bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparison between mechanisms of action of different nicotinic blocking agents on rat submandibular ganglia
Authors: Large W.A. , Sim J.A. 
Published: July 2012

The blocking properties of tubocurarine, decamethonium, hexamethonium and trimetaphan on nicotinic agonists applied by repetitive ionophoretic pulses were examined in rat submandibular ganglion cells using a two‐microelectrode voltage‐clamp technique at 30°C.
Hexamethonium, a proposed slowly dissociating, open‐channel blocker at concentrations of 2–20 μM did not produce a ‘use‐dependent’ run‐down of responses, but its antagonism was clearly dependent on membrane potential.
The voltage‐dependent reduction of agonist response by hexamethonium was not dependent on the nature of agonist used. Similar results were obtained with acetylcholine (ACh) and carbamylcholine (CCh) ionophoresis.
(+)‐Tubocurarine (5 μM) and decamethonium (10 μM) produced ‘use‐dependent’ run‐down of agonist responses which became more pronounced at higher frequency and as the cell was hyperpolarized, consistent with open‐channel blockade. In contrast, trimetaphan (2.5 μM), a receptor antagonist did not cause ‘use‐dependent’ run‐down of responses.
Hence, the antagonism produced by hexamethonium, unlike tubocurarine and decamethonium, could not be accounted for in terms of open‐channel blockade but requires an alternative mechanism, the nature of which is discussed.
Evidence against VIP as the inhibitory transmitter in non‐adrenergic, non‐cholinergic nerves supplying the longitudinal muscle of the mouse colon
Authors: Fontaine J. , Grivegnee A.R. , Robberecht P. 
Published: July 2012

Vasoactive intestinal peptide (VIP) had two types of effects on the longitudinal muscle of the mouse distal colon.
At low concentrations (10−8 M) VIP induced a contraction which seemed to be related to the production of prostaglandins as it was abolished after preincubation with indomethacin (10−6 M).
At higher concentrations (3 × 10−8 and 10−7 M) VIP induced relaxations which developed slowly and were related to stimulation of the adenylate cyclase activity of the smooth muscle cells.
There is no evidence that VIP is the non‐adrenergic, non‐cholinergic transmitter released by electrical stimulation in this preparation and responsible for rapid relaxation of the smooth muscle.
Comparative antiarrhythmic and electrophysiological effects of drugs known to inhibit calmodulin (TFP, W7 and bepridil)
Authors: Barron E. , Marshall R.J. , Martorana M. , Winslow E. 
Published: July 2012

The potential antiarrhythmic and electrophysiological actions of drugs known to inhibit calmodulin, i.e. trifluoperazine (TFP) and N‐(6‐aminohexyl)‐5‐chloro‐1‐naphthalene sulphonamide (W7) have been compared with bepridil, whose antiarrhythmic actions have previously been ascribed to blockade of the fast inward sodium current in cardiac tissue.
Like bepridil, both TFP and W7 reduced the severity of arrhythmias evoked by 30 min of coronary artery occlusion in tha anaesthetized rat.
TFP (2.5–10 mg kg−1, i.v.), W7 (2.5–10 mg kg−1, i.v.) and bepridil (1–5 mg kg−1, i.v.) also antagonized the development of ventricular fibrillation induced by 5 min of occlusion followed by reperfusion. All three drugs also reduced mortality. TFP and bepridil also reduced the incidence of reperfusion‐induced ventricular tachycardia whilst all 3 drugs reduced its duration.
Although TFP was shown to possess α‐adrenoceptor blocking properties, the classical α‐blocker, phentolamine, failed to reduce significantly the incidence or severity of reperfusion arrhythmias.
In contrast to bepridil (2–20 μM), which markedly reduced the maximum rate of depolarization (Vmax) of guinea‐pig isolated papillary muscle, W7 (5–50 μM) showed only weak effects on Vmax and was at least 10 times less potent than bepridil whilst TFP only reduced Vmax in high concentrations (40–100 μM) which lowered resting membrane potential.
Unlike bepridil, neither TFP (4–40 μM) nor W7 prolonged the absolute refractory period.
The results suggest that drugs which inhibit calmodulin confer protection against both ischaemia ‐ and reperfusion‐induced arrhythmias in the rat. Although the electrophysiological actions of bepridil would adequately account for its antiarrhythmic activity, the same cannot be said of W7 and especially TFP.
In conclusion, calmodulin antagonism may constitute a mechanism of antiarrhythmic activity.
Changes in cardiovascular sensitivity of alloxan‐treated diabetic rats to arachidonic acid
Authors: Boura A.L.A. , Hodgson W.C. , King R.G. 
Published: July 2012

Arachidonic acid (AA, 0.125‐2.0 mg kg−1) administered intravenously to male Wistar rats produced a dose‐dependent fall in diastolic blood pressure. However AA (0.125‐1.0 mg kg−1) injected into the autoperfused hindquarters via the aorta produced a dose‐dependent increase in perfusion pressure. Both these responses to AA were inhibited by indomethacin (5 mg kg−1).
The thromboxane A2 receptor antagonist AH23848 (5 mg kg−1, i.v.) inhibited pressor responses to AA in the autoperfused hindquarters, but potentiated depressor responses to AA (0.125‐0.5 mg kg−1) in the whole animal.
Alloxan‐treated diabetic rats (14 days after a single s.c. injection of alloxan, 175 mg kg−1) displayed reduced sensitivity to the depressor effects of AA (1–2 mg kg−1) in the whole animal, increased sensitivity to the pressor effects of AA (0.5‐1.0 mg kg−1) in the perfused hindquarters, and reduced sensitivity to the pressor effects of the thromboxane A2 mimetic U46619 (0.5–8.0 μg kg−1, i.a.) in the perfused hindquarters.
These results suggest that AA can be predominantly converted to either pressor or depressor metabolites depending on the vasculature. In the diabetic state the ratio of the metabolites formed appears to change favouring a major pressor metabolite, which is probably thromboxane A2.
Prevention of physostigmine‐induced lethality by the opioid analgesic meptazinol in the mouse
Authors: Bottoncetti Anna , Galli Alessandro 
Published: July 2012

The prophylactic action of meptazinol against physostigmine‐and neostigmine‐induced lethality was evaluated in mice. Meptazinol proved to be effective against physostigmine (1 mg kg−1 i.p.), but not against neostigmine (0.5 mg kg−1 i.p.).
The antagonism by meptazinol of physostigmine‐induced poisoning was maximal when the drug was administered 15 min before physostigmine. Under these conditions the ED50 (95% confidence limits) of meptazinol was 24 (22.0–26.1) mg kg−1 s.c. A 30 mg kg−1 dose of the drug prevented lethality in 89% of the animals.
The action of meptazinol was not antagonized by naloxone hydrochloride (2 mg kg−1 i.p.), injected 10 min before meptazinol.
Pretreatment of mice with 30 mg kg−1 meptazinol 15 min before physostigmine (1 mg kg−1) poisoning increased brain acetylcholinesterase (AChE) activity on average, from 8 to 31% of control values.
The protection of cholinesterases against physostigmine‐and neostigmine‐induced inactivation was demonstrated in vitro directly on purified preparations of the enzymes using a dilution method. The ED50 values (95% confidence limits) for the protective effect of meptazinol of electric eel AChE against 1 and 3 μm physostigmine and 1 μm neostigmine were 2.6 (1.4‐4.9), 9.5 (5–18) and 3 (1.6‐5.7) μm, respectively, while for protection of horse serum butyrylcholinesterase (BuChE) against the same inhibitors, the ED50 values were 12 (5.4–26.4), 42 (27–65.1) and 8 (3.6–17.6) μm, respectively.
It is suggested that prevention of physostigmine‐induced lethality by meptazinol is a consequence of its protective action on AChE in the central nervous system.
Differential classification of vascular smooth muscle and endothelial cell 5‐HT receptors by use of tryptamine analogues
Authors: Leff P. , Martin G.R. , Morse J.M. 
Published: July 2012

In ring preparations of the rabbit external jugular vein contracted with the thromboxane‐mimetic U‐46619, submicromolar concentrations of 5‐hydroxytryptamine (5‐HT) and chemically related analogues produced relaxations that were dependent on the integrity of the vascular endothelium.
The receptor mediating endothelium‐dependent relaxations was evidently similar to previously described endothelial 5‐HT receptors since relaxation responses to α‐methyl‐5‐HT were not blocked by atropine, (±)‐propranolol, yohimbine, indomethacin, ketanserin or MDL‐72222, but were noncompetitively antagonized by methysergide, methiothepin and cyproheptadine.
The activities of some tryptamine agonists and antagonists at the endothelial 5‐HT receptor in rabbit jugular vein were compared with their activities at the smooth muscle 5‐HT2‐receptor in rabbit aortic rings. Differences in the tryptamines' affinities and relative efficacies showed that the endothelial 5‐HT receptor was not of the 5‐HT2‐type.
The high agonist potencies of 5‐HT and 5‐carboxamidotryptamine, the susceptibility to antagonism by both methiothepin and methysergide and the resistance to blockade by selective 5‐HT2 and 5‐HT3 (‘M’) receptor antagonists implies that the endothelial receptor belongs to the ‘5‐HT,‐like’ class. However, the agonist potency order 5‐HT = α‐methyl‐5‐HT > 5‐carboxamidotryptamine suggested that the receptor is not the same as the peripheral ‘5‐HT1‐like’ receptors reported to mediate directly contraction of the dog saphenous vein or relaxation of vascular and non‐vascular smooth muscles. At these receptors, the potency order is 5‐carboxamidotryptamine > 5‐HT > α‐methyl‐5‐HT.
These results constitute preliminary evidence that peripheral ‘5‐HT1‐like’ receptors, like central 5‐HT1 recognition sites, are a heterogeneous population. Further comparative studies with a wider range of receptor probes are necessary to establish whether or not these receptors represent functional counterparts of the ligand binding sites in the brain.
A role for corticosterone in the in vivo regulation of the extraneuronal uptake of [3H]‐isoprenaline into rat atria
Authors: Morton A.J. 
Published: July 2012

The role of corticosterone, a potent in vitro inhibitor of extraneuronal uptake, in the regulation of the extraneuronal accumulation of [3H]‐isoprenaline into rat atria was examined.
Procedures which increased plasma corticosterone levels resulted in a decrease in the corticosterone‐sensitive component of extraneuronal accumulation of [3H]‐isoprenaline (64% after reserpine treatment and 25% after chronic cold exposure).
Procedures which decreased levels of plasma corticosterone resulted in an increase in the corticosterone‐sensitive component of extraneuronal accumulation of [3H]‐isoprenaline (approximately 20% after adrenalectomy and 32% after hypophysectomy). This increase was partially prevented by the in vivo administration of dexamethasone (40 μg kg−1).
There was a strong inverse correlation between the plasma corticosterone concentration and the level of extraneuronal uptake into atria (P < 0.01).
Corticosterone appears to play a major role in the regulation of extraneuronal uptake into tissues of the rat.
Relationship between β‐adrenoceptors and calcium channels in human ventricular myocardium
Authors: Ferry D.R. , Kaumann A.J. 
Published: July 2012

The stoichiometric relationship between adrenoceptors and saturable binding sites for 1,4‐dihydropyridines in calcium channels was investigated in human ventricular myocardium. Membrane particles were prepared from heart specimens of patients undergoing open heart surgery. The patients suffered from hypertrophic obstructive cardiomyopathy (HOCM) or mitral valve disease.
Using [3H]‐prazosin and [125I]‐2‐β‐hydroxy‐3‐iodiphenyl‐ethyl‐aminoethyl tetralone ([125I]‐HEAT) as labels we detected only a marginal density of α1‐adrenoceptors, regardless of disease. No α2‐adrenoceptors were detected with [3H]‐rauwolscine.
In HOCM patients we estimated 72 ± 10 fmol mg−1 (n = 12) β‐adrenoceptors labelled with [3H]‐(‐)‐dihydroalprenolol and 74 ± 5 fmol mg−1 (n = 2) β‐adrenoceptors labelled with [125I]‐(‐)‐iodocyanopindolol; the equilibrium dissociation constants KD, were 1.2 ± 0.2 nmol l−1 for [3H]‐(‐)‐dihydroalprenolol and 7 ± 1 pmol l−1 for [125I]‐(‐)‐iodocyanopindolol. In patients with mitral valve disease we estimated 84 ± 11 fmol mg−1 (n = 3) labelled with [3H]‐(‐)‐dihydroalprenolol and 66 ± 13 fmol mg−1 (n = 2) labelled with [125I]‐(‐)‐iodocyanopindolol. The KD values were 1.8 ± 0.6 nmol l−1 for [3H]‐(‐)‐dihydroalprenolol and 8 ± 2 pmol l−1 for [125I]‐(‐)‐iodocyanopindolol.
In 14 HOCM patients we estimated 107 ± 12 fmol mg−1 calcium channel sites labelled with [3H]‐nimodipine with a KD of 280 ± 4 pmol l−1. In 5 patients with mitral valve disease the density of calcium channel sites labelled with [3H]‐nimodipine was 78 ± 5 fmol mg−1 with a KD of 290 ± 20 pmol l−1, In HOCM patients the density of calcium channel sites labelled with the benzoxadiazol 1, 4‐dihydropyridine ([3H]‐(+)‐PN 200–110) was 1.6 fold of that labelled with [3H]‐nimodipine with a KD of 84 ± 11 pmol l−1.
In a group of 4 HOCM patients in which calcium channels were labelled with [125I]‐iodipine, the density of sites was 1.37 ± 0.07 fold the density of sites labelled by [3H]‐(+)‐PN 200‐11‐. The KD value of [125I]‐iodipine was 246 ± 16 pmol−1. (+)‐PN 200‐110 was approximately 100 fold more potent than (‐)‐PN 200‐110 as a competitor of [125I]‐iodipine binding.
For the HOCM group a significant correlation was found between β‐adrenoceptor density and calcium channel density, whereas in the mitral valve group no such correlation was found. This does not prove that there is causal interaction leading to a relationship between the density of β‐adrenoceptors and calcium channels. However, because positive inotropic effects of catecholamines mediated by β‐adrenoceptors are associated with opening of calcium channels, this suggests that the density of both β‐adrenoceptors and calcium channels could be co‐regulated.
The antianaphylactic action of histamine H2‐receptor agonists in the guinea‐pig isolated heart
Authors: Blandina P. , Brunelleschi Sandra , Fantozzi R. , Giannella Eliana , Mannaioni P.F. , Masini Emanuela 
Published: July 2012

The effects of histamine and of H1‐and H2‐receptor agonists on the response to specific antigen were studied in isolated hearts taken from actively sensitized guinea‐pigs.
Histamine and H2‐receptor agonists (dimaprit, impromidine) dose‐dependently decrease the positive chronotropic and inotropic effects, and the severity of arrhythmias evoked by the challenge of sensitized hearts with specific antigen.
Nordimaprit and the selective H1‐receptor agonist 2‐pyridyl‐ethyl‐amine (2‐PEA) did not modify the patterns of cardiac anaphylaxis.
The positive inotropic and chronotropic responses of the isolated heart to exogenous histamine appear to be partly reduced in the presence of dimaprit.
The H2‐receptor agonists decrease the amount of histamine released during cardiac anaphylaxis which is increased by cimetidine, while nordimaprit and PEA were ineffective, indicating an inhibitory function afforded by H2‐receptors in cardiac anaphylaxis.
Release of γ‐aminobutyric acid and acetylcholine by neurotensin in guinea‐pig ileum
Authors: Nakamoto Mitsuharu , Tanaka Chikako , Taniyama Kohtaro 
Published: July 2012

The release of γ‐aminobutyric acid (GABA) and acetylcholine (ACh) from the strips of guinea‐pig ileum was investigated in the presence of neurotensin.
Neurotensin evoked the release of [3H]‐GABA from the strips preloaded with [3H]‐GABA, and the evoked release was Ca2+‐dependent and tetrodotoxin‐sensitive.
Hexamethonium, scopolamine, [D‐Pro2, d‐Trp7,9] substance P and pretreatment with substance P did not alter the neurotensin‐evoked release of [3H]‐GABA.
Pretreatment with neurotensin inhibited the release of [3H]‐GABA evoked by neurotensin but not by high K+, thereby indicating that neurotensin induced a specific desensitization of its own receptor. These observations indicate that neurotensin may stimulate the GABAergic neurone through its own receptor.
Neurotensin evoked the release of [3H]‐ACh from strips preloaded with [3H]‐choline and this release was Ca2+‐dependent and tetrodotoxin‐sensitive.
The evoked release of [3H]‐ACh was not affected by hexamethonium, scopolamine and [D‐Pro2, d‐Trp7,9] substance P.
Bicuculline partly inhibited the neurotensin‐evoked release of [3H]‐ACh; thus neurotensin seems to induce a release of ACh partly through the release of endogenous GABA.
All this evidence indicates that neurotensin induces release of GABA as well as ACh from the myenteric neurones of the guinea‐pig ileum.
Changes in tissue blood flow and β‐receptor density of skeletal muscle in rats treated with the β2‐adrenoceptor agonist clenbuterol
Authors: Rothwell Nancy J. , Stock Michael J. , Sudera Deepak K. 
Published: July 2012

Rats injected with the β2‐adrenoceptor agonist clenbuterol (2 mg kg−1per day) for 18 days gained significantly more weight than controls.
Tissue blood flow assessed 24 h after the last injection from the distribution of radiolabelled microspheres was increased in white (5 fold) and brown (3 fold) adipose tissue of clenbuterol‐treated rats but was unaffected in kidney, brain and diaphragm, and was reduced by about 80% in skeletal muscle.
Acute injection of clenbuterol one hour before measuring blood flow, increased blood flow to brown fat (20 fold) in both treated and control groups. Blood flow to skeletal muscle increased more in the rats treated chronically with clenbuterol (6 fold increase) than in control rats (2 fold increase), but absolute flow rates were still significantly lower in the rats treated chronically with clenbuterol.
Skeletal muscle β‐adrenoceptor density and subtype were assessed from ligand binding and displacement studies using [3H]‐dihydroalprenolol. Rats treated with clenbuterol for 18 days showed a 50% reduction in β‐receptor density, but the ratio of β1/β2‐receptors was unaffected (15% β1/85% β2).
The results indicate that, although clenbuterol produces acute increases in muscle blood flow, chronic treatment results in lower flow rates immediately (1 h) and 24 h after the previous injection. The attenuated response following chronic treatment is associated with a marked reduction in skeletal muscle β‐adrenoceptor density.
The data suggest that any anabolic effects of clenbuterol on muscle which may require, or may be mediated by increases in blood supply, cannot be sustained by chronic treatment. Conversely, blood flow to white and brown adipose tissue would appear to be potentiated by chronic treatment, possibly reflecting increases in lipolytic and/or thermogenic activity.
The consequences of loss followed by recovery of noradrenergic nerve function on muscarinic receptors in the chick expansor secundariorum muscle
Authors: Lot Theodore Y. 
Published: July 2012

The effects of chemical sympathectomy with 6‐hydroxydopamine on the response of the expansor secundariorum muscle to noradrenergic nerve stimulation, noradrenaline and acetylcholine have been investigated.
Expansor muscles from 60 day old chicks were sensitive to noradrenergic nerve stimulation and exogenous noradrenaline but virtually unresponsive to acetylcholine.
Chemical sympathectomy with 6‐hydroxydopamine caused loss of function of noradrenergic nerves of the expansor muscle, induced supersensitivity to exogenous noradrenaline and gradually increased the response of the expansor muscle to acetylcholine.
As the patency of noradrenergic nerves reappeared there was a decline in the extent of supersensitivity to noradrenaline and the response to acetylcholine gradually declined.
The time courses of these changes differed, indicating that the mechanisms responsible for changes in response to noradrenaline and acetycholine are different.
Competitive and non‐competitive antagonism exhibited by ‘selective’ antagonists at atrial and ileal muscarinic receptor subtypes
Authors: Eglen R.M. , Whiting R.L. 
Published: July 2012

The affinity of a number of ‘selective’ agonists and antagonists has been assessed at atrial or ileal muscarinic receptors by use of in vitro functional analysis.
The most selective compound for ileal muscarinic receptors was silabenzhexol (approx. 50 fold), and to a lesser extent benzhexol (approx. 5 fold). Conversely, the most selective compound for the atrial muscarinic receptors was AF‐DX 116 (approx. 6 fold).
The novel M1‐receptor antagonist, telenzepine and other antagonists such as propantheline and isopropamide did not distinguish between atrial and ileal receptors.
Dicyclomine, adiphenine, hexahydroadiphenine and oxyphenonium exhibited competitive antagonism at atrial receptors but non‐competitive antagonism at ileal receptors. No conclusions could, therefore, be drawn with regard to their selectivity.
The agonists, arecaidine propargyl ester (APE), ethoxyethyltriethylammonium (EOE) and carbachol, exhibited some selectivity in potency but little difference in affinity.
It is concluded that the study supports the existence of ileal and atrial muscarinic receptor subtypes. However, the use of dicyclomine and related compounds in receptor classification is limited.
Pharmacological effects of isopolar phosphonate analogues of ATP on P2‐purinoceptors in guinea‐pig taenia coli and urinary bladder
Authors: Cusack Noel J. , Hourani Susanna M.O. , Loizou George D. , Welford Laurence A. 
Published: July 2012

Isopolar methylene phosphonate analogues of adenosine triphosphate (ATP) were synthesized and tested on the guinea‐pig isolated taenia coli (where ATP causes relaxation) and urinary bladder (where ATP causes contraction), to see if restoration of the electronegativity of the methylene linkage would enhance pharmacological potency. The compounds used were the dichloromethylene and difluoromethylene analogues of adenosine 5′‐(β,γ‐methylene)triphosphonate (AMP‐PCP), l‐adenosine 5′‐(β,γ‐methylene)triphosphonate (l‐AMP‐PCP) and 2‐methylthioadenosine 5′‐(β,γ‐methylene)‐triphosphonate (2‐methylthio‐AMP‐PCP).
The order of potency of the analogues depended on the tissue, and was independent of the nature of the purine or ribose moieties. None of the analogues was degraded by ectonucleotidases on either tissue.
In the taenia coli the order of potency for relaxation was difluoromethylene > dichloromethylene > methylene, and this reflected the order of electronegativity of the analogues. The isopolar analogues of l‐AMP‐PCP were inactive in the taenia coli.
In the bladder the order of potency for contraction was difluoromethylene > methylene > dichloromethylene, suggesting that electronegativity is of lesser importance here. The isopolar analogues of l‐AMP‐PCP were active in this tissue.
The differences between the two tissues in the order of potency for these non‐degradable analogues supports suggestions that P2‐purinoceptors in the taenia coli (P2Y) are different from those in the bladder (P2X). The isopolar analogues of l‐AMP‐PCP, like l‐AMP‐PCP itself, were selective agonists at the P2X‐purinoceptor.