bluuebunny/crossref_metadata_2025_split huggingface dataset:
The action of palytoxin on the isolated detrusor muscle of the rat
Authors: Posangi J. , Zar M.A. , Harris J.B. 
Published: July 2012

The effects of a coelenterate toxin, palytoxin (PTX) have been studied in the isolated detrusor muscle of the rat.
PTX (1–100 nm) initiated concentration‐dependent contractions of the detrusor; the contraction led to an irreversible tachyphylaxis. Muscle desensitized to PTX continued to respond to acetylcholine (ACh) and excess K+ but the contractions were reduced compared to pre‐PTX contractions.
Contractions evoked by PTX were not affected by the presence of atropine (10 μm), indomethacin (10 μm) or tetrodotoxin (0.5 μm) but were greatly reduced by nifedipine (3 μm) and by the absence of K+. PTX could not evoke contractions in the absence of Ca2+ or in tissues depolarized by exposure to excess K+.
PTX abolished the neurogenic contractile responses to electrical field stimulation (EFS).
Combined treatment with atropine (10 μm) plus nifedipine (3 μm) abolished contractile responses to EFS and greatly reduced the contractile response to PTX.
The contractile response to PTX (100 nm) was reduced following exposure of the muscle to α,β‐methylene ATP.
Exposure to PTX (100 nm) for 1–3 h reduced both the ACh content of the detrusor (by more than 80%), and the immunoreactivity of neuropeptide Y‐containing nerve fibres compared to control.
It is concluded that the primary effect of PTX is to promote the release of endogenous motor transmitters, leading to their eventual depletion.
The effects of combined angiotensin converting enzyme inhibition and β‐adrenoceptor blockade on plasma renin activity in anaesthetized dogs
Authors: Cambridge D. , Whiting M.V. , Butterfield L.J. , Allan G. 
Published: July 2012

The effects of β‐adrenoceptor blockade on the changes in plasma renin activity (PRA) following angiotensin enzyme (ACE) inhibition were investigated in pentobarbitone‐chloralose anaesthetized dogs.
ACE‐inhibition, with enalapril (2 mg kg−1), caused a significant reduction in systemic arterial blood pressure (BP) with little or no effect on cardiac function, and a significant elevation of plasma renin activity (PRA). By contrast β‐adrenoceptor blockade with atenolol (1 mg kg−1), caused a similar reduction in BP but in addition, significantly reduced cardiac function and PRA.
A combination of enalapril with atenolol, caused a significant reduction in BP, cardiac function and PRA, hence there was no elevation of PRA, as was seen following ACE‐inhibition with enalapril alone.
The observations with β‐adrenoceptor blockade alone, show that there is an important homeostatic role for the renal sympathetic innervation, mediated by β‐adrenoceptors, in controlling basal renin levels. Furthermore, the renal sympathetic innervation appears to be an important contributor to the renin release caused by an ACE‐inhibitor as the additional presence of a β‐adrenoceptor blocking agent will prevent this release.
BW B385C (2 mg kg−1), which combines both ACE‐inhibition and β‐adrenoceptor blocking properties, also produced reductions in BP and cardiac function similar to those seen with the enalapril/atenolol combination. In addition, for an equivalent degree of ACE‐inhibition by BW 385C, to that seen with enalapril alone, the elevation of PRA was attenuated.
A combination of ACE‐inhibition and β‐adrenoceptor blocking activity in a single entity, such as BW B385C, therefore also produces a reduced renin release when compared with an ACE‐inhibitor, such as enalapril. This provides further confirmation of the importance of the renal sympathetic innervation in the renin response to ACE‐inhibition, and supports the concept of combining ACE‐inhibition with β‐adrenoceptor blockade.
Evidence for a glutamate receptor of the AMPA subtype which mediates insulin release from rat perfused pancreas
Authors: Bertrand G. , Gross R. , Puech R. , Loubatières‐Mariani M.M. , Bockaert J. 
Published: July 2012

The effect of l‐glutamate has been studied on insulin secretion by the isolated perfused pancreas of the rat. The glutamate receptor subtype involved has been characterized.
In the presence of a slightly stimulating glucose concentration (8.3 mm), l‐glutamate (5 × 10−5−4 × 10−3 m) induced an immediate, transient and concentration‐dependent insulin response. On the other hand, in the presence of a non stimulating glucose concentration (2.8 mm), l‐glutamate (10−3 m) did not modify the basal insulin secretion.
The three non‐NMDA receptor agonists, kainate (10−4−10−3 m), α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA, 5 × 10−5−10−4 m) and quisqualate (5 × 10−6−5 × 10−5 m) all provoked a transient and concentration‐dependent insulin response from pancreas perfused with 8.3 mm glucose. Compared with glutamate, kainate exhibited a similar efficacy, whereas AMPA and quisqualate elicited only a 3 fold lower maximal insulin response. In contrast, NMDA (10−4−10−3 m) was ineffective.
An antagonist of non‐NMDA receptors, 6‐cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX; 5 × 10−5 m) totally prevented the stimulatory effect of l‐glutamate (4 × 10−4 m) and kainate (2 × 10−4 m). In contrast, the NMDA receptor antagonist, (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclohepten‐5,10‐imine ((+) MK801) was without effect.
The insulin secretory effect of glutamate (4 × 10−4 m) was not affected by atropine (3 × 10−7 m) or tetrodotoxin (3 × 10−6 m).
Quisqualate at a high maximally effective concentration (4 × 10−4 m) inhibited glutamate (10−3 m) or kainate (4 × 10−4 m)‐induced insulin release.
This study shows that l‐glutamate stimulates insulin secretion in rat pancreas, by acting on an excitatory amino acid receptor of the AMPA subtype.
Purinoceptors mediating relaxation and spasm in the rat gastric fundus
Authors: Matharu Manjit S. , Hollingsworth Michael 
Published: July 2012

The relaxant and spasmogenic effects of purines and analogues were studied in longitudinal strips of rat gastric fundus to characterize the purinoceptors involved. Classification was studied by use of agonist potency orders and of antagonists in circumstances where the influence of confounding factors was reduced. In general tone was raised by carbachol (0.1 μm).
Adenosine produced relaxation and was potentiated by nitrobenzylthioinosine (NBTI, 0.3 and 30 μm), an adenosine‐uptake inhibitor. 8‐Sulphophenyl‐theophylline (8‐SPT, 30 μm), a selective P1‐purinoceptor antagonist, antagonized adenosine and 5′‐N‐ethylcarboxamidoadenosine (NECA), a selective agonist at P1‐purinoceptors.
At resting tone, adenosine 5′‐triphosphate (ATP) induced a small, phasic relaxation followed by a maintained spasm. When tone was raised by carbachol, ATP induced a larger relaxation followed by a smaller spasm. NBTI did not potentiate ATP, nor did 8‐SPT antagonize ATP, suggesting that ATP does not act directly or indirectly at P1‐purinoceptors.
With raised tone, and in the presence of indomethacin (10 μm) and 8‐SPT (30 μm), 2‐methylthio ATP (2‐MeSATP) and ATP produced relaxations followed by spasms while α,β‐methylene ATP (α,β‐MeATP) induced only relaxation; all responses were concentration‐dependent. The compounds had similar slopes and maxima for relaxation and spasm. The rank orders of potency were 2‐MeSATP ≫ α,β‐MeATP > ATP for relaxation and 2‐MeSATP ≫ ATP for spasm.
With raised tone, and in the presence of indomethacin and 8‐SPT, desensitization to α,β‐MeATP (100 μm) completely and only slightly suppressed responses to ATP and 2‐MeSATP, respectively, as relaxants but had no effect on relaxant responses to adenosine. The magnitude of the spasms to ATP and 2‐MeSATP was considerably increased by desensitization with α,β‐MeATP but the spasm to KCl was not affected.
With raised tone, and in the presence of indomethacin and 8‐SPT, reactive blue 2 (10 μm) non‐selectively antagonized ATP, 2‐MeATP, α,β‐MeATP, adenosine and isoprenaline as relaxants. Reactive blue 2 prevented the spasms to ATP and 2‐MeSATP but not spasm to KCl.
With raised tone, and in the presence of indomethacin, suramin (100 μm) antagonized ATP, but not adenosine, as relaxants and antagonized ATP, but not KCl, as spasmogens.
It is proposed that adenosine is susceptible to nucleoside‐specific uptake and acts predominantly via a P1‐purinoceptor and also by a non‐P1‐purinoceptor mechanism. ATP‐ and α,β‐MeATP‐induced relaxations probably occur via a P2X‐purinoceptor. The anomalous nature of the 2‐MeSATP‐induced relaxation suggests it acts both via a P2X‐purinoceptor and an additional mechanism. A P2Y‐purinoceptor is most likely to be involved in the spasms to ATP and 2‐MeSATP. Therefore, the functional nature of the responses mediated by P2X‐ and P2Y‐purinoceptors, relaxation and spasm respectively, are opposite to those seen in most smooth muscles.
Effects of a potassium channel opener (SDZ PCO 400) on guinea‐pig and human pulmonary airways
Authors: Chapman I.D. , Kristersson A. , Mathelin G. , Schaeublin E. , Mazzoni L. , Boubekeur K. , Murphy N. , Morley J. 
Published: July 2012

SDZ PCO 400 evoked dose‐related relaxation of isolated airway smooth muscle. For human bronchus precontracted by endogenous tone or addition of carbachol (10−5 m), IC50 values were 1.74 μm and 1.82 μm respectively. With guinea‐pig trachea contracted by endogenous tone, a comparable IC50 (1.79 μm) was observed, but no IC50 (< 100 μm) could be determined following contraction by carbachol (10−6 m).
Airway obstruction induced by intravenous bombesin in the anaesthetized ventilated guinea‐pig was diminished by intravenous injection of SDZ PCO 400 (ID50 54 μg kg−1) or by introduction into the duodenum (ID50 1.0 mg kg−1). Inhalation of nebulized SDZ PCO 400 (0.1 mg kg−1) diminished airway obstruction due to intravenous injection of histamine (3.2–5.6 μg kg−1) for up to 20 min.
Increased bronchoconstrictor responses to bombesin (180–240 ng kg−1) following intravenous infusion of platelet activating factor (PAF) or (±)‐isoprenaline, or to histamine (1.0–3.2 μg kg−1) following intravenous injections of immune complexes, were suppressed following concomitant intravenous infusion of SDZ PCO 400 (ID50 0.3 mg kg−1 h−1, 1.0 mg kg−1 h−1 and 0.1 mg kg−1 h−1 respectively).
Intravenous injection of SDZ PCO 400 (0.1 mg kg−1) effected transient (< 10 min) inhibition of histamine‐induced bronchospasm, yet diminished, for prolonged periods [up to 40 min] the enhanced bronchoconstrictor responses to histamine that followed intravenous injections of immune complexes. The capacity of SDZ PCO 400 to resolve such established airway hyperreactivity was prevented by prior intraduodenal instillation of a potassium channel antagonist, glibenclamide (30 mg kg−1).
In sensitized guinea‐pigs, SDZ PCO 400 inhaled as a dry powder (5.7 mg kg−1) suppressed development of allergic airway hyperreactivity to histamine (1.8–3.2 μg kg−1, i.v.), but failed to diminish accumulation of eosinophils or other inflammatory cells within the airway lumen 24 h after inhalation of ovalbumin.
Preincubation (30 min) of isolated sensitized trachea of guinea‐pig with SDZ PCO 400 (10−5−10−4 m) did not influence contractile responses to ovalbumin. However in anaesthetized sensitized guinea‐pigs, insufflation of SDZ PCO 400 (1.25 mg) as a powder substantially diminished airway obstruction that followed inhalation of ovalbumin. This effect was prevented by prior vagal section.
It is concluded that SDZ PCO 400 reduces airway obstruction not only through direct actions on airway smooth muscle but also by impairing the expression of airway hyperreactivity, without directly influencing inflammatory events in the airways.
The role of induction of nitric oxide synthesis in the altered responses of jugular veins from endotoxaemic rabbits
Authors: Vallance Patrick , Palmer Richard M.J. , Moncada Salvador 
Published: July 2012

Endotoxaemia is characterized by hypotension, peripheral vasodilatation and a reduced response to vasoconstrictors. Clinical studies have indicated that venodilatation contributes to the haemodynamic changes, although there is no direct evidence for abnormal venous reactivity. In the present study, the role of nitric oxide (NO) in modifying the responses of rabbit isolated jugular veins was examined in vitro, 4 h after intravenous injection of endotoxin.
Treatment with endotoxin reduced the contractile response to the thromboxane‐mimetic, 9,11‐dideoxy‐11α, 9α‐epoxymethano‐prostaglandin F2α (U‐46619). This affect was endothelium‐independent. The response was partially restored by the NO synthase inhibitor, NG‐monomethyl‐l‐arginine (l‐NMMA 300 μm).
Jugular veins from control animals did not contract to l‐NMMA whereas those from endotoxin‐treated animals showed concentration‐dependent contractions to l‐NMMA. The contractions produced by l‐NMMA were reversed by l‐arginine but not by d‐arginine. Treatment of the animals with dexamethasone (4 mg kg−1) 1 h prior to administration of endotoxin significantly attenuated the response to l‐NMMA.
The response to sodium nitroprusside did not differ significantly between veins from control and endotoxin‐treated animals. Endothelial denudation did not alter the sensitivity of the veins to sodium nitroprusside. Acetylcholine produced endothelium‐dependent relaxations which were similar in veins from control and endotoxin‐treated animals.
The results of this study demonstrate that intravenous administration of endotoxin induces hyporesponsiveness to U‐46619 in jugular veins. This effect is mediated, at least in part, by the induction of NO synthesis in smooth muscle. The induction is prevented by prior treatment with dexamethasone.
Dose‐dependent effects of angiotensin converting enzyme (ACE) inhibitors on glomerular prostanoid production by normotensive rats
Authors: Harding P. , Stonier C. , Aber G.M. 
Published: July 2012

This study was designed to investigate whether the angiotensin converting enzyme (ACE) inhibitors, captopril, enalapril and fosinopril have a dose‐dependent effect on the production of prostaglandin E2 (PGE2), prostaglandin I2 (prostacyclin, PGI2) and thromboxane A2 (TxA2) by glomeruli isolated from normotensive Wistar‐Kyoto rats.
Measurements of glomerular prostanoid production were made under basal conditions and in the presence of excess exogenous arachidonic acid.
All three ACE inhibitors demonstrated dose‐dependent effects upon glomerular prostanoid production which varied with the individual ACE inhibitor.
Enalapril induced a dose‐dependent increase in the ratio of (PGE2 + PGI2)/TxA2, from 2.17 ± 0.20 to 5.35 ± 0.84 and to 10.0 ± 1.16 with the low and high doses of enalapril respectively. In contrast, the high dose of captopril tended to reduce the ratio when compared to the low dose.
The results obtained in this study suggest that although all three ACE inhibitors appear to induce prostacyclin synthetase and/or modulate phospholipase A2 (PLA2) activity, these effects differ with the ACE inhibitor studied and the dose employed.
This study has demonstrated dose‐dependent effects of three ACE inhibitors on glomerular prostanoid production which may be significant in modulating glomerular haemodynamics and growth characteristics of glomerular cells.
Time‐dependent blockade of neurogenic plasma extravasation in dura mater by 5‐HT1B/D agonists and endopeptidase 24.11
Authors: Huang Zhihong , Byun Barkjang , Matsubara Toshio , Moskowitz Michael A. 
Published: July 2012

The delayed effects of stimulating the trigeminal ganglion unilaterally in rats and guinea‐pigs were assessed by measuring the leakage of radiolabelled albumin from blood into the dura mater at intervals for up to 120 min after a 5 min stimulation period (5 Hz, 0.6 mA, 5 ms).
[125I]‐albumin (50 μCi kg−1) was injected i.v. as a tracer 0, 20, 50, 80 or 110 min after stimulation and the animals were killed 10 min later. Extravasation of plasma protein developed for up to 90 min poststimulation.
To examine the mechanism underlying delayed plasma protein extravasation, CP‐93,129 (5‐HT1B receptor agonist, 460 nmol kg−1), sumatriptan (5‐HT1B/D receptor agonist, 24 nmol kg−1), or neutral endopeptidase 24.11 (1 nmol kg−1) were administered 45 or 75 min after trigeminal stimulation and 5 min before radiolabelled albumin. The extravasation response was reduced at 45 min. CP‐23,129 also blocked extravasation when injected 25 min after capsaicin administration (1 μmol kg−1).
If the tracer was injected 5 min prior to electrical trigeminal stimulation, endopeptidase 24.11 (1 nmol kg−1) given 10 min before stimulation blocked the leakage (as reported previously for CP‐93,129 or sumatriptan). All three compounds blocked the leakage when administered 30 min (but not 60 min) poststimulation in this paradigm.
The data support the previously made contention that neuropeptide release from sensory fibres mediates the plasma extravasation response following trigeminal ganglion stimulation, and that release and plasma leakage continue many minutes beyond the stimulation period. Hence, drugs that inhibit neuropeptide release (CP‐93,129, sumatriptan), or enhance breakdown of neuropeptide mediators (endopeptidase 24.11) block the delayed extravasation response. Extravasation developing later than 45 min poststimulation was not neurogenically mediated.
Potentiation of aggregation and inhibition of adenylate cyclase in human platelets by prostaglandin E analogues
Authors: Matthews Jane S. , Jones Robert L. 
Published: July 2012

The 16‐phenoxy prostaglandin E analogue sulprostone consistently potentiates primary aggregation waves induced by adenosine 5′‐diphosphate (ADP), PAF and 11,9‐epoxymethano PGH2 (U‐46619) in platelet‐rich plasma from human donors. The effect is not blocked by the TP‐receptor antagonists, EP 092 and GR 32191. The high potency of sulprostone (threshold concentration = 4–10 nm) and the weak block of sulprostone potentiation by the EP1‐receptor antagonist, AH 6809 (pA2 = 4.3) suggest the involvement of EP3‐receptors as opposed to EP1‐ or EP2‐subtypes.
Eight prostaglandin E (PGE) analogues were compared against sulprostone for their effects on PAF‐induced aggregation in human platelet‐rich plasma (PRP) in the presence of GR 32191 and the DP‐receptor antagonist, BW A868C. PGE2 and 11‐deoxy PGE2‐1‐alcohol showed evidence of both potentiating and inhibitory actions and butaprost showed only inhibitory activity at high concentrations. The remaining analogues always elicited potentiation, with the following potency ranking: sulprostone = 16,16‐dimethyl PGE2 > MB 28767 > misoprostol >GR 63779X = 17‐phenyl‐ω‐trinor PGE2. The results again indicate that EP3‐ rather than EP1‐ or EP2‐receptors are involved. However, relative potentiating potency could be affected by differences in plasma protein binding and the very high sensitivity of the human platelet to prostacyclin (IP)‐receptor‐mediated inhibition (IC50 for the specific IP‐receptor agonist cicaprost = 0.8 nm).
On human washed platelet suspensions the PGE analogues, with the exception of butaprost, inhibited the rise in adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) induced by cicaprost (8 nm). PGE2 produced a monophasic inhibition curve (IC50 = 5.4 nm, 92% inhibition at 600 nm). The potency ranking was 16,16‐dimethyl PGE2 > sulprostone > MB 28767 = PGE2 > misoprostol > GR 63778X > 17‐phenyl‐ω‐trinor PGE2> 11‐deoxy PGE2‐1‐alcohol. AH 6809 inhibited the effect of sulprostone and 17‐phenyl‐ω‐trinor PGE2 with pA2 values of 5.75 and 5.32 respectively; these values are at least one log unit lower than those found for EP1‐receptor block in smooth muscle.
There is a statistically significant correlation between IC50 values for the PGE analogues on the human platelet cyclic AMP assay and the guinea‐pig vas deferens (standard EP3 preparation): slope = 1.00, r = 0.80, P < 0.05. However the correlation is far from ideal and GR 63779X in particular has a lower potency in the cyclic AMP assay. At this time we suggest that it is prudent to describe the human platelet receptor as ‘EP3‐like’.
We believe that our results provide further evidence for linking PGE‐induced potentiation of aggregation to inhibition of adenylate cyclase. Sulprostone is a suitable agonist for further study of this system and in particular the nature of the G‐protein linkage(s) involved. In addition the necessity to consider potentiation of platelet aggregation in relation to the clinical use of PGE analogues in man is emphasised.
Interaction of selective compounds with muscarinic receptors at dispersed intestinal smooth muscle cells
Authors: Barocelli E. , Chiavarini M. , Ballabeni V. , Bordi F. , Impicciatore M. 
Published: July 2012

The characterization of muscarinic receptors on single cells of the guinea‐pig ileum longitudinal smooth muscle, devoid of neuronal elements, was functionally studied by estimating the affinities of muscarinic antagonists on acetylcholine‐induced contractions.
Atropine (5 × 10−11 to 5 × 10−6 m), 4‐diphenylacetoxy‐N‐methyl‐piperidine methiodide (4‐DAMP, 5 × 10−8 to 5 × 10−6 m), cyclohexyl(4‐fluoro‐phenyl) (3‐piperidinopropyl) silanol (pFHHSiD, 5 × 10−7 to 5 × 10−5 m) as well as pirenzepine (5 × 10−7 to 5 × 10−5 m) competitively antagonized the acetylcholine‐dependent contractions with different affinities (atropine > 4‐DAMP > pFHHSiD > pirenzepine).
Methoctramine (5 × 10−7 to 5 × 10−5 m), and AF‐DX 116 (5 × 10−6 and 5 × 10−5 m) also showed antagonist properties but these deviated from simple competition. These compounds, which discriminate between M2 and M3 receptors, showed a potency lower than that of pirenzepine, the rank order of potencies being pirenzepine > methoctramine > AF‐DX 116. When concentrations of AF‐DX 116, methoctramine and pirenzepine were increased an unspecific contractile effect occurred.
McN‐A‐343, a partial agonist on intact guinea‐pig longitudinal smooth muscle strips, on this preparation induced a weak contraction (about 7% in comparison to control) that was not reversed by antimuscarinic agents.
These data indicate that M3 rather than M2 receptor sites are present on this tissue.
A comparison of the inhibitory effects of sodium nitroprusside, pinacidil and nifedipine on pressor response to NG‐nitro‐l‐arginine
Authors: Wang Yong‐Xiang , Zhou Ting , Pang Catherine C.Y. 
Published: July 2012

The inhibitory effects of sodium nitroprusside (SNP), a nitric oxide (NO) donor, on mean arterial pressure (MAP) responses to NG‐nitro‐l‐arginine (l‐NNA) (NO synthase inhibitor), angiotensin II (AII) and noradrenaline (NA) were compared with those of pinacidil (KATP channel opener) and nifedipine (L‐type calcium antagonist) in conscious, unrestrained rats.
Intravenous bolus injections of l‐NNA (1–64 mg kg−1), AII (0.02–1.28 μg kg−1) and NA (0.25–16 μg kg−1) dose‐dependently increased MAP to similar maxima. Intravenous infusions of SNP (1, 4 and 16 μg kg−1 min−1) dose‐dependently increased ED50s of l‐NNA, AII and NA. However, the maximum response evoked by l‐NNA, but not by AII nor NA, was dose‐dependently reduced by SNP. Moreover, the inhibitory effect of SNP on the pressor response to l‐NNA ceased when the infusion of SNP was terminated.
Pinacidil (80 μg kg−1 min−1 for 30 min followed by 5 μg kg−1 min−1) increased ED50s of l‐NNA, AII and NA but did not decrease the maximum responses to any of these agents.
Nifedipine (1 mg kg−1 min−1) non‐selectively reduced maximum responses to l‐NNA, AII and NA to similar levels and increased ED50s of AII and NA but not l‐NNA.
The results show that SNP causes a selective, non‐competitive and reversible inhibition of the pressor response to l‐NNA. This inhibition by SNP is unlikely to be related to hypotension, the opening of ATP‐sensitive potassium channels or blockade of L‐type calcium channels.