissue sections of human right atrial appendage was time‐dependent (K1 = 4.11 ± 1.01 × 108 m−1 min−1, K−1 = 1.47 ± 0.25 × 10−3 min−1, n = 3), saturable (42.02 ± 2.96 pM, n = 4) and stereoselective with respect to the optical isomers of propranolol (pKD (—):8.97 ± 0.02, (+):6.88 ± 0.06, n = 3).

The proportions of β‐adrenoceptor subtypes were determined in slide‐mounted tissue sections using the antagonists CGP 20712A (β1‐selective) and ICI 118,551 (β2‐selective). In right atrial appendage and left ventricular papillary muscle 40% (34–45%) of the β‐adrenoceptors were of the β2‐subtype.

Images from X‐ray film and nuclear emulsion coated coverslips exposed to (—)‐[125I]‐CYP‐labelled sections showed an even distribution of β‐adrenoceptor subtypes over the myocardium of the right atrial appendage, left ventricular papillary muscle and left atrial free wall. Sections of pericardium exhibited predominantly β2‐adrenoceptors. β2‐Adrenoceptors were localized to the intimal surface of coronary arteries.

The selective β1‐adrenoceptor agonist R0363 and β2‐selective agonist procaterol produced concentration‐dependent inotropic responses in right atrial appendage strips. Responses to R0363 were antagonized by CGP 20712A (pKB = 9.29) suggesting an interaction with β,‐adrenoceptors. Responses to procaterol were antagonized by ICI 118,551 (pKB = 9.06) suggesting an interaction at β2‐adrenoceptors.

The finding that a significant proportion of human myocardial adrenoceptors are of the β2‐subtype has important clinical implications for the involvement of these receptors in the control of heart rate and force, and the autoradiographic evidence suggests other roles in the coronary vasculature and pericardium.
l‐Proline depolarizes rat spinal motoneurones by an excitatory amino acid antagonist‐sensitive mechanism
Authors: Ault Brian , Wang Ching M. , Yawn Beverly C.
Published: July 2012

Isolated spinal cords prepared from neonatal rats were used to examine the effects of l‐proline (l‐Pro).

l‐Pro (1–8 mm) depolarized ventral and dorsal roots in a dose‐dependent manner with one sixth of the potency of l‐glutamate (l‐Glu). l‐Pro was four times more potent than d‐Pro. Prolonged application of l‐Pro produced a plateau depolarization of motoneurones with no apparent fade.

Omission of calcium ions from the medium potentiated the depolarizing actions of l‐Pro, l‐Glu and quisqualate.

L‐Pro was antagonized by concentrations of 2‐amino‐5‐phosphonovalerate (25 μm), γ‐d‐glutamylglycine (100 μm) and Mg2+ ions (1 mm) that depressed responses to N‐methyl‐d‐aspartate (NMDA). The NMDA receptor‐mediated component of the response to l‐Pro was estimated to be 60–70%.

These data suggest that l‐Pro should be considered as a possible excitatory neurotransmitter and that, because l‐Pro is a neutral compound, excitatory amino acid receptors may not require an agonist to possess two anionic groups and one cationic group.
The effects of agonists on the components of the cardiac muscarinic receptor
Authors: Burgen A.S.V.
Published: July 2012

The binding of eleven agonists to muscarinic receptors in the rat heart has been measured in competition with [3H]‐N‐methylscopolamine.

Full analysis of binding required the resolution of three components (SH, H and L).

The proportion of the H component was independent of agonist structure. The proportion of the SH component ranged from 2–36% of the total and was dependent on the agonist. The proportion of the L component varied in a complementary way from 59‐22% of the total.

The ratios of the affinities of ten of the agonists to the three components of the receptors were constant; the weakest binding agonist, choline, had lower ratios of affinity.

When saturated with guanylylimidodiphosphate (GppNHp) the SH receptor population was no longer detectable and the H receptor population was reduced by 63%: about 85% of the receptors was in the L population.

The affinity constants of agonists for the H and L forms of the receptors were not changed by GppNHp.

The results are interpreted in terms of the effects of accessory proteins on the proportions of binding and non‐binding conformations of the receptor.
Effects of amiodarone and thyroid dysfunction on myocardial calcium, serum calcium and thyroid hormones in the rat
Authors: Gammage M.D. , Franklyn J.A. , Logan S.D.
Published: July 2012

Myocardial calcium content was found to be elevated and serum calcium reduced in hypothyroid rats.

Treatment of rats with amiodarone at either 30 mg kg−1 or 150 mg kg−1 daily did not result in any significant changes in myocardial or serum calcium.

The administration of amiodarone to hypothyroid rats attenuated the changes in serum but not myocardial calcium, suggesting that amiodarone may exert a thyroid hormone‐like effect in the hypothyroid state.

The administration of amiodarone to thyroid hormone‐treated rats resulted in attenuation of the effects on serum calcium and calculated intracellular calcium; this was consistent with an antagonistic interaction between amiodarone and thyroid hormones.

Administration of amiodarone resulted in significant changes in circulating thyroid hormone levels in the rat; triiodothyronine was reduced and basal thyrotrophin elevated compared to euthyroid controls. Serum thyroxine was not changed; this is in contrast to the effects in man.

Amiodarone does not exert its anti‐arrhythmic action via changes in total myocardial calcium content in the euthyroid rat; nonetheless the described interactions between the drug and thyroid hormones may be involved in its mechanism of action.
A study on the effect of a single dose of tamoxifen on uterine hyperaemia and growth in the rat
Authors: Marshall K. , Senior J.
Published: July 2012

The effect of a single subcutaneous dose of tamoxifen on the rat uterotrophic response was investigated.

The parameters examined were uterine blood flow (measured by the microsphere technique), uterine wet and dry weights and the concentrations of cytosolic and nuclear oestrogen receptors.

Tamoxifen or its metabolites proved to be capable of eliciting a uterotrophic response of 35–42 days duration. The changes seen in uterine blood flow and weight are discussed in relation to oestrogen receptor distribution.
Differential selectivity of endothelium‐derived relaxing factor and nitric oxide in smooth muscle
Authors: Shikano Kazuhisa , Ohlstein Eliot H. , Berkowitz Barry A.
Published: July 2012

The selectivity of endothelium‐derived relaxing factor (EDRF) and nitric oxide (NO) on smooth muscle relaxation was examined and compared. EDRF released from bovine pulmonary arterial endothelium (BPAE) in culture and NO were superfused over vascular, tracheal, gastrointestinal and uterine smooth muscle. EDRF relaxed vascular smooth muscle but not tracheal, gastrointestinal or uterine smooth muscle. NO relaxed vascular and gastrointestinal smooth muscle but not tracheal or uterine smooth muscle. There was a differential selectivity between the relaxant effect of EDRF and NO on smooth muscle
Effect of chlorpromazine on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta
Authors: Nedergaard O.A. , Abrahamsen J.
Published: July 2012

The effects of chlorpromazine on sympathetic neuroeffector transmission have been studied in the rabbit isolated pulmonary artery and aorta.

Chlorpromazine (10−8‐10−5 m), prazosin (10−9‐10−7 m) and phentolamine (3 × 10−8‐3 × 10−5 m) decreased the contractions of pulmonary artery evoked by electrical field stimulation (150 pulses; 3 Hz). The rank order of inhibitory potency (ID50) was prazosin > chlorpromazine > phentolamine.

Rauwolscine (3 × 10−9 m‐4 × 10−6 m) enhanced the neurogenic response by up to 201%. However, higher concentrations (6 × 10−6‐3 × 10−5 m) reduced the contractions evoked by transmural stimulation.

The inhibitory effect of prazosin (10−6 m) was reversible, while that of chlorpromazine (10−8 m) was not.

Chlorpromazine (10−8‐10−4 m), desmethylimipramine (3 × 10−9‐10−5 m), cocaine (10−7‐3 × 10−4 m) and phentolamine (10−5‐3 × 10−4 m) reduced the accumulation of [3H]‐noradrenaline ([3H]‐NA, 10−8 m) by aorta. The rank order of inhibitory potency (ID50) was: desmethylimipramine > chlorpromazine > cocaine > phentolamine. Prazosin (10−7‐10−5 m) and rauwolscine (10−8‐10−4 m) did not reduce [3H]‐NA accumulation.

Chlorpromazine (10−8‐10−6 m) and prazosin (3 × 10−9‐10−7 m) antagonized the contractions of aorta evoked by exogenous noradrenaline (10−9‐3 × 10−4 m) and phenylephrine (10−9‐3 × 10−3 m). The pA2 values for chlorpromazine on the α1‐adrenoceptors were 8.24 (noradrenaline) and 8.27 (phenylephrine). The corresponding values for prazosin were 8.64 and 8.57, respectively.

It is concluded that chlorpromazine and prazosin are potent inhibitors of postsynaptic α1‐ adrenoceptors. Chlorpromazine and phentolamine, unlike prazosin and rauwolscine, are also inhibitors of Uptake.
The cholecystokinin receptor antagonist L364,718 increases food intake in the rat by attenuation of the action of endogenous cholecystokinin
Authors: Hewson G. , Leighton G.E. , Hill R.G. , Hughes J.
Published: July 2012

To determine the role of endogenous cholecystokinin (CCK) in the regulation of food intake, the effects of the potent CCK receptor antagonist L364,718 were investigated on the intake of a palatable diet in non‐deprived rats. The effect of a single dose of proglumide was also investigated for comparative purposes. In addition, the ability of L364,718 to antagonize the reduction in food intake produced by exogenous cholecystokinin‐octapeptide (CCK8) or bombesin in food‐deprived rats was determined.

L364,718 (10–100 μg kg−1, i.p.) increased the intake of palatable diet during the 30 min test period. Proglumide (300 mg kg−1, i.p.) also increased the intake of palatable diet. Conversely, CCK8 (0.5–5 μg kg−1, i.p.) produced a reduction in the intake of the diet.

In fasted rats, L364,718 (100 μg kg−1, i.p.) antagonized the reduction in food intake produced by CCK8 (10 μg kg−1, i.p.) but not that produced by bombesin (50 μg kg−1, i.p.). L364,718 did not increase food intake in these animals when measured over a 6 h period.

It is concluded that L364,718 is a potent, selective antagonist of the effects of CCK8 on food intake. The observation that L364,718 and proglumide increase the intake of a palatable diet provides some evidence that endogenous CCK is involved in the control of food intake in this model.
Antinociceptive effects of the novel opioid peptide BW443C compared with classical opiates; peripheral versus central actions
Authors: Follenfant R.L. , Hardy G.W. , Lowe L.A. , Schneider C. , Smith T.W.
Published: July 2012

To investigate peripherally mediated antinociceptive effects of opioids, the activity of a novel polar enkephalin analogue H‐Tyr‐d‐Arg‐Gly‐Phe (4‐NO2)‐Pro‐NH2 (BW443C) has been compared with those of classical tertiary opiates against different nociceptive stimuli in the mouse.

In chemically‐induced writhing models BW443C, administered subcutaneously, demonstrated dose‐related antinociceptive effects less potent than morphine and of a similar order to pethidine and d‐propoxyphene. In assays using heat as the noxious stimulus BW443C was markedly less potent than any of the opiates tested.

In heat‐induced assays, but not in chemically‐induced writhing assays, BW443C demonstrated a ‘U’‐shaped dose‐time response relationship. Morphine, pethidine and d‐propoxyphene showed simple, approximately linear, dose‐time effects in all assays.

When given subcutaneously, the inhibitory effects of BW443C and morphine in chemically‐induced writhing were antagonized by naloxone given intraperitoneally. The inhibitory effects on writhing of BW443C, but not those of morphine, were also antagonized by prior intraperitoneal administration of the quaternary opioid antagonist N‐methyl nalorphine. When this antagonist was administered intracerebroventricularly, the antinociceptive effects in writhing of both BW443C and morphine were antagonized.

It is concluded that BW443C, being only poorly able to cross the blood brain barrier, demonstrates peripherally mediated opioid antinociceptive effects in chemically‐induced writhing models. In heat‐induced models, that detect centrally acting opioids, BW443C is effective only at high doses and at time intervals after dosing sufficient to allow slow penetration of drug into the CNS. It is suggested that the peripheral antinociceptive actions of BW443C are mediated by inhibition of sensory neurones.
Differential antagonism by Bay K 8644 of vasodilator effects of nifedipine, diltiazem, nicorandil and nitroglycerin in dog femoral circulation
Authors: Sato Yoshinori , Ishii Kuniaki , Taira Norio
Published: July 2012

The modification by Bay K 8644 of the vasodilator effects of nifedipine, diltiazem, nicorandil and nitroglycerin was investigated in the femoral arterial bed of anaesthetized dogs.

The right femoral artery was cannulated and its arterial bed was perfused with autologous blood at a constant pressure slightly higher than the mean systemic arterial blood pressure. Bay K 8644 was infused intra‐arterially (i.a.) and the 4 vasodilators were injected i.a. as bolus doses.

The vasodilator effects of nifedipine (0.3–10 nmol), diltiazem (0.01–1 μmol), nicorandil (0.1–10 μmol) and nitroglycerin (0.3–100 nmol) were all suppressed by infusions of Bay K 8644 (3–100 nmol min−1).

The dose‐response curve of nifedipine was shifted parallel to the right by the infusion of Bay K 8644 and the dose‐ratio was the greatest of the 4 drugs.

The dose‐response curve of diltiazem was also shifted to the right by Bay K 8644. However, the dose‐ratio was far smaller than that of nifedipine.

The vasodilator effect of nicorandil was not antagonized as much by Bay K 8644 as that of nitroglycerin. This less effective antagonism of nicorandil by Bay K 8644 can be explained if nicorandil, which although structurally a nitrate, can in addition cause relaxation of vascular smooth muscle by hyperpolarizing the membrane which would result in Bay K 8644 being less effective.
Effect of dopamine antagonists on the urine flow of rats infused with hypotonic saline
Authors: Angchanpen Pichian , Marin‐Grez Marcos , Schnermann Jürgen
Published: July 2012

The probable involvement of dopamine in the regulation of water excretion was investigated by administering dopamine antagonists intravenously to barbiturate ‐ anaesthetized rats undergoing a water diuresis induced by the infusion of 0.83% glucose with 0.3% NaCl at the rate of 9 ml h−1.

Administration of 100 μg of the D1‐/D2‐dopamine antagonist, haloperidol, reduced the enhanced urine flow of rats infused with the hypotonic solution by 69% (from 75.4 ± 13.0 to 23.6 ± 6.0 μl min−1, P < 0.01). Similarly, the D1‐receptor antagonist, SCH 23390, reduced urine flow by 58% (from 77.5 ± 9.2 to 32.7 ± 7.2 μl min−1, P < 0.01) and the D2‐receptor antagonist, sulpiride, by 47% (from 66.2 ± 8.6 to 35.1 ± 6.8 μl min−1, P < 0.05).

The injection of SCH 23390 increased the urine osmolality from 189.6 ± 27.5 to 479.8 ± 45.8 mosm kg−1 (P < 0.05). There was no significant change in sodium and potassium excretion in any of the experiments. Blood pressure (BP) decreased after haloperidol and SCH 23390 injection from control values of 121.7 ±1.7 and 116.5 ±7.4 to 113.3 ±3.3 and 106.0 ± 8.8 mmHg respectively (P < 0.05).

To study whether the influence of dopamine antagonists on urine flow during water diuresis depends on antidiuretic hormone (ADH), we administered 0.6 μg d(CH2)5‐D‐Phe‐Ile‐AVP (an ADH antagonist) shortly after the injection of 100 μg SCH 23390. The preferential V2 ADH‐antagonist abolished the antidiuretic effect of SCH 23390 but did not affect its blood pressure reducing effect (from 118.6 ± 5.6 to 103.2 ± 4.6 mmHg, P < 0.01).

These results suggest that dopamine antagonists blunted the hypotonic saline‐induced diuresis by favouring ADH release through an interference with an inhibitory dopaminergic pathway.
Cardiac and renovascular effects in the anaesthetized dog of BW A575C: a novel angiotensin converting enzyme inhibitor with β‐adrenoceptor blocking properties
Authors: Cambridge D. , Whiting M.V. , Allan G.
Published: July 2012

In the anaesthetized open‐chest dog, BW A575C (N‐(1‐(S)‐carboxy‐5‐[4(3‐isopropylamino‐2‐(R,S)‐hydroxypropoxy)indole‐2‐carboxamido]pentyl)‐(R,S)‐alanyl‐(S)‐proline) causes a dose‐dependent inhibition of the isoprenaline response (increased cardiac rate). In this preparation BW A575C is approximately 50 times less active than propranolol, and 500 times less active than pindolol at the cardiac β1‐adrenoceptor.

At equieffective cardiac β1‐adrenoceptor blocking doses in the anaesthetized, open‐chest dog, BW A575C (5.0 mg kg−1, i.v.) significantly reduces diastolic blood pressure and reduces cardiac contractility and rate. By contrast, propranolol (0.1 mg kg−1, i.v.) and pindolol (0.01 mg kg−1, i.v.) have little effect on diastolic blood pressure, but significantly reduce cardiac contractility and rate. The effects of BW A575C on cardiac rate are not significantly different from those of propranolol and pindolol, but its effects on cardiac contractility are significantly less than those of propranolol. BW A575C also produces some increase in left ventricular internal dimensions at end‐diastole. This small cardiac dilatation is not significantly different from that observed with pindolol but is significantly less than that of propranolol.

In the anaesthetized closed‐chest dog, BW A575C causes a dose‐dependent inhibition of the angiotensin I pressor response. In this preparation BW A575C is approximately equiactive with enalapril at preventing the pressor response due to conversion of exogenous angiotensin I to angiotensin II (inhibition of angiotensin converting enzyme (ACE)).

At equieffective ACE‐inhibition doses in the anaesthetized, closed‐chest dog, BW A575C (1.0 mg kg−1 by i.v. infusion) significantly reduces diastolic blood pressure, cardiac contractility and rate, whereas enalapril (1.0 mg kg−1 by i.v. infusion) only significantly reduces diastolic blood pressure. This blood pressure lowering effect of enalapril is not significantly different from that of BW A575C. In this preparation BW A575C and enalapril also significantly increase renal blood flow, and renal excretion of urine and Na+. There is however no significant difference between their renovascular effects.

These studies demonstrate that BW A575C produces changes in cardiac and renovascular function which can be ascribed to its being an ACE‐inhibitor and a β‐adrenceptor blocking agent. The combination of these pharmacological properties results in a fall in blood pressure without compromising either cardiac performance or renal function.
Involvement of α‐adrenoceptors in myometrial responses in the pro‐oestral rat
Authors: Acritopoulou‐Fourcroy Stella , Marçais‐Collado Hélène
Published: July 2012

Myometrial responses to different agents acting on adrenoceptors were examined in vivo in the pro‐oestrous rat. Changes in spontaneous uterine mechanical activity were recorded isometrically and evaluated in terms of amplitude and duration of uterine contractions.

Phenylephrine (10 μg kg−1) markedly increased the amplitude and duration of contractions and 40 μg kg−1 gave rise to tetanic contractions.

Administration of either nicergoline (400 μg kg−1) or phentolamine (1000 μg kg−1) to phenylephrine‐primed rat uterus reduced the strength of contractions and phentolamine abolished the phenylephrine‐induced uterine contracture.

Following blockade of α2‐adrenoceptors by yohimbine (1000 μg kg−1) and β‐adrenoceptors by propranolol (2400 μg kg−1), a single injection of phenylephrine (100 μg kg−1) increased the amplitude of uterine contractions by 30%.

Noradrenaline reduced the amplitude of contractions and caused elevation of the baseline level. The response of myometrium to the combination of both propranolol and noradrenaline was the establishment of uterine contracture with subsequent increase of the duration of contractions.

These results clearly demonstrate the involvement of α‐adrenoceptors in the myometrial activity of the rat in vivo during pro‐oestrus.
Suppressive effects of somatostatin in dog Purkinje fibres
Authors: Lin Cheng‐I , Su Mei‐Tsu , Luk Hsiang‐Ning , Wu Hsueh‐Ling
Published: July 2012

The effects of somatostatin (SS, 1 nm‐3 μm) on the electrical and mechanical activities of isolated Purkinje fibres of the dog were studied.

In most Purkinje fibres driven electrically in normal [K]o Tyrode solution, SS decreased the force of contraction slightly and had very little effect on the fast response action potential. However, in sensitive fibres SS induced a moderate reduction of action potential duration and contractile force in normal [K]o and depressed the slow response action potentials in high [K]o.

In spontaneously beating Purkinje fibres, SS decreased the regular rhythms slightly but abolished bursts of fast rhythms at a concentration as low as 1 nm.

When the fibres were depolarized in the presence of 0.2 mm barium or in Na‐free solution, SS suppressed the Ca‐dependent slow response action potentials.

These findings suggest that SS may suppress abnormal automatic activity of dog Purkinje fibres through a reduction of transmembrane Ca influx or a modulation of intracellular calcium.
Relaxing actions of procaterol, a β2‐adrenoceptor stimulant, on smooth muscle cells of the dog trachea
Authors: Fujiwara T. , Sumimoto K. , Itoh T. , Suzuki H. , Kuriyama H.
Published: July 2012

The effects of procaterol, a β2‐adrenoceptor agonist, on smooth muscle cells of the dog trachea were investigated by use of microelectrode and isometric tension recording methods, and by measurement of Ca transients as estimated fromthe fura‐2 fluorescence, adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) and breakdown of phosphatidylinositols.

Procaterol hyperpolarized the membrane and increased the ionic conductance (above 10 nm) in a dose‐dependent manner. These actions were inhibited by propranolol.

Procaterol inhibited the mechanical responses evoked by acetylcholine (ACh), histamine or 5‐hydroxytryptamine (5‐HT), in the presence or absence of Ca2+ in the bath solution, but not that evoked by high concentrations of ACh (1 μm). The ID50 value of procaterol for the peak amplitude of the ACh‐induced contraction (30 nm) was 0.3 nm. The equivalent values for the histamine‐induced phasic and tonic responses (10 μm) were 0.15 and 0.01 nm), respectively.

Procaterol (over 1 nm) increased the amount of cyclic AMP in a dose‐dependent manner which was blocked by prior application of propranolol.

Procaterol did not alter the changes in the amounts of phosphatidylinositol 4,5‐bisphosphate (PI‐P2) and phosphatidic acid (PA) induced by ACh, histamine or 5‐HT. Thus, the synthesis of inositol 1,4,5‐trisphosphate is not affected by stimulation of the β2‐adrenoceptor.

ACh increased the free Ca2+ concentration to a greater extent than that produced by histamine or 5‐HT. These changes were reduced by procaterol, except for those induced by high concentrations of ACh (over 1 μm).

It is concluded that procaterol relaxes tissues precontracted by various agonists due to a reduction in the free Ca2+. This inhibitory action may be due to an increase in the amount of cyclic AMP but does not result from an inhibition of the hydrolysis of phosphatidyl inositols. The hyperpolarization induced by procaterol may partly contribute to the observed relaxation.
Effects of the potassium channel blocking dendrotoxins on acetylcholine release and motor nerve terminal activity
Authors: Anderson A.J. , Harvey A.L.
Published: July 2012

The effects of the K+ channel blocking toxins, the dendrotoxins, on neuromuscular transmission and motor nerve terminal activity were assessed on frog cutaneous pectoris, mouse diaphragm and mouse triangularis sterni nerve‐muscle preparations. Endplate potentials (e.p.ps) and miniature e.p.ps were recorded with intracellular microelectrodes, and nerve terminal spikes were recorded with extracellular electrodes placed in the perineural sheaths of motor nerves.

Dendrotoxin from green mamba (Dendroaspis angusticeps) venom and toxin I from black mamba (D. polylepis) venom increased the amplitude of e.p.ps by increasing quantal content, and also induced repetitive e.p.ps.

Perineural recordings revealed that dendrotoxins could decrease the component of the waveform associated with K+ currents at the nerve terminals, and induce repetitive activation of nerve terminals.

In frog motor nerves, dendrotoxins are known to block the fast f1 component of the K+ current at nodes of Ranvier. Blockade of a similar component of the K+ current at motor nerve terminals may be responsible for the effects of these toxins on neuromuscular transmission.

Similar conclusions can be drawn from the results obtained from mouse neuromuscular junctions.
Antagonism of N‐methylaspartate and synaptic responses of neurones in the rat ventrobasal thalamus by ketamine and MK‐801
Authors: Salt T.E. , Wilson D.G. , Prasad S.K.
Published: July 2012

Extracellular single neurone recordings were made in the ventrobasal thalamus of urethaneanaesthetized rats.

Iontophoretically and intravenously administered ketamine and MK‐801 were found to be selective antagonists of responses of neurones to iontophoretically applied N‐methylaspartate.

Both antagonists, administered in N‐methylaspartate‐selective quantities, reduced the synaptic responses of ventrobasal thalamus neurones to a two‐second air jet directed at the peripheral receptive field.
Evidence for depressant 5‐HT1‐like receptors on rat brainstem neurones
Authors: Davies Michael , Wilkinson Lawrence S. , Roberts Malcolm H.T.
Published: July 2012

The technique of microiontophoresis was used to evaluate the contribution of 5‐HT1‐like, 5‐HT2‐ and 5‐HT3‐receptors to the depressant effects of 5‐hydroxytryptamine (5‐HT) on neurones in the midline of the medullary brainstem of the rat in vivo.

Depressant responses to 5‐HT were resistant to antagonism by the 5‐HT2‐receptor antagonist ketanserin and the 5‐HT3‐receptor antagonist MDL 72222 applied either microiontophoretically or administered systemically.

Microiontophoretic or systemic administration of the 5‐HT antagonist metergoline, which shows nanomolar affinity for the 5‐HT1‐binding site, also failed to attenuate the depressant responses to 5‐HT.

Systemic administration of high doses of methysergide (30–40 mg kg−1) attenuated the depressant responses to 5‐HT but did not block depressant responses to GABA or excitatory responses to glutamate.

The depressant effects of 5‐HT were potently mimicked by the 5‐HT1‐like receptor agonists 5‐carboxamidotryptamine and 8‐OH‐DPAT.

These results indicate that neither 5‐HT2‐receptors nor 5‐HT3‐receptors are involved in the depressant effects of 5‐HT on midline brainstem neurones. The depressant effects of 5‐carboxamidotryptamine (5‐CT) and 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT) and blockade of the response to 5‐HT by high doses of methysergide suggests the involvement of 5‐HT1‐like receptors. The lack of effect of metergoline, however, indicates that this receptor may be different from any of the 5‐HT1 binding sites yet described.
Effects of neostigmine and physostigmine on the acetylcholine receptor‐ionophore complex in frog isolated sympathetic neurones
Authors: Jun‐Ichi Sadoshima , Tokutomi Naofumi , Akaike Norio
Published: July 2012

The effects of neostigmine and physostigmine, reversible carbamate acetylcholinesterase (AChE)‐inhibitors, on nicotinic acetylcholine‐induced inward currents (IACH) were investigated in enzymatically isolated single sympathetic ganglion cells from the bullfrog. The ‘concentration clamp’ technique which combines intracellular perfusion with a rapid external solution change under single electrode voltage‐clamp conditions was used.

Pretreatment with neostigmine and physostigmine did not enhance IAch at any concentrations, suggesting that AChE activity had already disappeared during the enzymatic treatment of the preparation.

Both neostigmine and physostigmine inhibited IAch in a dose‐dependent manner with IC50 values of 7.0 × 10−4 m and 1.1 × 10−4 m, respectively. The blockade by neostigmine was competitive, while that by physostigmine was non‐competitive.

The inhibition of IAch by neostigmine and physostigmine showed no apparent voltage dependency.

Neostigmine did not cause obvious changes of the kinetics of IAch. However, physostigmine reduced both the fast and slow time constants of inactivation of IAch, thus facilitating the rate of inactivation without affecting the activation kinetics of IAch.

These results suggest that neostigmine and physostigmine have different direct actions on the ACh receptor‐ionophore complex. Neostigmine may act on the ACh‐receptor (the binding site of ACh) while physostigmine may interact with the ACh‐gated cation channels.
Neonatal capsaicin treatment of rats reduces ACTH secretion in response to peripheral neuronal stimuli but not to centrally acting stressors
Authors: Donnerer Josef , Lembeck Fred
Published: July 2012

Plasma adrenocorticotrophic hormone (ACTH) concentrations were measured in rats following exposure to anaesthetic agents, after stimulation of peripheral sensory nerves, and during psychological stress.

In rats, kept in their home cages, the i.p. injection of sodium pentobarbitone did not cause an increase in plasma ACTH, whereas injection of urethane increased plasma ACTH several times. In rats transferred to a glass dessicator and inhaling oxygen, plasma ACTH was more than 3 fold higher than in rats in their home cage. Exposure to nitrous oxide, halothane or ether in a glass dessicator produced significantly higher plasma ACTH concentrations when compared to exposure in the home cage.

In rats anaesthetized with pentobarbitone, the electrical stimulation of large myelinated afferents in the sciatic nerve did not trigger a measurable increase in ACTH secretion, whereas stimulation of afferent Aδ‐ and C‐fibres significantly elevated plasma ACTH concentrations. Rats treated as neonates with capsaicin showed an attenuated ACTH response to A and C‐fibre stimulation.

Similarly, capsaicin pretreatment reduced the increase in ACTH secretion during morphine withdrawal; a similar effect was produced by clonidine.

ACTH secretion following open field exposure, ether stress or hypoglycaemia was not changed by capsaicin pretreatment.

It was concluded that capsaicin‐sensitive afferents are involved in the secretion of ACTH elicited by somatosensory forms of stress. Centrally evoked ACTH release is not affected by capsaicin pretreatment.
Immediate anaphylactic bronchoconstriction induces airway hyperreactivity in anaesthetized guinea‐pigs
Authors: Daffonchio Luisa , Payne Adrian N. , Lees Ian W. , Whittle Brendan J.R.
Published: July 2012

The possible acute occurrence of airway hyperreactivity after immediate‐type bronchial anaphylaxis has been investigated in anaesthetized guinea‐pigs actively sensitized to ovalbumin (OA).

Aerosol challenge (OA 10 mg ml−1, 5s) provoked immediate bronchoconstriction which was substantially, although incompletely, reversed by isoprenaline (Iso) infusion (1 μg kg−1min−1) for 10 min).

Bronchoconstrictor responses to 5‐hydroxytryptamine (5‐HT) were enhanced in challenged animals when compared to those in non‐challenged animals that had also received Iso. This was seen as a leftward shift in the location of the dose‐response curve for the bronchoconstrictor effect of 5‐HT (dose‐ratio 2.45, 95% confidence limits 1.77–3.38;P< 0.01). This phenomenon was associated with pulmonary infiltration of polymorphonuclear leukocytes, which was not modified by Iso treatment.

Iso infusion alone caused a slight enhancement of airway reactivity seen as a small leftward shift of the dose‐response curve for the bronchoconstrictor effect of 5‐HT (dose‐ratio 1.51, 95% confidence limits 1.07–2.13;P< 0.05).

These results support a causal relationship between acute pulmonary inflammation and airway hyperreactivity in an animal model of human allergic asthma.
The influence of activation or inhibition of protein kinase C on the release of radioactivity from rat isolated atria labelled with [3H]‐noradrenaline
Authors: Ishac Edward J.N. , de Luca Anthony
Published: July 2012

The release of radioactivity from rat isolated atria preloaded with [3H]‐noradrenaline ([3H]‐NA) evoked by electrical field stimulation (2Hz, 1 ms, 60s) of intraneuronal sympathetic nerves, high potassium (64.7 mm) or tyramine (0.3μm) was used as an index of noradrenaline release.

Activation of protein kinase C by phorbol 12‐myristate 13‐acetate (PMA) produced a concentration‐dependent enhancement of field stimulation‐induced outflow of radioactivity, whereas polymyxin B, an inhibitor of protein kinase C, reduced [3H]‐NA release evoked by field stimulation. The enhancement observed in the presence of PMA was attenuated by polymyxin B (10 and 70 μm).

Release of noradrenaline evoked by membrane depolarization in a high potassium medium was similarly affected by PMA and polymyxin B.

In contrast, the release of noradrenaline evoked by the indirectly acting sympathomimetic amine, tyramine, was not altered by PMA. Polymyxin B in a concentration of 70 μm, but not 10 μm caused a slight reduction in tyramine‐induced outflow of radioactivity.

The spontaneous outflow of radioactive compounds was not affected by either PMA or polymyxin B in the bathing medium.

The findings suggest that protein kinase C may play a role in the exocytotic release of noradrenaline but not in the displacement of noradrenaline by indirectly acting sympathomimetic amines.
Effects of leukotriene D4 on the mechanical and electrical properties of guinea‐pig isolated trachealis
Authors: McCaig Dorothy J. , Rodger I. W.
Published: July 2012

The effects of leukotriene D4 (LTD4) on mechanical and electrical activity were examined in guinea‐pig isolated trachealis muscle and compared with two other bronchoconstrictors, methacholine and potassium chloride (KCl).

LTD4 elicited concentration‐dependent increases in tension in trachealis muscle which were slower in time course than responses induced by either methacholine or KCl. The maximum response to LTD4 was approximately 85% of the methacholine maximum.

At a concentration close to the EC50 for tension changes, LTD4 had no significant effect oneither transmembrane potential or slow wave activity recorded in single trachealis cells.

At a concentration close to the EC90 for tension changes, LTD4 caused significant membrane depolarization, transiently reduced the amplitude and increased the frequency of slow wave discharge and ultimately abolished slow wave discharge. LTD4‐induced depolarization was less marked, and developed more slowly, than that evoked by either methacholine or KCl.

These results show that LTD4 can elicit substantial increases in tension without altering transmembrane potential and are consistent with the view that LTD4 initiates contraction mainly through potential‐independent mechanisms. However, at high concentrations the depolarization evoked by LTD4 allows the possibility that potential‐dependent mechanisms may contribute to the spasm.