bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison of the effects of three substance P antagonists on tachykinin‐stimulated [3H]‐acetylcholine release in the guinea‐pig ileum
Authors: Featherstone R.L. , Fosbraey P. , Morton I.K.M. 
Published: July 2012

The potencies of three tachykinin antagonists [D‐Pro4,D‐Trp7,9,10]SP(4–11), [D‐Arg1,D‐Pro2,D‐Trp7,9,Leu11]SP(1–11) and [D‐Arg1,D‐Trp7,9,Leu11]SP(1–11) (spantide) against eledoisin were examined in the guinea‐pig ileum myenteric plexus, where a continuous superfusion system was employed to examine evoked release of [3H]‐acetylcholine ([3H]‐ACh]); effects on mechanical activity of the preparations were also measured.
Eledoisin was chosen as the standard tachykinin agonist since the rank order of potency observed in evoking release was eledoisin, kassinin, substance P, physalaemin; on this basis is may be presumed that an ‘SP‐E’ type receptor was involved in the release process.
The two undecapeptide antagonists both significantly reduced the response to eledoisin (10 nM) as assessed by both [3H]‐ACh release and mechanical activity which under these conditions was largely dependent on ACh release, and the response levels could be restored by increasing the concentration of eledoisin to 100 nM. The pA2 values for the two antagonists were estimated as 5.3 for [D‐Arg1,D‐Pro2,D‐Trp7,9,Leu11]SP(1–11) and 5.2 for [D‐Arg1,D‐Tip7,9,Leu11]SP(1–11). [D‐Pro4,D‐Trp7,9,10]SP(4–11) was markedly less potent with a pA2 value of < 4.8.
All three antagonists possessed considerable inherent stimulatory activity as measured both by [3H]‐ACh release and mechanical activity, [D‐Pro4,D‐Trp7,9,10]SP(4–11) being the most active in this respect, a 10 μM concentration producing 50% of the response seen with 10 nM eledoisin.
These findings are discussed both in relation to tachykinin receptor classifications and limitations in the use of such antagonists in the study of the role of tachykinins in neurotransmission.
Dermorphin analogues containing D‐kyotorphin: structure‐antinociceptive relationships in mice
Authors: Kisara Kensuke , Sakurada Shinobu , Sakurada Tsukasa , Sasaki Yusuke , Sato Takumi , Suzuki Kenji , Watanabe Hiromi 
Published: July 2012

The antinociceptive effects of synthetic dermorphin and its analogues containing D‐Arg in position 2 injected into the lateral cerebroventricle were examined in conscious mice.
Intracerebroventricular (i.c.v.) administration of dermorphin and [D‐Arg2] dermorphin produced potent and long‐lasting antinociceptive activity as assayed by the tail‐pressure test.
Dermorphin and [D‐Arg2] dermorphin were 210 and 52 times more potent than morphine, respectively.
The antinociceptive effects produced by these heptapeptides were antagonized by a low dose (0.5 mg kg−1, i.p.) of the opioid antagonist naloxone.
The ED50 values for [D‐Arg2] dermorphin (1–6), (1–5) and (1–4) were not significantly different from that for [D‐Arg2] dermorphin. The potency of the shortest fragment, [D‐Arg2] dermorphin (1–2) was found to possess a severely reduced activity, whilst [D‐Arg2] dermorphin (1–3) maintained activity and was 10 times more potent than morphine.
[D‐Arg2] dermorphin analogues showed almost identical effects when tested on the electrically‐induced contractions of the guinea‐pig isolated ileum.
These results led us to conclude that the presence of the N‐terminal tripeptide in the structure of [D‐Arg2] dermorphin is of crucial importance for the manifestation of the full intrinsic opioid‐like antinociceptive activity of [D‐Arg2] dermorphin, which is presumably mediated through opioid receptors in the brain.
The role of endothelial and non‐endothelial prostaglandins in the relaxation of isolated blood vessels of the rabbit induced by acetylcholine and bradykinin
Authors: Förstermann Ulrich , Hertting Georg , Neufang Brigitte 
Published: July 2012

Strips of rabbit extrapulmonary, coeliac and mesenteric arteries were mounted in organ baths for isotonic recording of changes in tissue length. The formation by the strips of the vasodilator prostaglandins PGI2 (measured as 6‐keto‐PGF1α) and PGE2 was determined by specific radioimmunoassays.
Removal of vascular endothelium initially increased and then permanently decreased the basal prostaglandin release of the tissues.
Acetylcholine (ACh) relaxed strips of all three arteries if the endothelium was intact. ACh also stimulated the formation of PGI2 and PGE2 from all three tissues; about 60% of these prostaglandins originated from endothelial cells. Indomethacin caused complete inhibition of prostaglandin formation and a slight inhibition of the ACh‐relaxation (not statistically significant). Complete inhibition of the ACh relaxation was achieved with nordihydroguaiaretic acid (NDGA). NDGA also partially inhibited prostaglandin formation. These data suggest that in blood vessels that are also prostaglandin‐sensitive, the ACh relaxation is predominantly mediated by a non‐prostaglandin endothelium‐derived relaxing factor.
Bradykinin was more potent that ACh in releasing prostaglandins from the same arteries. This release was activated in subendothelial components of the vascular wall. Neither this prostaglandin release nor the bradykinin‐induced relaxations were significantly reduced in endothelium‐denuded arteries. Indomethacin completely blocked the bradykinin‐induced prostaglandin release and the bradykinin relaxation. NDGA caused a moderate inhibition of the bradykinin‐induced prostaglandin release and slightly attenuated the bradykinin relaxation (neither effect of NDGA was statistically significant).
Under all experimental conditions (control, indomethacin, NDGA) and with all three arteries there was a good correlation between the bradykinin‐induced prostaglandin release and the respective mechanical response. No such correlation could be found for ACh.
Prostaglandin‐dependent relaxations of the coeliac and mesenteric artery are probably mediated by endogenous PGI2. The extrapulmonary artery is rather insensitive to PGI2 and is probably relaxed mainly by endogenous PGE2.
Adrenoceptor blocking properties of atropine‐like agents anisodamine and anisodine on brain and cardiovascular tissues of rats
Authors: Varma D.R. , Yue T.L. 
Published: July 2012

The cholinoceptor antagonists anisodamine and anisodine are widely used in the People's Republic of China for the management of acute circulatory shock but the mechanism of their beneficial effects is not fully known; we therefore investigated if these agents possessed adrenoceptor blocking properties.
The antagonistic effect of anisodamine and anisodine against the specific binding of the α1‐adrenoceptor ligand [3H]‐WB‐4101 to cardiac and brain tissue membrane preparations and against the effects of phenylephrine on isolated aortic strips and left atria of rats were compared with classical muscarinic receptor and adrenoceptor blocking agents.
Both anisodamine and anisodine possessed α1‐adrenoceptor blocking properties; the order of potency of various agents in displacing the binding of [3H]‐WB‐4101 to receptors and in antagonizing the effects of phenylephrine on aortic strips and left atria was: prazosin > atropine > anisodamine > scopolamine > anisodine.
It is concluded that both anisodamine and to a lesser extent anisodine possess α‐adrenoceptor blocking properties; this antagonistic activity of anisodamine may contribute to its salutary effects on the microcirculation. However, it is unlikely that anisodine produces a significant adrenoceptor blockade in the clinically used dose‐range.
Autoradiographic analysis of the distribution of β‐adrenoceptors in the dog splenic vasculature
Authors: Lipe Suzanne , Summers Roger J. 
Published: July 2012

The technique of in vitro labelling and autoradiography has been used to localize β‐adrenoceptors in sections of the splenic vascular bundle of the dog.
Binding of (−)‐[125I]‐cyanopindolol (Cyp) to sections of splenic vascular bundle equilibrated within 150 min and slowly dissociated after addition of (−)‐propranolol. The process was saturable with a dissociation constant (KD) of 40.3 ± 4.4 pM and Bmax of 18.9 ± 1.7 fM (in 6 sections).
Binding to sections was stereoselective, the (−)‐isomer of propranolol being 90 times more effective than the (+)‐isomer in competing for (−)‐[125I]‐Cyp binding.
Delineation of β‐adrenoceptor subtypes using the selective antagonists betaxolol (β1) and ICI 118,551 (β2) indicated that the receptors present were almost exclusively of the β2‐subtype.
Autoradiographic studies under the conditions evaluated in the biochemical experiments showed that β‐adrenoceptors are unevenly distributed in the dog splenic vein, artery and associated nerve bundles. High concentrations of receptors are associated with the splenic nerves and lower but still significant concentrations in the vasculature.
Higher resolution studies with nuclear emulsion coated coverslips revealed concentrations of β‐adrenoceptors over cells adjacent to the lumen in veins. In arteries most β‐adrenoceptors were found associated with the medial layer with fewer receptors towards the intima or adventitia. Serial sections of either artery or vein incubated with (−)‐[125I]‐Cyp in the presence of (−)‐propranolol showed low levels of non‐localized binding.
The effects of Bay K 8644 and nifedipine on the neural responses of the rabbit ear artery
Authors: Cheung D.W. , MacKay M.J. 
Published: July 2012

The effects of Bay K 8644 and nifedipine on the electrical and mechanical responses of the distal ear artery of the rabbit to stimulation of the perivascular nerves were studied.
Neural stimulation elicited excitatory junction potentials (e.j.ps) in the smooth muscle cells of the artery. An action potential was generated when the e.j.p. reached a threshold of about − 53 mV. Contraction was always triggered by the action potential.
Bay K 8644 at low concentrations (7 × 10−8 M) had no significant effect on the resting membrane potential and the e.j.p. However the amplitudes of the action potential, and the contraction were potentiated by Bay K 8644. Multiple action potentials could also be generated from a single e.j.p.
At higher concentrations, Bay K 8644 (3 × 10−6 M) caused membrane depolarization, development of vascular tone and spontaneous action potentials. All the effects of Bay K 8644 could be reversed by exposure to light.
Nifedipine (3 × 10−7 M) inhibited the action potential and the resulting contraction. The effect of nifedipine could be reversed by Bay K 8644 but not by light.
These results demonstrate that the excitatory and inhibitory effects of Bay K 8644 and nifedipine on vascular smooth muscle are associated with changes in the electrical responses.
Isothiouronium compounds as γ‐aminobutyric acid agonists
Authors: Allan Robin D. , Dickenson Helena W. , Hiern Barry P. , Johnston Graham A.R. , Kazlauskas Rymantas 
Published: July 2012

Analogues of γ‐aminobutyric acid (GABA) incorporating an isothiouronium salt as a replacement for a protonated amino functional group have been investigated for activity on: GABA receptors in the guinea‐pig ileum; [3H]‐GABA and [3H]‐diazepam binding to rat brain membranes; and GABA uptake and transamination.
For the homologous series of α‐isothiouronium alkanoic acids, maximum GABA‐mimetic activity was found at 3‐[(aminoiminomethyl)thio]propanoic acid.
Introduction of unsaturation into this compound gave two isomeric conformationally restricted analogues. The trans isomer was inactive at GABA receptors while the cis compound ((Z)‐3‐[(aminoiminomethyl)thio]prop‐2‐enoic acid (ZAPA)) was more potent than muscimol and GABA as a GABA agonist with respect to low affinity GABA receptor sites.
Both isomers were moderately potent at inhibiting the uptake of [3H]‐GABA into rat brain slices.
Comparison of possible conformations of the two unsaturated isomers by interactive computer graphics modelling and comparison with muscimol has led to a plausible active conformation of ZAPA, which may be a selective and potent agonist for low affinity GABA binding sites.
The effects of amiodarone on the electrocardiogram of the guinea‐pig are not explained by interaction with thyroid hormone metabolism alone
Authors: Stäubli M. , Studer H. 
Published: July 2012

The iodine‐containing contrast medium iopanoic acid induces alterations of thyroid hormone metabolism comparable to those observed with the iodine‐containing antiarrhythmic drug amiodarone. Both compounds inhibit the intracellular conversion of thyroxine (T4) to triiodothyronine (T3). Using iopanoic acid, the question was investigated, in guinea‐pigs, whether inhibition of T4→T3 conversion is by itself associated with the same changes in the electrocardiogram, i.e. QT prolongation and bradycardia, as those observed during amiodarone treatment.
At a dose of 4 g kg−1, iopanoic acid induced maximal inhibition of the T4→T3 conversion. Although these changes were even more pronounced than those in a control group of animals treated with 2.12 g amiodarone kg−1, neither prolongation of the QT nor a slowing of the heart rate was observed. QT prolongation and bradycardia were induced only by amiodarone treatment but not by iopanoic acid.
Iopanoic acid at the high toxic dose of 12 g kg−1 induced the same degree of inhibition of T4 → T3 conversion as the 4 g kg−1 dose. QT prolongation and slowing of the heart rate were apparent at this dose in parallel with a loss of weight.
It is concluded that even a maximal inhibition of the T4 → T3 conversion has no effect on the ECG of guinea‐pigs. The inhibition of the T4 → T3 conversion alone does not explain the QT prolongation and bradycardia observed with amiodarone treatment. The amiodarone effects on the ECG may represent a combination of interactions with thyroid hormones and antiadrenergic activity.
Neuropeptide Y: a powerful modulator of epithelial ion transport
Authors: Friel David D. , Miller Richard J. , Walker Mary W. 
Published: July 2012

Neuropeptide Y (NPY) is a major gut peptide localized in the intestinal mucosa of several mammalian species. Ileal mucosa from rabbit and guinea‐pig was mounted in Ussing chambers in order to study the effect of NPY on short circuit current.
Neuropeptide Y inhibited the short circuit current when applied to the serosal side of the tissue. The maximum change in short circuit current was − 50 ± 6 μA cm−2 in the rabbit ileum and − 49 ± 14 μA cm−2 in the guinea‐pig ileum. The EC50 was 3 × 10−8 M in both species.
Pretreatment of rabbit ileum with the α2‐adrenoceptor antagonist, yohimbine (1 × 10−6 M) for 10 min did not reduce the response of the tissue to neuropeptide Y (1 × 10−7 M).
When applied serosally to rabbit ileal mucosa, the related peptide YY caused a maximum change in short circuit current of − 60 ± 13 μA cm−2; the EC50 was 2 × 10−9 M.
Isotopic flux studies in rabbit ileum showed that 1 × 10−7 M neuropeptide Y enhanced mucosal‐toserosal Na+ and Cl− fluxes and reduced serosal‐to‐mucosal Cl− flux.
Replacement of chloride with gluconate on both sides of the tissue significantly reduced the change in short circuit current produced by neuropeptide Y (1 × 10−7 M), as did a similar replacement of bicarbonate.
It is concluded that neuropeptide Y and peptide YY are the most potent neurotransmitters or hormones so far described in their ability to attenuate electrogenic transport in the small intestine.
Effects of verapamil on the response of the guinea‐pig tracheal muscle to carbachol
Authors: Baba K. , Satake T. , Takagi K. , Tomita T. 
Published: July 2012

The effects of verapamil on the contraction of the guinea‐pig tracheal smooth muscle induced by calcium (Ca2+) or barium (Ba2+) were investigated in three different conditions: (a) in excess K solution, (b) in the presence of carbachol, and (c) in excess K solution containing carbachol. In order to clarify the contractions, the effects of removal and readdition of the divalent cations were also investigated.
In Ca2+‐loaded tissues, application of carbachol in Ca‐free medium produced a transient contraction, the magnitude of which decreased the longer the duration of exposure to Ca2+‐free solution.
In Ca2+‐depleted, Ba2+‐loaded tissues, application of carbachol in a Ba2+‐ and Ca2+‐free medium produced a transient contraction the magnitude of which decreased the longer the duration of exposure to the Ba2+‐ and Ca2+‐free solution.
After exposure to Ca2+‐free solution for 40 min, the sensitivity of the tissue to Ca2+ was greater in the presence of 30 μM carbachol (ED50 = 0.06 mM) than in the presence of 40 mM K+ (ED50 = 0.3 mM). The Ca2+‐sensitivity in the presence of 30 μM carbachol plus K+ (40 mM) was not different from that in the presence of 30 μM carbachol alone.
In Ca2+‐free solution, the sensitivity of the tissue to Ba2+ in the presence of 40 mM K+ (ED50 = 1.4 mM) was not different from that observed in the presence of 30 μM carbachol (ED50 = 1.3 mM).
After exposure to Ca2+‐free solution, verapamil produced a parallel rightward shift in the concentration‐response curves to added Ca2+ and Ba2+ in the presence of either 40 mM K+, 30 μM carbachol or 40 mM K+ plus 30 μM carbachol.
The pA2 values of verapamil against Ca2+ responses in the presence of 40 mM K+, 30 μM carbachol and 40 mM K+ plus 30 μM carbachol were 7.0, 6.5 and 6.5, respectively. The pA2 values of verapamil against Ba2+ responses under these conditions were 7.1, 7.0 and 7.1, respectively.
It is concluded that the sustained contraction produced by carbachol requires the influx of Ca2+ and that Ba2+ can substitute for Ca2+ in this process. Furthermore, the ionic channels which admit Ca2+ may be modified by carbachol to different degrees depending on the presence of Ca2+ or Ba2+. Such changes alter the affinity of the channel to verapamil.
Inhibition of neutrophil activation by p‐bromophenacyl bromide and its effects on phospholipase A2
Authors: Duque Ricardo E. , Fantone Joseph C. , Kramer Craig , Marasco Wayne A. , Phan Sem H. 
Published: July 2012

In an effort to elucidate the nature of the inhibitory effects of p‐bromophenacyl bromide (pBPB) on neutrophil stimulation, we have examined its effects on several stages of stimulus‐response coupling.
Pretreatment of rat neutrophils with pBPB resulted in a dose‐ and time‐dependent irreversible inhibition of both N‐formylmethionyl‐leucylphenylalanine (fMet‐Leu‐Phe)‐induced lysosomal enzyme release and change in transmembrane potential.
Inhibition of the biological responses to the chemotactic peptide f Met‐Leu‐Phe was not due to receptor inactivation since f Met‐Leu‐[3H]‐Phe binding to the formyl peptide receptor was not significantly altered by pBPB pretreatment.
Inhibition by pBPB of phorbol myristate acetate (PMA)‐induced changes in transmembrane potential and the generation of superoxide (0–2) was also observed.
pBPB treatment appeared to inhibit activation of the NADPH oxidase without a direct effect on the oxidase itself.
This inhibitory effect was not accompanied by cell death or decrease in cellular titratable sulphydryl groups (at least at doses < 20 μM).
There was, however, significant inhibition of a membranous fraction of f Met‐Leu‐Phe‐induced phospholipase A2 activity by pretreatment with 10 μM pBPB, although total cellular phospholipase A2 was only minimally (< 20% inhibition) affected.
These data would indicate that pBPB inhibits an early event associated with stimulus‐response coupling in rat polymorphonuclear leukocytes (i.e. change in transmembrane potential). The inhibitory effects of pBPB may be secondary to the inhibition of a critical membranous fraction of cell bound phospholipase A2 activity or its activation, necessary for the initiation of cell activation.
Mechanical and electrical aspects of the relaxant action of aminophylline in guinea‐pig isolated trachealis
Authors: Allen S.L. , Cortijo J. , Foster R.W. , Morgan G.P. , Small R.C. , Weston A.H. 
Published: July 2012

Aminophylline (1–1000 μmol 1−1) suppressed the spontaneous tone of guinea‐pig isolated trachealis in a concentration‐dependent manner.
In Krebs solution containing acetylcholine (1 mmol 1−1), histamine (200 μmol 1−1) or K+ (120 mmol 1−1) isolated trachealis muscle developed near‐maximal tension. The log concentration‐effect curve for aminophylline was shifted 20 fold, 3 fold and 4 fold to the right, respectively, in the presence of these spasmogens.
Three K+‐channel inhibitors were tested: tetraethylammonium (TEA, 8 mmol 1−1) did not modify the action of aminophylline, procaine (5 mmol 1−1) shifted the log concentration‐effect curve for aminophylline 2 fold to the left and 4‐aminopyridine (5 mmol 1−1) shifted the curve 2.5 fold to the right.
Intracellular electrophysiological recording showed that aminophylline 10 μmol 1−1 could cause relaxation in the absence of electrical changes. Higher concentrations of aminophylline (100–1000 μmol 1−1) suppressed spontaneous slow waves and hyperpolarized the trachealis cells.
In the presence of procaine (5 mmol 1−1) or TEA (8 mmol 1−1), the hyperpolarization induced by aminophylline (1000 μmol 1−1) was significantly reduced but its relaxant effect was unchanged.
In trachealis skinned of its plasma membranes, tension development induced by Ca2+ (20 μmol 1−1) was unaffected either by aminophylline (1000 μmol 1−1) or by isoprenaline (1 μmol 1−1).
In studies of the efflux of 86Rb+ from muscle‐rich strips of trachea, aminophylline (100–1000 μmol 1−1) was without effect whereas nicorandil (100 and 1000 μmol 1−1) increased the efflux rate constant.
It is concluded that aminophylline does not directly reduce the sensitivity of the contractile proteins to cytosolic Ca2+. In low concentration (1–10 μmol 1−1) its relaxant action is not accompanied by membrane potential change but towards the upper end of its effective concentration range, aminophylline evokes hyperpolarization. This hyperpolarization may involve the opening of K+‐channels which are inhibited by procaine and (to a lesser extent) by TEA. These K+‐channels may be impermeable to 86Rb+.
Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum
Authors: Ringdahl Björn 
Published: July 2012

Dissociation constants (KA) and relative efficacies of acetylcholine, (+)‐methacholine and (‐)‐methacholine at muscarinic receptors in the guinea‐pig isolated ileum were determined in the absence and presence of the cholinesterase inhibitor diisopropylfluorophosphate. The method used involved analysis of dose‐response data before and after fractional inactivation of receptors with propylbenzilylcholine mustard.
The KA values, estimated after cholinesterase inhibition, of acetylcholine, (+)‐ and (‐)‐methacholine were 1.7, 2.0 and 620 μM, respectively.
The large (730 fold) difference in spasmogenic activity between (+)‐ and (‐)‐methacholine is due primarily to a difference in affinity for ileal muscarinic receptors although differences in efficacy (2 to 4 fold) also contribute.
It is suggested that the methyl group at the chiral centre of (+)‐methacholine has no apparent effect on the binding to muscarinic receptors, whereas the corresponding methyl group of (‐)‐methacholine interferes with binding, presumably by stabilizing a conformation of the drug which does not fit the receptor very well.