bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of Na+ in muscarinic receptor‐mediated catecholamine secretion in the absence of extracellular Ca2+ in cat perfused adrenal glands
Authors: Teraoka Hiroki , Yamada Yutaka , Nakazato Yoshikazu , Ohga Akira 
Published: July 2012

The role of Na+ in muscarinic receptor‐mediated catecholamine secretion, which is independent of extracellular Ca2+, was investigated by observing the effect of veratridine and ouabain in perfused adrenal glands of the cat.
Veratridine (10−4m) markedly enhanced catecholamine secretion evoked by acetylcholine (ACh, 10−4m) during perfusion with Ca2+‐free Locke solution containing hexamethonium (10−3m). The enhancement tended to be larger for noradrenaline secretion than for adrenaline secretion. Qualitatively the same result was obtained in the response to pilocarpine (5 × 10−4m).
Ouabain (10−4m) also enhanced ACh‐ and pilocarpine‐induced catecholamine secretions, especially noradrenaline secretion in the absence of extracellular Ca2+.
Tetrodotoxin (10−6m) blocked the enhancing effect of veratridine on ACh‐induced catecholamine secretion, but not that of ouabain in the absence of extracellular Ca2+.
When NaCl was replaced with sucrose, there was no secretory response to ACh regardless of the presence or absence of veratridine or ouabain. However, when ouabain, but not veratridine, was infused with Na+ before the replacement of NaCl, the response to ACh was substantially augmented.
These results indicate that Na+ is essential in the initiation of muscarinic receptor‐mediated catecholamine secretion and its enhancement by veratridine and ouabain in the absence of extracellular Ca2+. Both drugs seem to increase the intracellular concentration of Na+ through different mechanisms and result in increases in the efficiency of Ca2+ mobilization from intracellular Ca2+ pools linked to muscarinic receptors.
The effect of peptidase inhibitors on bradykinin‐induced bronchoconstriction in guinea‐pigs in vivo
Authors: Ichinose Masakazu , Barnes Peter J. 
Published: July 2012

Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea‐pigs in the presence of propranolol (1 mg kg−1 i.v.) The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7–44.6 nmol).
The dose‐response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98–8.9, and 2.0 nmol, 95% c.i. 0.65–6.2 nmol, respectively).
The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose‐response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40–11.7) and 1.8 nmol (95% c.i. 0.87–3.5 nmol), respectively.
After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose‐response curve for the effect of instilled BK (PD100 =1.1 nmol, 95% c.i. 0.37–3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone.
The kininase I inhibitor, dl‐2‐mercaptomethyl‐3‐guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose‐response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7–32.0 nmol).
These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.
Mode of inhibitory actions of acute and chronic chloroquine administration on the electrically stimulated mouse diaphragm in vitro
Authors: Okwuasaba F.K. , Otubu J.A.M. , Udoh F.V. 
Published: July 2012

The effects of bath applied chloroquine (Chlo) and of acute and chronic Chlo administration on skeletal muscle reactivity to electrical stimulation and to drugs have been studied on mouse hemidiaphragm preparations in vitro.
Chlo (0.15–150 μm) produced a concentration‐dependent inhibition of twitch and tetanic contractions due to direct muscle stimulation (MS). Acute and chronic administration of Chlo (45 mg kg−1 i.p. daily, for 3–28 days) progressively shifted the concentration‐response curve to bath‐applied Chlo to the right, with maximum effect occurring from day 14 of Chlo pretreatment.
Acute and chronic administration of Chlo decreased the twitch and tetanus tension, raised the minimal fusion frequency (MFR) for tetanic contraction to occur and did not alter the twitch/tetanus tension ratio. Tetanus tension unlike twitch tension was not significantly decreased on day 3.
Caffeine (5–500 μm) ‐ and isoprenaline (0.001‐0.8 μm)‐induced potentiations of twitch contraction were attenuated in a concentration‐dependent manner by bath‐applied Chlo and by acute and chronic administration of Chlo. Higher concentrations of caffeine (0.1–5 μm) and KCl (10 mM‐130 mm) produced contracture of the muscle which was sensitive to inhibition by Chlo (50–150 μm). Moreover, the spike contractions superimposed on caffeine contracture were more sensitive to the inhibitory effect of Chlo than the contracture.
The inhibitory effects of dantrolene sodium and (+)‐tubocurarine on MS and on indirectly stimulated hemidiaphragm respectively were not significantly altered by acute and chronic administration of Chlo. In contrast, the inhibitory concentration‐response curve to procaine was shifted to the right.
The inhibitory effect of bath‐appled Chlo, or acute and chronic pretreatment on twitch tension (MS) was not significantly antagonized by stepwise increase in extracellular Ca2+ (0.05‐2.5 mm). Sodium thiocyanate (1–5 mm) reversed in a concentration‐dependent manner the inhibitory effects of Chlo.
Complete recovery of twitch contractions occurred after 3 days of stopping daily Chlo administration, with partial recovery to tetanic tension after 28 days and no recovery of MFR. The reactivity of the diaphragm to bath applied Chlo was progressively restored, whereas the tension curve area to caffeine and KCl was still attenuated even 28 days after stopping Chlo pretreatment.
It is concluded that acute and chronic Chlo administration results in changes in reactivity of the hemidiaphragm muscle to electrical stimulation and to drugs such that there is a decrease in muscle strength and tolerance to Chlo in vitro. These effects are dependent on its direct inhibitory action on skeletal muscle and may result from interference with Ca2+ mobilization within the muscle.
Stimulation of cyclic GMP production in cultured endothelial cells of the pig by bradykinin, adenosine diphosphate, calcium ionophore A23187 and nitric oxide
Authors: Boulanger Chantal , Schini Valerie B. , Moncada Salvador , Vanhoutte Paul M. 
Published: July 2012

The effects of bradykinin, adenosine diphosphate, calcium ionophore A23187 and nitric oxide on the production of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) were investigated in cultured aortic endothelial cells of the pig.
Bradykinin (10−7m), adenosine diphosphate (3 × 10−5m), nitric oxide (2 × 10−6m) and A23187 (10−6m) stimulated the production of cyclic GMP. This stimulation reached a maximum within 1 min and declined rapidly with the first three agonists whereas that induced by A23187 was long‐lasting.
These concentrations of bradykinin, A23187 and nitric oxide had no effect on cyclic AMP production. However, adenosine diphosphate (3 × 10−5m) slightly but significantly enhanced its production by about 1.7 fold.
The basal content of cyclic GMP in endothelial cells was significantly reduced by haemoglobin (10−5m, a scavenger of endothelium‐derived relaxing factor(s) and methylene blue (10−5m, an inhibitor of the activation of soluble guanylate cyclase) and was significantly enhanced by superoxide dismutase (500 u ml−1, a scavenger of superoxide anions). The basal content of cyclic GMP was not affected by NG‐monomethyl‐l‐arginine (10−5m, a specific inhibitor of the formation of nitric oxide from l‐arginine) and was slightly but significantly increased by its d‐enantiomer, NG‐monomethyl‐d‐arginine.
The production of cyclic GMP stimulated by bradykinin, adenosine diphosphate, A23187 and nitric oxide was inhibited by haemoglobin (10−5m) and methylene blue (10−5m) but was unaffected by superoxide dismutase (500 u ml−1).
The production of cyclic GMP stimulated by bradykinin, adenosine diphosphate or A23187, but not that stimulated by nitric oxide, was significantly reduced by NG‐monomethyl‐l‐arginine (10−5m). The production of cyclic GMP evoked by nitric oxide, but not that induced by the other three agents, was enhanced significantly by NG‐monomethyl‐d‐arginine by about 1.5 fold.
These data indicate that the endothelium‐dependent vasodilators bradykinin, adenosine diphosphate and A23187 activate the production of cyclic GMP in endothelial cells via the synthesis of nitric oxide, which in turn stimulates the soluble guanylate cyclase.
Reversible and selective antagonism by suramin of ATP‐activated inward current in PC12 phaeochromocytoma cells
Authors: Nakazawa Ken , Fujimori Kannosuke , Takanaka Akira , Inoue Kazuhide 
Published: July 2012

The effects of suramin on an adenosine 5′‐triphosphate (ATP)‐ activated inward current were investigated in PC12 phaeochromocytoma cells with whole‐cell voltage‐clamp techniques.
Suramin (30 to 300 μm) inhibited the ATP‐activated current in a dose‐dependent manner. The inhibitory effects were reversible and competitive.
Suramin also suppressed the current activated by adenosine 5′‐0‐(3‐thio triphosphate) but did not affect the current activated by nicotine. Suramin did not affect the suppression of a K current induced by methacholine.
The results suggest that suramin antagonizes the ATP‐receptor‐operated membrane current reversibly and selectively.
The pharmacokinetics of γ‐glutamyl‐l‐dopa in normal and anephric rats and rats with glycerol‐induced acute renal failure
Authors: Boateng Yaw A. , Barber Harold E. , MacDonald Thomas M. , Petrie James C. , Lee Michael R. , Whiting Paul H. 
Published: July 2012

The pharmacokinetics of γ‐glutamyl‐l‐dopa (gludopa) and its metabolite, l‐dopa, have been studied in normal rats at three dose levels of gludopa: 2 mg kg−1, 5 mg kg−1 and 7.5 mg kg−1. The extent of metabolism in normal rats, and the pharmacokinetics in anephric rats and rats with glycerol‐induced acute renal failure (ARF) were also studied at a gludopa dose of 2 mg kg−1.
Gludopa was extensively metabolised to l‐dopa with only about 10% of an injected dose being excreted unchanged. Normal rats had a rapid gludopa clearance of 50.9 ± 9.6 ml min−1 kg−1 and elimination rate constant of 2.99 ± 0.27 h−1. The mean residence time and half‐life were 20.9 ± 1.4 and 14.4 ± 1.0 min, respectively. The apparent volume of distribution at steady state was 1.05 ± 0.181 kg−1.
No statistically significant differences were found in the main pharmacokinetic parameters between ARF and controls for either gludopa or its metabolite l‐dopa.
In anephric rats and controls the kidneys were found to contribute about 68.5% and 67.2% to the elimination of gludopa and the metabolite l‐dopa, respectively.
These results confirm that gludopa is an efficient pro‐drug for l‐dopa, and that the kidneys are the major site of gludopa metabolism. It seems likely that the renal specificity of gludopa persists in ARF.
The role of cyclic AMP and its protein kinase in mediating acetylcholine release and the action of adenosine at frog motor nerve endings
Authors: Hirsh Jody K. , Silinsky Eugene M. , Solsona Carles S. 
Published: July 2012

The importance of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and its protein kinase (protein kinase A, PKA) in promoting acetylcholine (ACh) release was studied at frog motor nerve endings. The effects of cyclic AMP‐dependent protein phosphorylation on the action of adenosine receptor agonists were also investigated.
Cyclic AMP was delivered to a local region of the cytoplasm just beneath the plasma membrane of motor nerve endings using phospholipid vesicles (liposomes) as a vehicle. Cyclic AMP in liposomes produced a parallel reduction in the mean level of evoked ACh release (m) and spontaneous ACh release (miniature endplate potential frequency; m.e.p.p.f) in most experiments. These inhibitory effects of cyclic AMP on quantal ACh release resemble the action of adenosine.
The effects of global increases in cytoplasmic cyclic AMP concentrations using lipophilic cyclic AMP analogues were generally different from those observed with cyclic AMP. 8‐(4‐Chlorophenylthio) cyclic AMP (CPT cyclic AMP) produced approximately two fold increases in m and m.e.p.p.f. Dibutyryl cyclic AMP (db cyclic AMP) also increased m and m.e.p.p.f, with the effect on m being smaller and more variable.
All three cyclic AMP analogues reduced the effects of adenosine receptor agonists on spontaneous and evoked ACh release.
The roles of protein phosphorylation in mediating ACh release and the inhibitory effects of adenosine were studied with the protein kinase inhibitor H7. H7 (30–100 μm) produced no consistent effect on evoked or spontaneous ACh release. At these concentrations, however, H7 exerted an unfortunate inhibitory action on the nicotinic ACh receptor/ion channel.
H7 prevented the increases in spontaneous ACh release produced by CPT cyclic AMP (250 μm). Thus H7 is likely to inhibit PK A in frog motor nerve endings.
H7 did not alter the inhibitory effect of adenosine on evoked and spontaneous ACh release.
The results suggest: (i) that the adenylyl cyclase‐cyclic AMP‐PK A system is compartmentalized within the motor nerve terminal, (ii) that phosphorylation does not play a major role in ACh release and (iii) the cyclic AMP‐PK A system modulates rather than mediates the inhibitory effects of adenosine.
Pharmacological studies of human erectile tissue: characteristics of spontaneous contractions and alterations in α‐adrenoceptor responsiveness with age and disease in isolated tissues
Authors: Christ George J. , Maayani Saul , Valcic Mira , Melman Arnold 
Published: July 2012

The pathophysiology of impotence related to vascular smooth muscle dysfunction in the male corpus cavernosum was studied on human isolated erectile tissue (HET). Studies were conducted on 140 sections of HET obtained from 38 male patients undergoing surgery for implantation of penile prostheses to correct underlying erectile dysfunction.
Spontaneous myotonic oscillations were characteristic of greater than 90% of all HET preparations at 37°C. These spontaneous oscillations were markedly attenuated by indomethacin, BW755C, nifedipine, removal of extracellular Ca2+, or lower temperatures (≤ 32°C), but were not sensitive to inhibition by atropine, phentolamine or tetrodotoxin. Our data suggest that the oscillations may, at least in part, result from the generation and/or release of a stable cyclo‐oxygenase product and a consequent increase in transmembrane Ca2+ influx.
The phenylephrine‐induced contractions in HET may be reliably assayed up to 24 h after surgical removal, without significant alterations in the EC50, maximum response (Emax) or slope index of the steady‐state concentration‐response curve to phenylephrine.
The competitive and surmountable nature of the antagonism of phenylephrine‐induced contractions by prazosin and yohimbine allowed calculation of antagonist dissociation constants. The calculated pKb values for prazosin and yohimbine, respectively, were 9.47 ± 0.49 and 5.54 ± 0.22. The rank order of agonist potency in HET was: noradrenaline = phenylephrine ≫ clonidine. These data indicate the presence of a population of membrane receptors that are predominantly of the α1‐adrenoceptor subtype.
The entire patient population was stratified on a decennial basis into five age groups, and each age group was subsequently subdivided into diabetic and nondiabetic diagnostic categories. With respect to the steady‐state phenylephrine concentration‐response curves, a Winer two‐factor analysis of variance revealed a significant effect of age on the calculated pEC50 value, as well as a significant age‐diagnosis interaction. A post hoc statistical analysis for unpaired samples yielded significant differences between pEC50 values for diabetic and nondiabetic patients in age groups 41–50 and 61–70 years. In addition, a Winer two‐factor analysis of variance also detected a significant effect of age on the calculated Emax value.
In conclusion, our studies demonstrate that spontaneous contractions in HET are likely to be mediated by the generation and release of a stable cyclo‐oxygenase product. Furthermore, the results of both agonist and antagonist studies are consistent with the presence of a homogeneous α1‐adrenoceptor population. Lastly, the responsiveness of isolated HET to phenylephrine was shown to be altered by both age and disease.
The effectiveness of α2‐adrenoceptor activation increases from the distal to the proximal part of the veins of canine limbs
Authors: Guimaraes Serafim , Nunes Jose P. 
Published: July 2012

The effectiveness of α1‐ and α2‐adrenoceptor activation was compared at different levels of the saphenous and cephalic vein of the dog in vitro.
Helically cut strips were used to determine concentration‐response curves to phenylephrine, noradrenaline, UK‐14, 304 (5‐bromo‐6‐(imidazoline‐2‐ylamino)‐quinoxaline) and B‐HT 920 (2‐amino‐6‐allyl‐5,6,7,8‐tetra‐hydro‐4H‐(thiazo)‐4,5‐d‐azepine). The effect of prazosin and yohimbine on these curves was also studied.
At the distal level, the maximum response to UK‐14,304 amounted to 33 and 50% of those to noradrenaline in the saphenous and cephalic vein, respectively, while at the proximal level the maximum response to UK‐14,304 amounted to 72 and 78% of those to noradrenaline, in the saphenous and cephalic vein, respectively.
In both vessels, the results obtained with B‐HT 920 were very similar to those for UK‐14,304.
The pD2 values for UK‐14,304 — which were identical at the three levels of both vessels — and the pA2 values for the antagonism exerted by either prazosin or yohimbine against the responses to UK‐14,304 indicate that the α2‐adrenoceptors are identical at the different levels of both vessels.
These results show that the effectiveness of α2‐adrenoceptor stimulation increases from the distal to the proximal regions of canine limb veins. Apparently, this is due to a greater density of α2‐adrenoceptors in the proximal regions.
Yohimbine is much more potent against phenylephrine distally than proximally in both vessels. However, after 30 nm phenoxybenzamine — a concentration which eliminates the vast majority of α1‐adrenoceptors without affecting α2‐adrenoceptors — yohimbine became equally potent at both levels, suggesting that the difference existing before phenoxybenzamine depended on α1‐adrenoceptors. Hence it is concluded that α1‐adrenoceptors in distal and proximal portions may differ.
GABAA receptor‐mediated stimulation of non‐adrenergic non‐cholinergic neurones in the dog ileocolonic junction
Authors: Boeckxstaens Guy E. , Pelckmans Paul A. , Rampart Marc , Ruytjens Isabelle F. , Verbeuren Tony J. , Herman Arnold G. , Van Maercke Yvan M. 
Published: July 2012

The inhibitory effects of γ‐aminobutyric acid (GABA), the GABAA receptor agonist homotaurine and the GABAB receptor agonist (±)‐baclofen were investigated on circular muscle strips of the dog terminal ileum and ileocolonic junction.
In the presence of atropine, GABA and homotaurine induced concentration‐dependent relaxations, similar to the non‐adrenergic non‐cholinergic (NANC)‐mediated relaxations evoked by electrical stimulation or by acetylcholine. The ileocolonic junction was more sensitive to GABA and homotaurine than the ileum. (±)‐Baclofen had no effect. Cross desensitization only occurred between GABA and homotaurine.
The GABAA receptor antagonist bicuculline shifted the concentration‐response curves to GABA and homotaurine to the right. The maximal relaxation to GABA remained unaffected.
GABA‐induced relaxations were not inhibited by timolol, guanethidine, domperidone, hexamethonium and desensitization to ATP, but were abolished by tetrodotoxin.
Bicuculline, and pretreatment with GABA or (±)‐baclofen had no effect on the NANC‐evoked relaxations to electrical stimulation and acetylcholine.
In conclusion, GABA stimulates GABAA receptors located on inhibitory NANC neurones in the dog ileocolonic junction. Our results suggest that it is unlikely that GABA is the final inhibitory NANC neurotransmitter.
Adverse effects on rat cardiac function ex vivo after repeated administration of the benzodiazepine partial inverse agonist, FG7142
Authors: Stanford S.C. , Gettins D. , Littel H.J. 
Published: July 2012

The Langendorff preparation was used to investigate functional changes in rat heart one week after the last of a course of repeated injections of the benzodiazepine inverse agonist, FG7142 (20 mg kg−1 i.p; three times weekly for five weeks).
Under these conditions, FG7142 caused a statistically significant reduction in both cardiac basal tension and the inotropic effect of noradrenaline at doses giving 50 and 100% of the maximum response.
Basal heart rate, basal coronary perfusion pressure and the effects of noradrenaline ex vivo on these parameters were all unaffected by repeated administration of FG7142.
FG7142 had no intrinsic effects on cardiac function when administered in vitro.
We discuss mechanisms which could underlie the effects of FG7142 on cardiac tension ex vivo and consider the possibility that this action may be related to the anxiogenic or proconvulsant actions of this drug.
Structure‐activity studies on bradykinin and related peptides: agonists
Authors: Rhaleb Nour‐Eddine , Drapeau Guy , Dion Stéphane , Jukic Daniela , Rouissi Noureddine , Regoli Domenico 
Published: July 2012

Bradykinin, kallidin, T‐kinin, [Hyp3]‐bradykinin and several analogues were prepared by solid‐phase synthesis and purified by high performance liquid chromatography.
The various peptides were tested for their abilities to relax the dog carotid and renal arteries, or to contract the rabbit jugular vein and aorta, in order to measure their activities on BK2 (the first three preparations) or BK1 (the rabbit aorta) receptors. The dog renal artery without endothelium was also used as a BK1 receptor system.
T‐kinin was found to be less active than bradykinin, while the replacement of Pro3 with Hyp favoured BK2 receptor occupation. [Hyp3,Tyr(Me)8]‐BK was found to be a selective BK2 receptor agonist.
Amidation or methylation of the C‐terminal carboxyl decreased activity, while extension of the N‐terminal with Sar or d‐Arg increased affinity and selectivity for BK1 (Sar) and affinity for BK2 (d‐Arg) receptors. Acetylation of N‐terminal amide brought affinity down to 10% or less.
Replacement of the peptide bonds Phe8‐Arg9 to protect from kininase I and II, decreased affinities slightly, but was incompatible with additional changes at the N‐terminal or in the peptide bond Gly4‐Phe5.
Substitution of C‐terminal Phe in desArg9‐BK (the BK1 receptor stimulant) with d‐Phe increased potency and selectivity for BK1 receptors while protecting from carboxypeptidases. Sar[d‐Phe8]desArg9‐BK was found to be a potent and selective BK1 receptor agonist.