bluuebunny/crossref_metadata_2025_split huggingface dataset:
Membrane hyperpolarization, cyclic nucleotide levels and relaxation in the guinea‐pig internal anal sphincter
Authors: Baird A. Anne , Muir T.C. 
Published: July 2012

Changes in membrane potential (measured with an intracellular microelectrode) and in cyclic nucleotide (adenosine 3′:5′‐cyclic monophosphate, cyclic AMP and guanosine 3′:5′‐cyclic monophosphate, cyclic GMP) levels (measured by radioimmunoassay) in response to inhibitory non‐adrenergic non‐cholinergic (NANC) field stimulation and drugs were investigated in the guinea‐pig internal anal sphincter (gpIAS) in the presence of phentolamine and atropine (each 10−6 m).
Inhibitory NANC nerve stimulation (single pulse, 5 pulses at 5, 10 and 20 Hz, 0.5 ms supramaximal voltage) and adenosine triphosphate (ATP, 10−7‐10−3 m) inhibited spike discharge, hyperpolarized the membrane and relaxed the sphincter. The effects of inhibitory nerve stimulation were blocked by tetrodotoxin (TTX, 10−6m) and, with those of ATP, were blocked by apamin (5 χ 10−6m).
Isoprenaline (10−9‐10−4m), cromakalim (10−9‐10−5m), sodium nitroprusside (NaNP 10−5m), M&B 22948 (10−4m) and 8‐bromocyclic GMP (8‐Br‐cyclic GMP, 10−4m) also inhibited spike discharge, hyperpolarized the membrane and relaxed the sphincter. The effects of isoprenaline were blocked by propranolol (10−6m). However, forskolin (10−9‐10−7m), M&B 22948 (10−9‐10−5m) and lower concentrations of NaNP (10−9‐10−6m) relaxed the sphincter without affecting the membrane potential.
The characteristics of the membrane potential changes in response to different inhibitory stimuli in the gpIAS differed. Hyperpolarization produced by inhibitory NANC nerve stimulation and ATP were rapid in onset, of brief duration and of comparable amplitude. Isoprenaline and direct electrical stimulation also hyperpolarized the membrane and relaxed the muscle although the extent of the relaxation in these two cases was much less than that with nerve stimulation and ATP. In each case, the membrane potential change preceded relaxation and probably accounted for it.
Both inhibitory NANC nerve stimulation (80 pulses 8 Hz supramaximal voltage 0.5 ms) and ATP (10−4m) raised levels of cyclic GMP significantly and to a comparable degree and relaxed the sphincter. The effect of nerve stimulation was prevented by TTX (10−6m) but not by apamin (5 χ 10−6 m). Isoprenaline (10−4 m), cromakalim (10−5 m) and forskolin (10−5 m) were ineffective.
Inhibitory NANC nerve stimulation (80 pulses 8 Hz 0.5 ms supramaximal voltage) and ATP (10−4m) raised levels of cyclic AMP significantly to a comparable degree and relaxed the sphincter. The increase produced by nerve stimulation was abolished by TTX (10−6m) and apamin (5 × 10−6 m). Isoprenaline (10−4 m), cromakalim (10−5 m) and forskolin (10−5 m) raised levels of this nucleotide significantly.
Effect of diadenosine polyphosphates on catecholamine secretion from isolated chromaffin cells
Authors: Castro E. , Torres M. , Miras‐Portugal M.T. , Gonzalez M.P. 
Published: July 2012

The action of several diadenosine polyphosphates (AP3A, AP4A and AP5A) on basal, and on nicotine‐and high K+‐evoked, catecholamine (CA) release has been investigated. Each of the three diadenosine polyphosphates weakly but significantly increased basal CA secretion. This enhancement represented about 10% of the response evoked by 2 μm nicotine.
The evoked secretory response to diadenosine polyphosphates had an absolute requirement for extracellular Ca2+.
In contrast, these compounds had an inhibitory action on nicotine‐evoked release. This response was concentration‐dependent, EC50 values being 3.2 ± 0.4 μm, 4.0 ± 1.6 μm and 19.3 ± 4.0 μm for AP3A, AP4A, and AP5A, respectively. The lower the concentration of nicotine used to evoke secretion, the higher the inhibitory power of these compounds.
The CA secretion evoked by K+‐rich solutions was further enhanced by AP3A and AP5A, whereas AP4A inhibited it. The possible physiological role of these dual actions is discussed.
GABAB receptor‐mediated inhibition of the neurogenic vasopressor response in the pithed rat1
Authors: Kohlenbach Andreas , Schlicker Eberhard 
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) and related drugs on the vasopressor response induced by electrical stimulation (single pulse of 30 V and 1 ms) of the preganglionic sympathetic nerve fibres or by injection of noradrenaline 0.3 nmol kg−1 were studied in the pithed rat.
The electrically‐induced increase in diastolic blood pressure was inhibited by GABA and the GABAB‐receptor agonist R‐(−)−baclofen but was not affected by its S‐(+)‐enantiomer and by the GABAA‐receptor agonists muscimol and 3‐aminopropane sulphonic acid.
The dose‐response curve of R‐(−)−baclofen for its inhibitory effect on the electrically‐induced vasopressor response was shifted to the right by the GABAB‐receptor antagonist 2‐hydroxysaclofen, but was not affected by the GABAA‐receptor antagonist bicuculline. 2‐Hydroxysaclofen and bicuculline by themselves did not affect the electrically‐induced vasopressor response.
The increase in diastolic blood pressure induced by exogenous noradrenaline was not affected by the GABA‐related drugs, which also had no (or very slight) effects on the basal diastolic blood pressure.
It is concluded that GABA inhibits catecholamine release in the resistance vessels of the rat via GABAB‐receptors, probably located presynaptically on the postganglionic sympathetic nerve fibres.
Platelet‐leukocyte interaction in adhesion to endothelial cells induced by platelet‐activating factor in vitro
Authors: Hirafuji Masahiko , Shinoda Hisashi 
Published: July 2012

Platelet‐activating factor (PAF, 10 nm) did not induce platelet adhesion to endothelial cells cultured in monolayer but it induced their adhesion to protein‐coated plastic. However, PAF induced a marked platelet adhesion to endothelial cells when polymorphonuclear leukocytes (PMNs) were present. Lyso‐PAF had no effect.
Phase‐contrast microscopic examination showed that single platelets rather than their aggregates adhered to the endothelial cell surface around aggregating and adhering PMNs.
Significant platelet adhesion was induced by PAF at concentrations higher than 0.01 nm with the maximal response at 10 nm. Platelet adhesion occurred within minutes after PAF addition, reaching a maximum approximately after 30 min. Platelet adhesion also occurred significantly at a PMN: platelet ratio of 1:800, and linearly up to 1:50.
The PAF‐induced platelet adhesion was suppressed by three structurally unrelated PAF antagonists, WEB 2086, ONO 6240 and BN 52021, in a concentration‐dependent manner.
PAF also increased PMN adhesion to endothelial cell monolayers, which was further augmented by the presence of platelets.
The present study demonstrates that PAF induces platelet adhesion to endothelial cells in vitro when PMNs are present and that there is a close interaction between platelets and PMNs in their adhesion to endothelial cells. The present study further suggests that PMNs could play a central role in platelet adhesion to vascular endothlium in certain pathological conditions.
Regulation of bradykinin receptor level by cholera toxin, pertussis toxin and forskolin in cultured human fibroblasts
Authors: Etscheid Beth G. , Ko Peter H. , Villereal Mitchell L. 
Published: July 2012

The effect of bacterial toxins on bradykinin‐triggered release of arachidonic acid was studied in serum‐deprived human foreskin (HSWP) fibroblasts prelabelled with [3H]‐arachidonic acid. An 18‐h exposure of HSWP cells to cholera toxin, pertussis toxin, or forskolin enhanced the bradykinin‐stimulated release of arachidonic acid and metabolites.
Prolonged treatment of HSWP cells with these agents also caused a 3 to 4 fold rise in cell surface [3H]‐bradykinin binding. The rise was inhibited by concurrent incubation with cycloheximide or actinomycin D. In addition, cholera toxin and foreskolin increased [3H]‐bradykinin binding in wildtype PC12 cells, but not in mutant PC12 cells with reduced cyclic AMP‐dependent protein kinase type II activity.
In conclusion, cholera toxin, pertussis toxin and forskolin enhanced arachidonic acid release in response to bradykinin, and increased the number of bradykinin receptors in HSWP fibroblasts. A cyclic AMP‐dependent mechanism appears to mediate the actions of the toxins and forskolin.
The spider toxin, argiotoxin636, binds to a Mg2+ site on the N‐methyl‐d‐aspartate receptor complex
Authors: Reynolds Ian J. 
Published: July 2012

The mechanism of action of the arylalkylamine spider toxin, argiotoxin636, on the N‐methyl‐d‐aspartate (NMDA) receptor was investigated by use of [3H]‐dizocilpine binding to well‐washed membranes obtained from rat brain.
Argiotoxin636 decreased [3H]‐dizocilpine binding with an apparent potency of about 3 μm. The inhibition of [3H]‐dizocilpine by argiotoxin636 was insensitive to the concentration of glutamate, glycine and spermidine in the assay.
Argiotoxin636 alone had no effect on the dissociation of [3H]‐dizocilpine. However, argiotoxin636 reversed the actions of Mg2+ on the dissociation of [3H]‐dizocilpine by decreasing the apparent potency of Mg2+. Argiotoxin636 also reversed the action of Ca2+ on the dissociation of [3H]‐dizocilpine.
These results suggest that argiotoxin636 exerts a novel inhibitory effect on the NMDA receptor complex by binding to one of the Mg2+ sites located within the NMDA‐operated ion channel.
Inhibition by galanin and by high K+ of human basophil histamine release triggered by calcium ionophores but not responses induced by anti‐IgE, chemotactic peptide or phorbol ester
Authors: Bergstrand Håkan , Lundquist Britta , Ahrén Bo 
Published: July 2012

Galanin concentration‐dependently blocked human leukocyte histamine release triggered by the calcium ionophores A23187 and ionomycin. Almost complete inhibition of release was recorded at 410 nm whereas 41 nm galanin mediated close to 50% inhibition of responses.
Pretreatment of the cells with pertussis toxin did not influence the inhibitory effects of galanin.
Leukocyte responses triggered by anti‐IgE, the chemotactic peptide formyl‐methionyl‐leucyl‐phenylalanine (FMLP) or 4β‐phorbol 12‐myristate 13‐acetate (PMA) were not affected by galanin.
Ionophore‐induced basophil histamine release, but not responses triggered by anti‐IgE, FMLP or PMA, was inhibited when cells were challenged in medium containing high potassium (120 mm).
We conclude that galanin and a depolarizing medium selectively inhibit ionophore‐induced basophil histamine release.
N‐nitro l‐arginine causes coronary vasoconstriction and inhibits endothelium‐dependent vasodilatation in anaesthetized greyhounds
Authors: Woodman O.L. , Dusting G.J. 
Published: July 2012

The effect of N‐nitro‐l‐arginine (l‐NNA), an inhibitor of nitric oxide biosynthesis, on large coronary artery diameter and coronary blood flow was examined in anaesthetized greyhounds. The effects of l‐NNA on the coronary vascular responses to acetylcholine (ACh), glyceryl trinitrate (GTN) and 5‐hydroxytryptamine (5‐HT) were also assessed.
l‐NNA (5 mg kg−1), infused into the left circumflex coronary artery, increased systemic mean arterial pressure and decreased the external diameter of the artery. Infusion of l‐NNA decreased coronary blood flow in 5 of the 7 dogs tested and increased mean coronary resistance but neither of these effects was statistically significant. There was no change in heart rate.
Intra‐arterial injection of both ACh (0.01–0.05 μg kg−1) and GTN (0.1–0.5μg kg−1) increased large coronary artery diameter and coronary blood flow. Coronary vascular responses to the endothelium‐dependent vasodilator ACh were significantly reduced by l‐NNA, whereas the responses to the endothelium‐independent vasodilator GTN were not significantly affected.
5‐HT (0.1 μg kg−1, injected into the left circumflex coronary artery) decreased coronary artery diameter but increased coronary blood flow. After the administration of l‐NNA the 5‐HT‐induced dilatation of the coronary resistance vessels was significantly attenuated whereas the constriction of the circumflex coronary artery was increased in 3 out of 3 dogs in which diameter could be measured, although the latter effect was not statistically significant.
These data indicate that l‐NNA causes coronary and systemic vasoconstriction and selectively inhibits endothelium‐dependent vasodilatation in the coronary circulation of the anaesthetized greyhound. Therefore endothelium‐derived NO has an important role in the regulation of coronary vascular tone in the large arteries and the resistance vessels.
Electrophysiological effects of the combination of mexiletine and flecainide in guinea‐pig ventricular fibres
Authors: Delpón Eva , Valenzuela Carmen , Tamargo Juan 
Published: July 2012

The effects of flecainide alone, mexiletine alone and their combination at the Na+ channel level were studied in guinea‐pig papillary muscles. The maximum upstroke velocity (Vmax) was used as an indirect index of the magnitude of the fast inward Na+ current (INa).
In muscles driven at 0.02 Hz, neither mexiletine (10−5 m) nor flecainide (10−6 m) nor the combination of both drugs modified the action potential characteristics. Mexiletine, but not flecainide, increased the effective refractory period/action potential duration ratio; this enhancement was greater when flecainide was also present.
Mexiletine or flecainide alone produced a frequency‐dependent Vmax block. Although at 0.5 Hz the blockade induced by the combination of flecainide and mexiletine was similar to that produced by flecainide alone, in muscles driven at 1 and 2 Hz the combination increased the magnitude and the onset rate of the Vmax block.
The time constant of recovery of Vmax block was similar in the presence of flecainide or the combination mexiletine plus flecainide (τre = 16.4 ± 2.3 s and 16.7 ± 2.7 s, respectively), but the combination decreased the magnitude of the slow component of reactivation induced by flecainide (93.8 ± 1.5% versus 68.9 ± 1.7%). Moreover, the combination of both drugs was more effective in inhibiting the Vmax of early test stimuli than either drug alone.
It is concluded that the combination of mexiletine and flecainide is synergistic at driving rates faster than 0.5 Hz without detracting from the characteristics of flecainide.
A comparison of the effects of angiotensin II and Bay K 8644 on responses to noradrenaline mediated via postjunctional α1‐and α2‐adrenoceptors in rabbit isolated blood vessels
Authors: Dunn W.R. , Daly C.J. , McGrath J.C. , Wilson V.G. 
Published: July 2012

The effects of angiotensin II (AII) and Bay K 8644 on responses to noradrenaline (NA) mediated via postjunctional α1‐ and/or α2‐adrenoceptors have been compared in three isolated venous preparations from the rabbit, the lateral saphenous vein, the left renal vein and the ear vein.
A similar action of AII and Bay K 8644 was observed only in the lateral saphenous vein; each potentiated responses to NA after isolation of a homogeneous population of postjunctional α2‐ adrenoceptors. However, even in this preparation the mechanism of action for these agents was not identical. The sensitivity of KCl‐induced contraction to changes in extracellular calcium ions (reflecting activation of voltage‐dependent Ca2+ channels) was enhanced by Bay K 8644 but reduced by AII.
AII produced a selective facilitation of responses mediated via postjunctional α2‐adrenoceptors. In the lateral saphenous vein it reduced the effectiveness of prazosin and facilitated responses after isolation of α2‐adrenoceptors with phenoxybenzamine and rauwolscine. It directly enhanced responses to NA in the ear vein, where only α2‐adrenoceptors are involved. In contrast, AII did not influence responses mediated via postjunctional α1‐adrenoceptors in the left renal vein (even after the receptor reserve had been removed with phenoxybenzamine) nor the ‘rauwolscine‐resistant’ component of responses to NA in the saphenous vein.
Bay K 8644 enhanced contractile responses to NA mediated both via α2‐adrenoceptors, in the lateral saphenous vein, and via α1‐adrenoceptors in the left renal vein. Thus, unlike angiotensin II, no preferential effect was apparent.
Bay K 8644 was inactive against responses to NA in the rabbit isolated ear vein. Since the sustained component of responses to NA in this preparation is dependent upon the influx of extracellular Ca2+, these observations suggest that the influx of Ca2+ stimulated by NA is mediated via receptor‐operated (1,4‐dihydropyridine‐resistant) Ca2+ channels.
Postjunctional α‐adrenoceptors in the rabbit isolated distal saphenous artery: indirect sensitivity to prazosin of responses to noradrenaline mediated via postjunctional α2‐adrenoceptors
Authors: Dunn W.R. , McGrath J.C. , Wilson V.G. 
Published: July 2012

Under normal experimental conditions, the rabbit isolated distal saphenous artery appears to contain a homogeneous population of postjunctional α1‐adrenoceptors. Prazosin competitively antagonized responses to noradrenaline (NA) with a pA2 value of 8.6, while a relatively high concentration of rauwolscine (1 μm), produced only a 2 fold rightward displacement of the NA cumulative concentration‐response curve (CCRC).
Despite the fact that angiotensin II (AII) was without effect on responses to NA or phenylephrine in this preparation, this peptide made responses to NA less susceptible to the antagonistic action of prazosin. This was particularly evident on the lower portion of the CCRC for NA. These results suggest that in the presence of AII, NA produces contractile responses by an action mediated through a prazosin‐resistant adrenoceptor.
An attempt was made to isolate a homogeneous population of postjunctional α2‐adrenoceptors by use of a receptor protection procedure involving the combination of rauwolscine and phenoxybenzamine. After the protection protocol no responses were observed to the α‐adrenoceptor agonists NA, phenylephrine or UK‐14304. In the presence of angiotensin II however, concentration‐dependent contractions were observed to each of these agonists. Under these conditions the rank order of potency, UK‐14304 > NA > phenylephrine, is consistent with that of an effect mediated through postjunctional α2‐adrenoceptors.
The responses to NA, after the protection protocol, in the presence of AII, were susceptible to the selective α2‐adrenoceptor antagonist, rauwolscine (1 μm), but resistant to the selective α1‐adrenoceptor antagonist prazosin (0.1 μm). Furthermore, the combination of rauwolscine (1 μm) and prazosin (0.1 μm) was no more effective in blocking responses to NA than was rauwolscine (1 μm) alone. These results are consistent with the presence of a homogeneous population of postjunctional α2‐adrenoceptors.
Inducing a small degree of tone with a low concentration of the selective α1‐adrenoceptor agonist, phenylephrine, markedly increased the threshold sensitivity to the selective α2‐adrenoceptor agonist UK‐14304, in a manner analogous to that seen with AII.
The results in the present study indicate that responses mediated via postjunctional α2‐adrenoceptors in the rabbit isolated distal saphenous artery are dependent upon a degree of vascular smooth muscle stimulation by some other receptor system. It is hypothesized that under normal experimental conditions, this function is fulfilled by stimulation of α1‐adrenoceptors, while after α1‐adrenoceptor blockade the necessary positive influence can be provided by stimulation of AII receptors. The implications for such an interaction between postjunctional α‐adrenoceptor subtypes in demonstrating prazosin‐resistant, rauwolscine‐ or yohimbine‐sensitive responses in isolated blood vessels is discussed.
The effects of nifedipine on α2‐adrenoceptor‐mediated contractions in several isolated blood vessels from the rabbit
Authors: Dunn W.R. , Daly C.J. , McGrath J.C. , Wilson V.G. 
Published: July 2012

The effects of the dihydropyridine calcium channel blocker, nifedipine, on noradrenaline‐induced contractile responses have been examined in several isolated blood vessels from the rabbit, with particular emphasis on responses mediated via postjunctional α2‐adrenoceptors.
In the isolated renal vein, ear vein, distal saphenous artery, saphenous vein and plantaris vein, 0.1 μm and 1 μm nifedipine reduced responses elicited by 54 mm KCl by more than 70%. The remaining responses were abolished by α‐adrenoceptor blockade, suggesting the involvement of noradrenaline released from neurones activating a dihydropyridine‐resistant mechanism.
In the renal vein (α1), ear vein (predominantly α2‐), distal saphenous artery (αr‐ > α2‐), saphenous vein and plantaris vein (α2‐ > α1‐), 0.01 μm and 0.1 μm nifedipine produced concentration‐related reductions in the maximum response to noradrenaline. However, 1 μm nifedipine was no more effective than 0.1 μm nifedipine and the reduction in the maximum varied from 10–25% of the control response. Thus, a sizeable component of the α‐adrenoceptor‐medaited response in all blood vessels is resistant to dihydropyridine calcium channel blockers and this appears to be unrelated to the α‐adrenoceptor subtype involved.
Following irreversible inactivation of α1‐adrenoceptors and isolation of functional α2‐adrenoceptors in the saphenous vein, plantaris vein and distal saphenous artery (the latter requiring the presence of angiotensin II), the effect of nifedipine on responses to noradrenaline was increased. However, a component of the α2‐adrenoceptor response in each preparation was present even after the concentration of nifedipine was increased to 1 μm.
In the saphenous vein, a preparation in which it has been demonstrated previously that α2‐adrenoceptor‐mediated responses are highly dependent upon the presence of extracellular calcium ions, partial depolarization with 20 mm KCl failed to increase the inhibitory effect of 0.1 μm nifedipine. This suggests the involvement of dihydropyridine‐resistant Ca2+ channels. The possible relationship between these dihydropyridine‐resistant Ca2+ channels, α‐adrenoceptor subtypes and ‘receptor‐operated’ Ca2+ channels is discussed.