bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of acute and chronic clozapine on dopamine release and metabolism in the striatum and nucleus accumbens of conscious rats
Authors: Invernizzi Roberto , Moralix Federica , Pozzi Laura , Samanin Rosario
Published: July 2012

The effect of single and repeated (once daily for 23 days) oral doses of 20 and 60 mg kg−1 clozapine on dopamine release and metabolism were studied by intracerebral dialysis in the striatum and nucelus accumbens of conscious rats.

The basal output of dopamine, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the striatum and nucleus accumbens of rats given clozapine 20 or 60 mg kg−1 chronically, measured one day after the last drug dose, was not significantly different from that of vehicle‐treated animals.

Challenge doses of 20 or 60 mg kg−1 clozapine produced similar increases in dopamine levels in the striatum and nucleus accumbens of animals which had received vehicle or clozapine 20 or 60 mg kg−1 once daily for 23 days, except that 1 h after administration 60 mg kg−1 clozapine had a greater effect in the nucleus accumbens.

In animals treated chronically with clozapine 20 and 60 mg kg−1 or vehicle, DOPAC levels in the striatum and nucleus accumbens were increased to the same extent by challenge doses of clozapine (20 or 60 mg kg−1). In animals treated chronically with clozapine, a challenge dose of 60 mg kg−1 had significantly greater effect on HVA only in the nucleus accumbens.

When DOPAC and HVA were measured post mortem in the striatum and nucleus accumbens 2h after various oral doses of clozapine, it was found that 10 mg kg−1 significantly increased dopamine metabolites only in the nucleus accumbens whereas 100 mg kg−1 had this effect in both regions. Clozapine, 30 mg kg−1 significantly raised DOPAC levels in both regions but HVA was elevated only in the nucleus accumbens.

There appeared to be no appreciable changes in dopamine release and metabolism nor any reduction in the effect of clozapine in the nucleus accumbens after chronic drug treatment. In fact the effect was greater in chronically treated rats, particularly in the nucleus accumbens of animals given 60 mg kg−1 clozapine.

It was confirmed that measurement of dopamine metabolites in post mortem tissue provides no valuable information on changes in the availability of synaptic dopamine.
The effect of putative protein kinase C inhibitors, K252a and staurosporine, on the human neutrophil respiratory burst activated by both receptor stimulation and post‐receptor mechanisms
Authors: Twomey B. , Muid R.E. , Dale M.M.
Published: July 2012

Two compounds, reported to be potent inhibitors of protein kinase C (PKC), K252a and staurosporine, have been examined in order to gain further information as to the possible role played by PKC in the signal transduction sequence of the neutrophil respiratory burst as determined by superoxide (O−2) production.

A number of stimuli were used in the study, some acting at receptors i.e. fMet‐Leu‐Phe (fMLP), opsonized zymosan and heat‐aggregated IgG (HAGG), one acting on a G‐protein, fluoride, and two direct PKC activators, dioctanoylglycerol (diC8) and phorbol myristate acetate (PMA).

K252a and staurosporine inhibited the respiratory burst with all the stimuli but the order of agonist sensitivity was very different with the two inhibitors.

For K252a‐induced inhibition of O−2 release, the order of potency was fluoride > fMLP, HAGG > opsonized zymosan > PMA, DiC8. For staurosporine‐induced inhibition of O−2 release, the order of potency changed to fluoride > DiC8, PMA > HAGG, fMLP > opsonized zymosan. The significance of this unexpected difference in relative rank order of potency is discussed with reference to the reported mechanism of action of the two inhibitors and the events involved in the oxidative burst.

Staurosporine at low concentrations increased the fMLP‐stimulated O−2 response by 100%, the maximum effect occurring at 35 nm.

To the extent that the compounds used are specific inhibitors of PKC, these findings support a role for the enzyme PKC in stimulus‐activation coupling in O−2 generation with all the stimuli used in this study.
The ‘calcium sensitising’ effects of ORG30029 in saponin‐ or Triton‐skinned rat cardiac muscle
Authors: Miller David J. , Steele Derek S.
Published: July 2012

The effects of a range of concentrations of ORG30029 (1 μm to 1 mm) were investigated on fully (Triton‐treated) or selectively (saponin‐treated) ‘skinned’ ventricle trabeculae from rat. The Ca‐sensitivity was increased by 100 μm and amounted to a mean reduction in the Ca2+ necessary for half‐maximal activation (1/Kapp) of 0.174 ± 0.053 (mean ± s.e.mean) pCa units. ORG30029 (50 μm) gave a smaller mean shift of 0.05 ± 0.016 pCa units. A slight shallowing of the relationship between ‐log[Ca2+] (pCa) and steady‐state tension was also generally found (mean Hill exponent reduction 0.37 ± 0.28 at 100 μm).

The Ca‐sensitizing action altered in a dose‐dependent fashion. Judged by the ability to enhance force from an initial level of activation of 10–20% of maximum Ca‐activated force (Cmax), the first significant effects occurred near 10 μm and continued to increase at 1 mm.

A small (3.7 ± 1.1%) but consistent increase in Cmax was produced by ORG30029 at 100 μm. Much larger increases were produced by the drug at higher concentrations (up to 20–50% at 1 mm).

The consequence of these changes is that at levels of activation likely to occur in the heart, the absolute increase in force by 100 μm ORG30029 was considerable: it amounted to a 150–200% increase at a [Ca2+] producing 20% at Cmax. At this drug concentration virtually all the effect was due to Ca‐sensitizing rather than increasing CMax.

In the saponin‐treated preparations, at concentrations up to 1 mm, ORG30029 did not release Ca from the sarcoplasmic reticulum, as indicated by the failure to evoke contracture under conditions where caffeine induced large responses.

At 100 μm, ORG30029 potentiated the transient, caffeine‐induced contracture (saponin‐treated preparation) to an extent consistent with the Ca‐sensitizing effect seen under conditions of steady‐state tension development.
Antiarrhythmic efficacy of labetalol as assessed by programmed electrical stimulation
Authors: Krumpl G. , Todt H. , Krejcy K. , Raberger G.
Published: July 2012

The purpose of the present study was to investigate the haemodynamic, electrophysiological and antiarrhythmic effects of labetalol in the late reperfusion phase after myocardial infarction in conscious dogs.

Labetalol was administered in cumulative doses (0.5, 1 and 3 mg kg−1 90 min−1, i.v.). Compared to control the systolic blood pressure was significantly decreased 20 min after 0.5, 1 and 3mg kg−1 and up to 30 min after 3 mg kg−1 labetalol. The diastolic blood pressure was significantly decreased 20 and 30 min after 0.5 and 3 mg kg−1 but was not significantly altered after 1 mg kg−1 labetalol.

Labetalol significantly increased the PQ, QRS, QT and QTc intervals, the 2:1 AV‐conduction point, the ventricular effective refractory periods and the intraventricular conduction time from the apex of the right ventricle to the infarcted LAD‐area. With the exception of the alterations in the PQ interval and 2:1 AV‐conduction point the effects described above were dose‐dependent.

Labetalol was active against arrhythmias induced by programmed electrical stimulation. This effect was already present after the lowest dose (0.5 mg kg−1).

The good antiarrhythmic activity of labetalol in this study can be explained by the adrenoceptor blocking properties and both the class I and III activity of this drug. Labetalol may be of potential benefit in controlling arrhythmias arising following myocardial infarction.
Role of nitric oxide in maintaining vascular integrity in endotoxin‐induced acute intestinal damage in the rat
Authors: Hutcheson Iain R. , Whittle Brendan J.R. , Boughton‐Smith Nigel K.
Published: July 2012

The role of endogenous nitric oxide (NO) in maintaining intestinal vascular integrity following acute endotoxin (E. coli. lipopolysaccharide) challenge was investigated in the anaesthetized rat by use of NG‐monomethyl‐l‐arginine (l‐NMMA), a selective inhibitor of NO synthesis.

l‐NMMA (10–50 mg kg−1, i.v.) pretreatment enhanced both the macroscopic and histological intestinal damage and the increases in vascular permeability, measured as the leakage of [125I]‐labelled human serum albumen, induced after 15 min by endotoxin (50 mg kg−1, i.v.).

The effects of l‐NMMA (50 mg kg−1, i.v.) were enantiomer specific, as d‐NMMA had no effect. Furthermore, these effects were reversed by l‐arginine (300 mg kg−1, i.v.), the precursor of NO synthesis but not by d‐arginine (300 mg kg−1, i.v.).

l‐NMMA (10–50 mg kg−1, i.v.) increased mean systemic arterial blood pressure but this does not appear to be the mechanism by which endotoxin‐induced intestinal damage was enhanced, since similar systemic pressor responses induced by phenylephrine (10 μg kg−1 min−1, i.v.), had no such effect.

The results suggest that synthesis of NO from l‐arginine has a role in maintaining the microvascular integrity of the intestinal mucosa following acute endotoxin challenge.
Differential effects of chronic lorazepam and alprazolam on benzodiazepine binding and GABAA‐receptor function
Authors: Galpern Wendy R. , Miller Lawrence G. , Greenblatt David J. , Shader Richard I.
Published: July 2012

Chronic benzodiazepine administration has been associated with tolerance and with downregulation of γ‐aminobutyric acidA (GABAA)‐receptor binding and function. However, effects of individual benzodiazepines on brain regions have varied.

To compare the effects of chronic lorazepam and alprazolam, we have administered these drugs to mice for 1 and 7 days (2 mg kg−1 day−1) and determined benzodiazepine receptor binding in vivo with and without administration of CL 218,872, 25 mg kg−1 i.p., and GABA‐dependent chloride uptake in 3 brain regions at these time points.

Benzodiazepine binding was decreased in the cortex and hippocampus at day 7 compared to day 1 of lorazepam, with an increase in CL 218,872‐resistant (Type 2) sites in both regions. Maximal GABA‐dependent chloride uptake was also decreased in the cortex and hippocampus at day 7.

Binding was decreased only in the cortex after 7 days of alprazolam, with no significant change in Type 2 binding. Maximal GABA‐dependent chloride uptake was also decreased only in the cortex.

These data suggest that the effects of chronic benzodiazepine administration on the GABAA‐receptor may be both region‐specific and receptor subtype‐specific.
Endotoxin‐induced impairment of vasopressor and vasodepressor responses in the pithed rat
Authors: Guc M. Oguz , Furman Brian L. , Parratt James R.
Published: July 2012

Effects of E. coli endotoxin on vascular responsiveness to a variety of agents were compared with those of the calcium channel blocking drug nicardipine in pithed rats.

Infusion of endotoxin (250 μg kg−1 h−1) produced a fall in mean arterial blood pressure (8 mmHg). A similar fall (11 mmHg) was seen in rats receiving nicardipine (1.0 mg kg−1).

Endotoxin impaired responsiveness to vasopressin, phenylephrine and cirazoline, producing a shift to the right in the dose‐response curves without any change in the maximum response. Responsiveness to 5‐hydroxytryptamine (5‐HT) and to the α2‐adrenoceptor agonists clonidine and BHT 933, was also impaired with a marked reduction in their maximum responses. The dose‐response curve to the pressor effects of endothelin was not significantly modified.

Nicardipine produced a similar pattern of impairment of responsiveness to these agents to that produced by endotoxin. However, nicardipine also shifted the pressor dose‐response curve to endothelin to the right with no significant alteration in its maximum response.

The pressor responses to endothelin and to 5‐HT were, respectively, preceded and followed by dose‐dependent depressor responses, which were markedly reduced by endotoxin and nicardipine.

The concomitant infusion of arginine vasopressin (0.64 iu kg−1 h−1) prevented endotoxin‐induced hypotension and also prevented the impairment in responsiveness to cirazoline and to BHT 933.

The similarity of the pattern of impaired pressor responsiveness (except in relation to endothelin) and depressor responsiveness produced by endotoxin and nicardipine may be consistent with a common mechanism of action.
The effect of E. coli STa enterotoxin on the absorption of weakly dissociable drugs from rat proximal jejunum in vivo
Authors: McEwan G.T.A. , Lucas M.L.
Published: July 2012

The effect of E. coli heat stable (STa) enterotoxin on the absorption of radio‐labelled weak electrolytes and their appearance in peripheral blood was assessed in vivo by use of an intestinal recirculation procedure.

STa reduced the luminal disappearance (P > 0.02) and peripheral blood appearance (P > 0.02) of label from salicylic acid as well as the luminal disappearance (P > 0.02) of diphenylhydantoin.

In contrast, STa increased the appearance in peripheral blood and disappearance from the lumen of label from morphine (P > 0.05), amphetamine (P > 0.01) and lignocaine (P > 0.01).

Increased weak base (lignocaine) absorption can also be achieved by a combination of forskolin and theophylline which resembles STa in its ability to neutralise the usually acid surface pH of the proximal jejunum.

Increased weak base absorption and hindered weak acid absorption occurs despite a uniform reduction in net fluid absorption after STa exposure, making it unlikely that variations in fluid absorption account for the variations in drug absorption.

The ability of STa to elevate the mucosal surface pH (or acid microclimate) to neutral values, thereby altering the proportion of uncharged weak‐electrolyte, may explain its different effects on weak acids and bases; neutralisation of the acid microclimate would increase the amount of undissociated weak base available for uptake.
Actions of acetylcholine and GABA on spontaneous contractions of the filariid, Dipetalonema viteae
Authors: Christ Daryl , Goebel Michael , Saz Howard J.
Published: July 2012

Isotonic contractions were recorded from the filarial nematode, Dipetalonema viteae (Acanthocheilonema viteae), in an isolated tissue chamber.

Nicotine (10−6 m) and pilocarpine (10−5 m) increased the spontaneous contractions in the intact filariid, but acetylcholine (ACh, 10−4 m) and muscarine (10−5 m) were inactive.

When ACh was applied to an opened D. viteae, it was 10,000 times more potent. This indicates that the cuticle is an effective barrier to the penetration of ACh to the muscle cells.

The effects of ACh on the opened D. viteae were not affected by hexamethonium (10−3 m) or atropine (10−5 m) and were only partially reduced by (+)‐tubocurarine (10−4 m).

γ‐Aminobutyric acid (GABA, 10−3 m) reduced the spontaneous activity of the intact D. viteae; however, the effect of GABA had a slow onset and recovery. Muscimol (10−5 m) was more potent than GABA and had a more rapid onset and recovery.

GABA was 1,000 times more potent on the opened D. viteae than on the intact D. viteae. Baclofen (10−3 m) was inactive on both preparations.

The effect of GABA was not antagonized by bicuculline (10−4 m), picrotoxin (10−5 m) or penicillin G (10−3 m).

It is concluded that the filariid cuticle acts like a lipid structure and blocks the penetration of polar substances, such as ACh and GABA. Also, due to the lack of efficacy of the ACh and GABA antagonists, it was concluded that the nematode receptors are somewhat different from the mammalian ACh and GABA receptors.
Differences in control of descending inhibition in the proximal and distal regions of rat colon
Authors: Hata Fumiaki , Kataoka Toshiya , Takeuchi Tadayoshi , Yagasaki Osamu , Yamano Naoyuki
Published: July 2012

Descending inhibition in the proximal and distal portions of rat colon was studied separately, in vitro.

In the proximal colon, localized distension with a small balloon caused three types of response (contraction; relaxation; relaxation, then contraction) of the circular muscle on the anal side of the distended region.

Distension caused descending relaxation of circular muscle in all segments of the proximal colon, although for this prostaglandin F2α (PGF2α) was necessary in some segments to increase muscle tone.

Atropine and guanethidine did not inhibit this descending relaxation, but tetrodotoxin did.

Hexamethonium inhibited the descending relaxation in 14 of 17 preparations of proximal colon tested, but not in the others.

In the distal colon, distension consistently caused an increase in the tone of the circular muscles. Descending relaxation was observed only after development of higher tone. Atropine and guanethidine did not inhibit the relaxation, but tetrodotoxin did.

Hexamethonium did not inhibit the descending relaxation in most of the preparations of distal colon examined.

AF64A, an inhibitor of choline uptake, inhibited the response mediated by cholinergic neurones in vitro to electrical transmural stimulation of the longitudinal muscle of proximal colon.

Treatment of colonic preparations with AF64A in vitro resulted in inhibition of descending relaxation in those of proximal, but not those of distal, colon.

The participation of intrinsic cholinergic neurones in the descending neuronal pathway is strongly suggested by the results in the proximal colon, but less so in the distal colon.

The tone and spontaneous contractile activity of colonic circular muscles are discussed in relation to their neuronal control.
No evidence for differences between pre‐ and postjunctional α2‐adrenoceptors in the periphery
Authors: Connaughton Sonia , Docherty J.R.
Published: July 2012

We have compared prejunctional α2‐adrenoceptors in rat and guinea‐pig vas deferens and rat and guinea‐pig atria with postjunctional α2‐adrenoceptors in human saphenous vein and human platelets employing the antagonists yohimbine and SK&F 104078 and other α2‐adrenoceptor antagonists.

Yohimbine was approximately 10 times more potent prejuunctionally than SK&F 104078 at antagonizing the inhibition by the α2‐adrenoceptor agonist xylazine of stimulation‐evoked contractions in rat and guinea‐pig vas deferens, and at increasing stimulation‐evoked release of tritium in rat and guinea‐pig atria pre‐incubated with [3H]‐noradrenaline.

Yohimbine was approximately 10 times more potent postjunctionally than SK&F 104078 at antagonizing contractions to noradrenaline in human saphenous vein and at displacing [3H]‐yohimbine binding in human platelet membranes.

For the antagonists yohimbine, SK&F 104078, prazosin, phentolamine, CH 38083 and urapidil, there was a significant correlation between prejunctional potency in rat vas deferens atrium and postjunctional potency in human platelet, although the correlation was improved by the omission of prazosin.

We have no evidence for differences between functional pre‐ and postjunctional α2‐adrenoceptors in the periphery, although these functional receptors may differ from the ligand binding site in the human platelet.
Chronic exposure of cultured endothelial cells to eicosapentaenoic acid potentiates the release of endothelium‐derived relaxing factor(s)
Authors: Boulanger Chantal , Schini Valérie B. , Hendrickson Helen , Vanhoutte Paul M.
Published: July 2012

The effect of chronic exposure of cultured porcine aortic endothelial cells to eicosapentaenoic acid on the release of indomethacin‐insensitive relaxing factor(s) was investigated (a) under bioassay conditions using preconstricted canine coronary artery rings without endothelium and (b) by the measurement of guanosine 3′:5′‐cyclic monophospate (cyclic GMP) content of endothelial cells.

Exposure of endothelial cells for 8–10 days to eicosapentaenoic acid (2.5 × 10−5 m) did not affect the relaxing activity of the perfusate from unstimulated endothelial cells.

The treatment with eicosapentaenoic acid significantly increased the relaxation of the bioassay ring observed upon stimulation of the endothelial cells with adenosine diphosphate (3 × 10−8 m to 3 × 10−4 m) and, to a lesser extent with bradykinin (10−8 to 3 × 10−8 m), while the relaxing activity evoked by the calcium ionophore A23187 (3 × 10−7 m) was not affected. Neither acetylcholine (10−6 m) nor 5‐hydroxytryptamine (10−6 m) stimulated the release of relaxing factor(s) from control or eicosapentaenoic acid‐treated endothelial cells.

Bradykinin (10−7 m), adenosine diphosphate (3 × 10−5 m), the calcium ionophore A23187 (10−6 m) and nitric oxide (2 × 10−6 m) stimulated haemoglobin‐sensitive increases in cyclic GMP content of porcine endothelial cells which were unaffected by prior chronic exposure to eicosapentaenoic acid.

These results suggest that chronic exposure of porcine aortic endothelial cells to eicosapentaenoic acid increases the release of relaxing factor(s) in response to activation of membrane‐associated receptors for purines and kinins. The lack of effect of eicosapentaenoic acid treatment on agonist‐stimulated production of cyclic GMP suggests that the enhanced relaxation observed under bioassay conditions is not due to an increased production of nitric oxide.
Effect of 5‐HT3 receptor antagonists on responses to selective activation of mesolimbic dopaminergic pathways in the rat
Authors: Hagan R.M. , Jones B.J. , Jordan C.C. , Tyers M.B.
Published: July 2012

The effects of 5‐hydroxytryptamine3 (5‐HT3) receptor antagonists on the behavioural hyperactivity response which results from injection of the neurokinin receptor agonist [pGlu5, MePhe8, Sar9]‐substance P (5–11) (DiMe‐C7) into the ventral tegmental area (VTA) of the rat midbrain have been determined.

Subcutaneous administration of ondansetron (GR38032) (0.001–0.3 mg kg−1), GR65630 (0.01 mg kg−1), ICS 205–930 (0.1 mg kg−1) and MDL 72222 (0.1 mg kg−1), inhibited the DiMe‐C7‐induced hyperactivity response.

The effects of ondansetron on DiMe‐C7‐induced changes in dopamine and 5‐HT metabolism in discrete areas of rat forebrain were studied in order to investigate further the possible mechanism of action of 5‐HT3 antagonists in modifying mesolimbic dopaminergic systems.

Intra‐VTA administration of DiMe‐C7 increased levels of dihydroxyphenylacetic acid (DOPAC) in the nucleus accumbens, olfactory tubercules and right amygdala, indicating increased mesolimbic dopamine metabolism. DOPAC levels were not significantly increased in the frontal cortex, left amygdala or striatum. Dopamine levels were not altered in any of these brain areas. DiMe‐C7 also increased 5‐hydroxyindoleacetic acid (5‐HIAA) levels in the amygdala but this was only statistically significant in the right amygdala. 5‐HT levels were not changed significantly by DiMe‐C7 treatment.

In control rats, pretreatment with ondansetron (0.1 mg kg−1) had no effect on the levels of dopamine, 5‐HT or their metabolites, but in rats given DiMe‐C7, ondansetron significantly inhibited the increase in DOPAC levels in the nucleus accumbens.

These results are in agreement with the proposed facilitatory role of 5‐HT3 receptor activation on mesolimbic dopaminergic transmission, and suggest that 5‐HT3 antagonists may have important therapeutic indications for the treatment of CNS disorders in which mesolimbic dopamine systems are perturbed.
An examination of the sources of calcium for contractions mediated by postjunctional α1‐ and α2‐adrenoceptors in several blood vessels isolated from the rabbit
Authors: Daly C.J. , Dunn W.R. , McGrath J.C. , Miller D.J. , Wilson V.G.
Published: July 2012

The roles of intracellular and extracellular‐derived Ca2+ in α‐adrenoceptor‐mediated contractions to noradrenaline (NA) have been investigated in several isolated blood vessels from the rabbit by examining responses in the presence of a modified Krebs‐Henseleit saline with 2.5 mm Ca2+ and a Ca2+‐buffered saline with 0.1 μm free Ca2+.

NA was tested in preparations of the abdominal aorta, distal saphenous artery, renal vein, lateral saphenous vein, plantaris vein and ear vein exposed to a Ca2+‐buffered saline with 0.1 μm [Ca2+]. A concentration of NA which was maximally effective in modified Krebs‐Henseleit saline, produced an initial transient contraction (ITC) followed by a relaxation towards baseline. This is evidence that α‐adrenoceptor‐mediated responses in all these blood vessels depend upon calcium from both sources.

The ITC was particularly pronounced in the arteries and was associated more closely with the α1‐receptor subtype. In the abdominal aorta, distal saphenous artery and renal vein the ITC can almost exclusively be attributed to an α1‐adrenoceptor (prazosin‐sensitive, rauwolscine‐resistant). In the ear vein, and to a lesser extent the plantaris vein, the ITC was mediated in part by an α2‐adrenoceptor (prazosin‐resistant, rauwolscine‐sensitive).

α2‐Adrenoceptors in the lateral saphenous vein largely account for the response to NA in modified Krebs‐Henseleit saline, but α1‐adrenoceptors mediate the ITC in Ca2+‐buffered saline. After selective inactivation of α1‐adrenoceptors with a combination of phenoxybenzamine and rauwolscine, responses to NA in modified Krebs‐Henseleit saline are slow in onset and there is no ITC in Ca2+‐buffered saline.

The possible significance of the coupling of postjunctional α2‐adrenoceptors to dual sources of Ca2+ is discussed in relation to the interaction between α‐adrenoceptor subtypes and the ease of demonstrating functional α2‐adrenoceptors in isolated blood vessels.
Resiniferatoxin, a potent capsaicin‐like stimulator of peripheral nociceptors in the neonatal rat tail in vitro
Authors: Dray A. , Bettaney J. , Forster P.
Published: July 2012

A spinal ventral root response was measured following the activation of peripheral fibres by noxious (heat at 48°C, capsaicin, bradykinin) and innocuous (brush) stimuli in a preparation of the neonatal rat spinal cord‐tail maintained in vitro.

Following superfusion of the tail with 0.1–1.0 nm of the potent irritant, resiniferatoxin (RTX), brief, irregular depolarization and a selective loss of capsaicin sensitivity was produced. RTX 10–100 nm evoked a tonic response, initiated transient irregular depolarizations and densitization to further applications of RTX and capsaicin but not to other stimuli. Following RTX 1 μm a prolonged loss of sensitivity to all noxious stimuli was produced.

When a selective densitization to capsaicin was produced by a long application of capsaicin, RTX was also ineffective.

Superfusion of the tail with 4β‐phorbol, 12, 13‐dibutyrate (PDBu), a protein kinase C activator, stimulated capsaicin‐sensitive peripheral fibres. Prolonged administration of PDBu attenuated or abolished further responses to PDBu and bradykinin but responses to RTX and capsaicin were unchanged. The protein kinase C inhibitor staurosporine (50–200 nm), attenuated the effects of PDBu and bradykinin but not those of RTX or capsaicin.

The present data suggest that neither RTX nor capsaicin act on peripheral nociceptors via a phorbol ester‐like stimulation of protein kinase C. Rather, RTX acts on nociceptors by a similar mechanism to capsaicin. These effects may be the basis for the irritant properties of RTX and may further relate to the antinociceptive actions observed in vivo. RTX is therefore a potent new tool with which to investigate the properties of nociceptive neurones and provides a prototype for further development of antinociceptive agents.
Effect of neuropeptide Y on cardiac output, its distribution, regional blood flow and organ vascular resistances in the pithed rat
Authors: MacLean Margaret R. , Hiley C. Robin
Published: July 2012

The effects of neuropeptide Y on cardiac output, its distribution and organ vascular resistances were determined with tracer microspheres in pithed rats.

Neuropeptide Y increased blood pressure by increasing both cardiac output and total peripheral resistance. The increase in cardiac output was due to an increase in stroke volume as heart rate was not changed. Increased vascular resistance in the splenic, renal, testicular, epididimidal, skeletal muscle, large intestinal and mesenteric vascular beds contributed to the increase in total peripheral resistance. Vasoconstriction was most pronounced in the mesenteric bed.

This study indicates that neuropeptide Y increases blood pressure by increasing cardiac output and total peripheral resistance. The increased cardiac output is possibly due to an increase in venous return, whilst the increased total peripheral resistance was due to regional vasoconstriction, particularly in the mesenteric bed.
Effects of pinaverium on voltage‐activated calcium channel currents of single smooth muscle cells isolated from the longitudinal muscle of the rabbit jejunum
Authors: Beech D.J. , MacKenzie I. , Bolton T.B. , Christen M.O.
Published: July 2012

Smooth muscle cells of the longitudinal muscle of the rabbit jejunum were dispersed by enzyme treatment and recordings of membrane current were made in the whole‐cell mode by patch clamp technique. The action of pinaverium bromide on the voltage‐dependent inward current of single isolated smooth muscle cells was studied in solutions containing normal concentrations of calcium or high concentrations of barium at room temperature.

Pinaverium reduced the voltage‐dependent inward current with an IC50 of 1.5 μm. This IC50 is similar to those of verapamil, diltiazem and flunarizine on these cells as described by others. Occasionally evidence of a potentiating action of pinaverium on the inward current was seen.

Repetitive stimulation of the cells did not increase blockade of inward current by pinaverium unlike the use‐dependent blockade seen with verapamil, methoxyverapamil, and diltiazem in these and in other smooth muscle cells.

The inactivation of inward current was studied by holding at various potentials for 2 or 10 s before evoking inward current. The voltage at which current was 50% available was changed very little by pinaverium although other calcium entry blockers, for example the dihydropyridines, have been reported to produce appreciable negative shifts which indicate considerable voltage‐dependence of their blockade. This may indicate that pinaverium has similar affinities for the closed available and inactivated calcium channel states so that blockade is not appreciably voltage‐dependent.
Atropine‐resistant relaxation induced by high K+ in iris dilator muscle of the rat and pig
Authors: Ryang S. , Takei S. , Kawai T. , Imaizumi Y. , Watanabe M.
Published: July 2012

The effects of high K+ ion concentration on the isometric tension in dilator muscle strips of the rat and porcine iris were examined. A high K+ solution, prepared by the replacement of Na+ in the medium with equimolar K+, was applied in the presence of 1 μm phentolamine, 1 μm propranolol and 1 or 10 μm atropine. High K+ (> 20 mm) induced a biphasic response; an initial phasic contraction followed by relaxation rather than tonic contraction.

An additional application of a Ca2+ antagonist, 1 μm nifedipine or nicardipine, almost completely blocked the K+‐induced initial contraction and enhanced the following relaxation. The effect of K+ under these conditions was concentration‐dependent in the range 20 to 80 mm. The maximum amplitude of the atropine‐resistant relaxation induced by high K+ corresponds to 50–75% of that produced by acetylcholine in the absence of atropine. A similar K+‐induced relaxation was observed in the porcine iris dilator.

The atropine‐resistant relaxation in the rat iris dilator was not affected by pretreatment with 10 μm ouabain. The relaxation induced by 40 or 80 mm K+ in the porcine dilator was slightly enhanced or not affected, respectively, in the presence of 1 μm ouabain. Application of 10 μm ouabain per se induced relaxation in the porcine iris dilator.

The low Na+ ion concentration present in high K+ solutions was not responsible for the K+‐induced relaxation since the complete replacement of Na in the medium with Tris did not affect significantly the relaxation produced by high K+‐containing solutions.

Neither 1 μm tetrodotoxin, 10 μm indomethacin, 10 μm nordihydroguaiaretic acid nor hypoxic conditions affected the high K+‐induced relaxation.

The inherent tone of the rat iris dilator was not affected by either 8‐bromo cyclic GMP, dibutyryl cyclic GMP (0.1‐0.3 mm) or nitroprusside (1–100 μm).

These results may suggest that the atropine‐resistant relaxation induced by high K+ is not due to either activation of the Na‐K pump or release of a relaxing factor produced by oxidative metabolism. Although the relaxation mechanism has not been elucidated, it is probably not mediated by an increase in cellular cyclic GMP levels.
Tetrahydroaminoacridine (tacrine) stimulates neurosecretion at mammalian motor endplates
Authors: Thesleff S. , Sellin L.C. , Tågerud S.
Published: July 2012

Tacrine (20 μm) induced, like 4‐aminoquinoline (4‐AQ, 200 μm), the appearance of a population of miniature endplate potentials (m.e.p.ps) with more than twice the normal amplitude or time‐to‐peak. The times‐to‐peak of nerve impulse‐evoked endplate potentials were not similarly affected.

Cholinesterase inhibition by edrophonium (25 μm) did not prevent tacrine or 4‐AQ from inducing this population of m.e.p.ps.

Nerve‐muscle preparations in which the normal calcium‐sensitive quantal release of acetylcholine had been blocked by botulinum neurotoxin type A also responded to tacrine by an increase in the frequency of giant or slow m.e.p.ps.

Reduction of the temperature from 30° to 14°C reduced the frequency of giant or slow m.e.p.ps induced either by tacrine or by 4‐AQ. A similar effect was obtained by colchicine (5 mm). This supports the idea that proximo‐distal axonal transport is required for the secretory activity.

The neurosecretion evoked by tacrine could explain the therapeutic effects of the drug claimed in the treatment of Alzheimer's type of dementia.
Cigarette smoke, nicotine and capsaicin aerosol‐induced vasodilatation in pig respiratory mucosa
Authors: Matran Régis , Alving Kjell , Lundberg Jan M.
Published: July 2012

Anaesthetized pigs were used to study vascular responses in the sphenopalatine artery (SPA), superior laryngeal artery (SLA) and bronchial artery (BA) upon exposure to cigarette smoke or aerosol of nicotine and capsaicin. Direct blood flow recordings were made with ultrasonic probes around the vessels.

Smoke from one cigarette was administered as inhalation for 2 min with or without a Cambridge filter which removes the particulate matter including nicotine from the smoke. Aerosols of nicotine (2.5 mg) or capsaicin (10 mg) were administered to the nose or the lower airways for 3 min.

Cigarette smoke exposure caused a reproducible reduction of the vascular resistance (VR) suggesting vasodilatation in the SPA, SLA, and especially the BA. The vasodilatation was not modified by the Cambridge filter, suggesting that it was caused by vapour phase components rather than nicotine.

The smoke effect was not changed after pretreatment with the cyclo‐oxygenase inhibitor, diclofenac, or with atropine, guanethidine, H1 or H2‐histamine receptor antagonists, nedocromil, or by vagotomy. The smoke‐evoked decrease in VR was not modified by the nicotinic receptor antagonist chlorisondamine in the SLA or BA.

In pigs pretreated with increasing doses of capsaicin two days earlier, the decrease in VR upon smoke exposure in both the BA and SLA was unaffected while the change in VR was attenuated in the SPA.

Nicotine aerosol had no effect on VR in the peripheral airways supplied by the BA while a decrease in VR was observed in the SLA and SPA. The nicotine response was reduced after capsaicin pretreatment in the nasal and upper tracheal circulation.

Capsaicin aerosol reduced VR in the vascular beds supplied by the SPA, SLA and BA and this response was markedly reduced after capsaicin pretreatment.

The mechanisms underlying vasodilatation upon cigarette smoke exposure in the bronchial mucosa are at the moment unclear while both non‐cholinergic parasympathetic and sensory components may be involved in the nose. Capsaicin induced a vasodilatation at all levels via sensory mechanisms, whereas nicotine‐evoked vasodilatation is restricted to the upper airway mucosa and is at least partly dependent on parasympathetic reflexes involving capsaicin‐sensitive sensory nerves.
The effects of phosphatidylserine on the decreased cardiovascular response to clonidine microinfused into the nucleus tractus solitarii of old rats
Authors: Mollace V. , Masuda Y. , Pelaggi T. , Nisticò G.
Published: July 2012

The cardiovascular effects of direct microinfusions of clonidine into the nucleus tractus solitarii (NTS) in rats of different ages were studied.

Clonidine microinfused into the NTS produced a dose‐dependent hypotensive and bradycardic response, which was reduced by previous microinfusion of yohimbine but not of propranolol or prazosin.

Unilateral microinfusion of clonidine into the NTS produced a significantly smaller hypotensive and bradycardic response in 16 month old rats than in 3 month old rats, whereas in older animals (24 month old) the same doses of clonidine were ineffective. In 16 month old rats, yohimbine given into the NTS produced a smaller pressor and tachycardic response than in 3 month old rats whereas in 24 month old animals yohimbine, at the same doses, was unable to change blood pressure and heart rate.

Oral administration of phosphatidylserine (50 mg kg−1 day−1 for 30 consecutive days) enhanced the hypotensive and bradycardic response to clonidine microinfused into the NTS in 16 month old rats. The same schedule of treatment with phosphatidylserine did not affect the cardiovascular response to clonidine in young (3 month old) rats and did not restore responsiveness to clonidine in older rats (24 month old).

Methoxamine and phentolamine, given intravenously, produced similar pressor and depressor responses, respectively in 3, 16 and 24 month old rats, suggesting that the decreased sensitivity to clonidine in old rats was not due to peripheral cardiovascular changes.

In conclusion, the present results indicate that, during aging, there is a decreased sensitivity of α2‐adrenoceptors in the brain. Such an alteration can be reversed by chronic treatment with phosphatidylserine during the initial but not the later stages of aging.
Pharmacological evaluation of a guinea‐pig tracheal epithelium‐derived inhibitory factor (EpDIF)
Authors: Fernandes Lynette B. , Goldie Roy G.
Published: July 2012

An epithelium‐derived inhibitory factor (EpDIF) released by guinea‐pig tracheal epithelium was evaluated in a co‐axial bioassay system consisting of an epithelium‐intact guinea‐pig tracheal tube surrounding endothelium‐denuded rat aortic strip.

Histamine and several muscarinic agonists induced concentration‐dependent relaxation of phenylephrine‐contracted rat aorta via the release of EpDIF. However, several other agonists did not induce the release of EpDIF from guinea‐pig trachea. These included the nicotinic cholinoceptor agonists nicotine (25 μm), 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP) (25 μm), calcium ionophore A23187 (0.5 μm), bradykinin (0.05‐0.5 μm), substance P (5 μm), platelet activating factor (PAF, 1–100 nm), the leukotrienes (LT) LTC4, LTD4 and LTE4 (0.1–10 nm) as well as hyperosmotic stimuli.

Prostaglandin E2 (PGE2) induced concentration‐dependent contraction of endothelium‐denuded rat aortic preparations, indicating that this prostanoid could not be EpDIF. Furthermore, relaxation to histamine and methacholine, mediated via EpDIF, was not significantly altered in the presence of phenidone (50 μm) the cyclo‐oxygenase/lipoxygenase inhibitor with radical scavenging properties or the cytochrome P‐450 inhibitors metyrapone (1 mm) and SKF 525A (25 μm). This suggests that EpDIF is neither a prostanoid nor a cytochrome P‐450 metabolite of arachidonic acid.

The soluble guanylate cyclase inhibitor, methylene blue (50 μm), caused small but significant increases in the potencies of both histamine and methacholine in co‐axial assemblies, indicating that EpDIF did not activate this enzyme and therefore was not NO or a related substance. The β‐adrenoceptor antagonist, (−)−propranolol (1 μm), and the PAF‐receptor antagonist, WEB 2086 (50 μm), also failed to alter significantly EpDIF‐modulated relaxations. These data suggest that EpDIF is neither a stimulant of β‐adrenoceptors nor of PAF receptors.

The present study provides some evidence that this vascular smooth muscle‐sensitive EpDIF may not be related to the putative EpDIF previously hypothesized to modulate directly spasmogen‐induced airway smooth muscle tone.
The role of adenosine in the hyperaemic response of the hepatic artery to portal vein occlusion (the ‘buffer response’)
Authors: Mathie R.T. , Alexander B.
Published: July 2012

Adenosine has been shown to be responsible for the hyperaemic response of the hepatic artery to portal vein occlusion (the hepatic arterial ‘buffer response’).

The effect of adenosine receptor blockade and of adenosine uptake inhibition on the hepatic arterial response to portal vein occlusion was investigated in three groups of anaesthetized dogs.

Venous return and arterial blood pressure were maintained during periods of portal occlusion by establishing a side‐to‐side portacaval shunt. Hepatic artery and portal vein blood flows were measured with electromagnetic flowmeters.

Hepatic arterial infusions of 8‐phenyltheophylline (500 μg kg−1 min−1) and 3‐isobutyl‐1‐methylxanthine (75 μg kg−1 min−1), doses sufficient to block the vasodilator response of the hepatic artery to exogenously applied adenosine, reduced the magnitude of the ‘buffer response’ by 50% and 75%, respectively.

Intravenous infusion of dipyridamole (100 μg kg−1 min−1), a dose sufficient to potentiate the vasodilator response of the hepatic artery to exogenously applied adenosine, had little effect on the ‘buffer response’.

It is concluded that adenosine is an important, but not the sole, agent responsible for the hepatic arterial ‘buffer response’.
Enhanced α‐adrenoceptor responsiveness and receptor number during global ischaemia in the Langendorff perfused rat heart
Authors: Butterfield Michelle C. , Chess‐Williams Russell
Published: July 2012

Idioventricular rate responses and adrenoceptor number have been examined in normal Langendorff hearts perfused at 70 cmH2O and in ‘ischaemic’ hearts perfused at 10 cmH2O.

In hearts perfused at normal pressure, ventricular rate responses to phenylephrine in the presence of propranolol were biphasic with low concentrations of phenylephrine reducing, and high concentrations increasing, ventricular rate. Both responses were abolished in the presence of prazosin (100 nm). In hearts perfused at low pressure, the negative chronotropic responses to phenylephrine were no longer present and positive chronotropic responses were enhanced compared with those of control tissues. The number of ventricular [3H]‐prazosin binding sites was also significantly increased during ischaemia.

Idioventricular rate responses to isoprenaline were depressed in ischaemic tissues compared with controls, but [3H]‐dihydroalprenolol binding was not altered in these hearts.

The incidence and duration of arrhythmias which occurred during 30 min of global ischaemia and reperfusion were not significantly altered in the presence of 100 nm prazosin.

These results demonstrate that reducing the perfusion pressure of rat isolated hearts enhances α‐adrenoceptor‐mediated responses and increases α‐adrenoceptor density. Whether the increase in α‐adrenoceptor responsiveness during ischaemia is involved in arrhythmogenesis requires further investigation.
Characterization of cardiac angiotensin converting enzyme (ACE) and in vivo inhibition following oral quinapril to rats
Authors: Fabris Bruno , Yamada Hiroshi , Cubela Rose , Jackson Bruce , Mendelsohn Frederick A.O. , Johnston Colin I.
Published: July 2012

Angiotensin converting enzyme (ACE) from the rat heart and lung was studied by use of the radioligand [125I]‐351A.

Displacement of the bound radioinhibitor [125I]‐351A was used to assess the relative potency of six ACE inhibitors in rat heart and lung homogenates and estimate the binding association constant (KA).

The KA for atrial preparations was significantly higher than that of the lung (P < 0.025) and also the ventricles (P < 0.005). Ventricular preparations and preparations from the lung also differed significantly (P < 0.05). These differences in KA were noted for all six ACE inhibitors used to displace the radioligand.

The rank order of potency of the ACE inhibitors was quinaprilat = benazeprilat > perindoprilat > 351A > lisinopril > fosinoprilat.

Cardiac ACE inhibition was studied ex vivo following oral administration of quinapril to rats. Following 0.3 mg kg−1 quinapril, the time course and degree of inhibition of ventricular and atrial ACE were similar.

These results suggest that the detected differences in KA noted have only a limited potential biological significance. The difference in KA may reflect variations in the structure or conformation of ACE in different tissues.
Antipyretic actions of human recombinant lipocortin‐1
Authors: Davidson J. , Flower R.J. , Milton A.S. , Peers S.H. , Rotondo D.
Published: July 2012

The effect of human recombinant lipocortin‐1 (hrLC‐1) on the pyrogenic actions of the synthetic polyribonucleotide polyinosinic: polycytidylic acid (poly I: C) has been studied in conscious rabbits. Poly I: C (2.5 μg kg−1) given i.v. produced a biphasic fever with a first peak after 90–105 min and a second peak between 225–240 min. hrLC‐1 (50 μg kg−1) given i.v. simultaneously with the poly I: C produced a significant reduction in the febrile response but without complete suppression. The thermal response index over 5 h (TRI5) was 4.69 ± 0.51 for poly I: C given with saline and the TRI5 for poly I: C given with hrLC‐1 was 2.66 ± 0.45 (values are for n = 5 ± s.e.mean, P < 0.05). hrLC‐1 administered alone had no effect on body temperature and its antipyretic activity was lost on heating. In a separate series of experiments 1 h pretreatment with dexamethasone (1 mg kg−1) given i.v. reduced the pyrogenic response (TRI5) to poly I: C (2.5 μg kg−1) from 4.87 ± 0.54 without dexamethasone to 2.00 ± 0.25 (n = 5, P < 0.05) and dexamethasone given alone had no effect on body temperature. These data demonstrate that LC‐1 possesses antipyretic actions and raises the possibility that the antipyretic actions of dexamethasone are mediated through the induction of LC‐1.
Antiarrhythmic properties of tedisamil (KC8857), a putative transient outward K+ current blocker
Authors: Beatch G.N. , Abraham S. , MacLeod B.A. , Yoshida N.R. , Walker M.J.A.
Published: July 2012

Rats were used to evaluate the antiarrhythmic properties of tedisamil, a novel agent with the electrophysiological properties of a Class III antiarrhythmic drug. Tedisamil was tested against coronary artery occlusion‐induced arrhythmias in conscious animals.

The actions of tedisamil on the ECG, as well as responses to electrical stimulation, were compared with those on the configuration of epicardial intracellular action potentials recorded in vivo.

Tedisamil (1–4 mg kg−1, i.v.) caused bradycardia, elevated blood pressure and dose‐dependently reduced ventricular fibrillation (VF) induced by occlusion of the left anterior descending coronary artery. Other ischaemia‐associated arrhythmias were not so well suppressed. Antiarrhythmic activity was greatest when the tedisamil‐induced bradycardia was prevented by electrically‐pacing the left ventricle.

Tedisamil dose‐dependently lengthened the effective refractory period and prevented electrically‐induced VF. In vivo, tedisamil (0.5–4 mg kg−1, i.v.) prolonged the duration of epicardial intracellular action potentials by up to 400%.

Results showed that tedisamil possessed antifibrillatory actions in rats that were related to Class III electrophysiological actions as revealed by electrical stimulation and electrophysiological analyses.