bluuebunny/crossref_metadata_2025_split huggingface dataset:
Muscarinic inhibitory receptors in pulmonary parasympathetic nerves in the guinea‐pig
Authors: Fryer Allison D. , Maclagan Jennifer 
Published: July 2012

In anaesthetized guinea‐pigs, gallamine produced a dose‐related potentiation of the bronchoconstriction induced by electrical stimulation of the cervical vagus nerves; (+)‐tubocurarine and suxamethonium lacked this effect.
The bronchoconstriction produced by intravenous injection of acetylcholine or histamine, however, was not potentiated by gallamine.
Vagally‐induced bradycardia was abolished by gallamine, confirming antagonism of the effect of acetylcholine on muscarinic receptors in the heart.
The muscarinic receptor agonist pilocarpine, had the opposite effect to gallamine in the lung as it inhibited vagally‐mediated bronchoconstriction.
Pretreatment of guinea‐pigs with either guanethidine or propranolol did not affect the gallamine‐induced potentiation of vagally‐mediated bronchoconstriction.
The potentiating effect of gallamine in the lung can be explained by blockade of inhibitory, muscarinic receptors located in the parasympathetic nerves supplying the lungs.
Histamine is an antagonist of the acetylcholine receptor at the frog endplate
Authors: Ariyoshi M. , Hasuo H. , Koketsu K. , Ohta Y. , Tokimasa T. 
Published: July 2012

The effects of histamine on the acetylcholine (ACh) receptor‐channel complex were examined by means of voltage‐clamp at the frog endplate. ACh was ionophoretically applied to the endplate. Histamine was added to the perfusate.
Histamine (100 nM − 1 mM) reversibly depressed the peak amplitude of the ACh‐induced inward current in a dose‐dependent manner.
The double reciprocal plot of the dose‐response relationship between the peak ACh current and the amount of ACh applied suggested that histamine (100 μM) depressed the ACh‐induced current in a competitive manner.
Histamine prevented the specific ACh binding site within the receptor‐channel complex from binding erabutoxin, a sea‐snake venom, which binds irreversibly to the specific ACh binding site.
Histamine had no detectable effects on the equilibrium potential of the endplate current but shortened the half‐decay time of the endplate current in a voltage‐dependent manner.
It was therefore concluded that histamine blocks not only the specific ACh binding site but also interacts with the ACh‐channel site.
The present experiments strongly suggest that histamine can act as an antagonist to modulate nicotinic cholinergic transmission.
Subcellular localization of [3H]‐nitrendipine binding sites in guinea‐pig ileal smooth muscle
Authors: Godfraind T. , Wibo M. 
Published: July 2012

The binding of [3H]‐nitrendipine was studied in microsomal fractions isolated from guinea‐pig ileal smooth muscle.
Only one class of specific binding sites was detected, with a KD of 0.4 nM. For various dihydropyridine derivatives, including the stereoisomers of nimodipine and the ‘Ca agonist’ Bay K 8644, the potency for inhibition of [3H]‐nitrendipine binding correlated well with the reported pharmacological potency in smooth muscle preparations.
To establish the subcellular localization of [3H]‐nitrendipine binding sites, untreated and digitonin‐treated microsomal fractions were subfractionated by isopycnic density gradient centrifugation. The density distribution of [3H]‐nitrendipine binding was markedly shifted by digitonin towards higher densities, as were the distributions of 5′‐nucleotidase and [3H]‐ouabain binding, whereas the distributions of NADPH:cytochrome c reductase and NADH:cytochrome c reductase were hardly modified by digitonin.
It is concluded that most, if not all, [3H]‐nitrendipine binding sites in guinea‐pig ileal smooth muscle are present in the plasma membrane, in agreement with the postulated mode of action of dihydropyridines as inhibitors of plasmalemmal Ca channels.
Vasomotor responses of cerebral arterioles in situ to putative dopamine receptor agonists
Authors: Edvinsson Lars , McCulloch James , Sharkey John 
Published: July 2012

The vasomotor responses of individual cerebral pial arterioles on the convexity of the cerebral cortex to subarachnoid perivascular micro‐injections of dopamine and the putative dopamine receptor agonists, apomorphine, SKF 38393 and LY 141865, have been examined in 38 anaesthetized cats.
The perivascular microapplication of dopamine (10−9–10−3 M) effected dose‐dependent reductions in pial arteriolar calibre, with the maximum reductions in calibre (22 ± 2% from preinjection levels: mean ± s.e.) being observed at 10−3 M. The cerebrovascular constriction produced by dopamine (10−5 M) could be significantly attenuated by the concomitant perivascular administration of phentolamine (10−6 M) or methysergide (10−6 M).
The perivascular microapplication of apomorphine (10−8–10−4 M) effected dose‐dependent increases in arteriolar calibre, with the maximum increase (31 ± 6%) being observed with apomorphine (10−5 M).
The perivascular administration of the putative dopamine D1‐receptor agonist, SKF 38393 (10−9–10−4 M) increased arteriolar calibre, with the maximum response (24 ± 3%) being observed with injection of 10−7 M. The putative dopamine D2‐receptor agonist, LY 141865, also increased cerebral arteriolar calibre, but only at high concentrations (maximum calibre increase 25 ± 6.1 with 10−4 M).
The cerebrovascular dilatations elicited by apomorphine and by SKF 38393 were markedly attenuated by the concomitant perivascular microapplication of the putative dopamine D1‐receptor antagonist, SCH 23390 (10−8 M). The perivascular administration of SCH 23390 (10−9–10−5 M) per se did not alter arteriolar calibre nor the arteriolar dilatation provoked by microinjections of acidic cerebrospinal fluid.
These results point to the presence on cat cerebral arterioles of dopamine receptors (probably of D1 subtype) mediating dilatation.
The mechanism of adenosine release from hypoxic rat liver cells
Authors: Belloni Francis L. , Elkin Peter L. , Giannotto Beverly 
Published: July 2012

Uptake of [14C]‐adenosine into freshly dispersed rat hepatocytes was inhibited 44% by dipyridamole (50 μM) and 60% by nitrobenzylthioinosine (NBTI, 20 μM). The results are consistent with the known ability of these drugs to inhibit adenosine transport in other cell types.
The nucleotide analogue, α,β‐methylene adenosine diphosphate (AOPCP, 50 μM), inhibited by 84% the degradation of exogenous 5′ AMP that occurred rapidly when this substrate alone was presented to isolated hepatocytes. This confirms the ecto‐5′‐nucleotidase inhibitory properties of this analogue in isolated hepatocytes.
During hypoxic incubation, isolated hepatocytes released adenosine, which accumulated in the extracellular volume. Dipyridamole and NBTI each markedly attenuated this extracellular adenosine accumulation. In contrast, AOPCP had no inhibitory effect on net hypoxic adenosine release.
It is concluded that hypoxic rat hepatocytes produce adenosine intracellularly and that this adenosine is released via facilitated diffusion to the extracellular space, based on the inhibition observed with the transport inhibitors. The plasma membrane enzyme ecto‐5′‐nucleotidase does not appear to participate in hypoxic adenosine release from these cells as indicated by the lack of effect of the nucleotidase inhibitor, AOPCP.
Insensitivity of calcium‐dependent endothelial stimulation in rat isolated aorta to the calcium entry blocker, flunarizine
Authors: Miller R.C. , Schoeffter P. , Stoclet J.C. 
Published: July 2012

In rat aortic segments complete with endothelium, acetylcholine (1 μM) relaxed noradrenaline, phenylephrine and prostaglandin F2α (PGF2α‐induced contractions of various magnitudes. Maximal 1 μM phenylephrine‐induced contractions were relaxed to a greater extent than were maximal contractions induced by the other two agonists.
Contractions elicited by various concentrations of phenylephrine and PGF2α in the presence of a maximal effective concentration of the calcium entry blocker flunarizine (3 μM) were relaxed by acetylcholine to about the same residual tension as were contractions elicited in the absence of flunarizine.
Acetylcholine (1 μM) and phenylephrine (1 μM) increased tissue levels of guanosine cyclic 3′5′‐monophosphate (cyclic GMP) by about 37 fold and 2 fold respectively. Preincubation of tissues in the absence of calcium abolished these agonist‐induced increases in cyclic GMP levels, but preincubation with flunarizine had no significant effect on the increase in cyclic GMP level induced by the agonists. Pretreatment with flunarizine had no significant effect on the basal tissue level of cyclic GMP, but pretreatment in calcium‐free solution reduced the basal tissue level of the cyclic nucleotide by about half.
It is concluded that in rat aorta, endothelium‐dependent acetylcholine‐induced relaxation and endothelium‐dependent acetylcholine and phenylephrine‐induced increases in tissue levels of cyclic GMP, are dependent on extracellular calcium, but are not antagonized by flunarizine. This may indicate that if calcium channels of endothelial cells are activated by these agonists, their characteristics are not identical with those of the calcium channels of the smooth muscle cells.
Action of agonists and antagonists at muscarinic receptors present on ileum and atria in vitro
Authors: Clague R.U. , Eglen R.M. , Strachan A.C. , Whiting R.L. 
Published: July 2012

The action of ‘selective’ agonists and antagonists at muscarinic receptors mediating ileal contractions, and the rate and force of atrial contractions has been assessed.
The effect of nicotinic receptor stimulation, catecholamine release and acetylcholinesterase (AChE) action on muscarinic activity has also been assessed.
The nicotinic actions of carbachol did not affect its agonist potency nor the antagonist affinity data obtained when this agonist was used in atrial and ileal preparations.
Antagonist data indicated that muscarinic receptors mediating the rate and force of atrial contractions did not differ. Differences in agonist potencies at these two muscarinic receptors were attributable to either differences in intrinsic efficacy or susceptibility to the action of acetylcholinesterase. The small differences in agonist potency observed between atrial and ileal muscarinic receptors were considered not sufficient to indicate receptor heterogeneity.
The pirenzepine affinity data indicated that all three receptors are of the M2 type. Affinity data using secoverine and 4‐diphenyl‐acetoxy‐N‐methyl piperidine methiodide indicated that ileal and atrial muscarinic receptors differ. Data obtained using gallamine, pancuronium and stercuronium cannot be regarded as indicative of receptor affinity since the antagonism is not competitive; it did nonetheless corroborate the conclusion that ileal and atrial muscarinic receptors are different.
Stimulation and inhibition of gastrointestinal propulsion induced by substance P and substance K in the rat
Authors: Holzer P. 
Published: July 2012

Substance P and substance K (neurokinin A) (dose range: 0.08–80 nmol kg−1) were tested for their effects on gastrointestinal propulsion in the rat. The peptides were given by intraperitoneal injection concurrently with the intragastric administration of a test meal containing charcoal and 51Cr.
Examination 3 min after the test meal showed that high doses of substance P (> 0.74 nmol kg−1) and substance K (> 8.8 nmol kg−1) inhibited gastric emptying and gastrointestinal transit. This inhibitory effect was changed to a stimulant effect by pretreatment of the rats with atropine (3.5 μmol kg−1). Guanethidine pretreatment (67 μmol kg−1) revealed a facilitatory effect of low doses of the two tachykinins (about 1 nmol kg−1) on gastrointestinal propulsion.
Examination 15 min after the test meal demonstrated that substance P (> 0.74 nmol kg−1) dose‐dependently enhanced gastrointestinal propulsion, an effect that was also seen after atropine pretreatment. Low doses of substance K (about 1 nmol kg−1) also stimulated gastrointestinal propulsion but this effect was abolished by atropine. In addition, atropine pretreatment revealed a stimulant effect of high doses of substance K (88 nmol kg−1) on gastric emptying.
These results show that the effects of substance P and substance K on gastrointestinal propulsion vary with dose and time and involve, at least partly, activation of the autonomic nervous system.
Pharmacological activity of ACC‐7513, a selective α‐adrenoceptor and 5‐hydroxytryptamine receptor blocking agent
Authors: Anderson William G. , Kam Sheung‐Tsam 
Published: July 2012

The pharmacological activity of N‐ [2‐(2,6‐dimethoxyphenoxy) ethyl]‐2‐(2‐methoxyphenoxy) ethanaminium chloride (ACC‐7513) was determined in isolated smooth and cardiac muscle and its effect on blood pressure and heart rate assessed in the spontaneously hypertensive rat (SHR).
ACC‐7513 was found to be a potent α‐adrenoceptor blocking agent (pA2:8.33) and a 5‐hydroxytryptamine (5‐HT) antagonist (pA2:7.01), both in rabbit aortic strips. The affinity for α‐adrenoceptors was about 20 times greater than that for 5‐HT‐receptors.
High concentrations of ACC‐7513 did not block histamine in rabbit aortic strips, or β1‐ or β2‐adrenoceptor responses induced by isoprenaline in guinea‐pig right atria and trachea, respectively, but did block cholinoceptor responses induced by carbachol in rat uterus, non‐competitively.
High concentrations of ACC‐7513 also produced sino‐atrial depression in guinea‐pig right atria and direct relaxation of depolarized rabbit aortic strips.
ACC‐7513 depressed blood pressure of conscious SHRs and produced a reflex increase in heart rate. The reductions in pressure were modest and of short duration.
It is concluded that: (a) ACC‐7513 is a potent, selective α‐adrenoceptor and 5‐HT receptor antagonist; and (b) ACC‐7513 is not likely to be useful in the treatment of hypertension.
Changes in the behavioural response to a TRH analogue following chronic amitriptyline treatment and repeated electroconvulsive shock in the rat
Authors: Bennett G.W. , Green A.R. , Lighton Celia , Marsden C.A. 
Published: July 2012

The arousal elicited in rats by injection into the nucelus accumbens of the thyrotrophin‐releasing hormone analogue CG 3509 (orotyl‐histidyl‐prolineamide) was used to assess the responsiveness to thyrotrophin‐releasing hormone following repeated treatment with amitriptyline or electroconvulsive shock.
Fourteen day administration of amitriptyline (15 mg kg−1 i.p. twice daily) reduced the behavioural response to bilateral intra‐accumbens injection of CG 3509 (2 × 2.5 μg). CG 3509‐induced hyperactivity, recovery from pentobarbitone‐induced anaesthesia and the reversal of both pentobarbitone‐induced hypothermia and decreased respiration, were all significantly reduced compared to either the response of the animals prior to amitriptyline administration or that observed in rats following chronic saline administration.
Repeated administration of electroconvulsive shock (5 shocks over 10 days) significantly increased CG 3509‐induced hyperactivity and the degree of reversal of pentobarbitone‐induced hypothermia and respiratory depression following CG 3509 administration.
The results demonstrate that chronic antidepressant treatments alter the central functional responsiveness to thyrotrophin‐releasing hormone. These changes are discussed with respect to the effects of antidepressant treatments on 5‐hydroxytryptamine receptors and possible thyrotrophin‐releasing hormone ‐ aminergic interactions.
The relaxant action of nicorandil in guinea‐pig isolated trachealis
Authors: Allen S.L. , Foster R.W. , Morgan G.P. , Small R.C. 
Published: July 2012

Nicorandil (1–1000 μmol 1–1) caused concentration‐dependent relaxation of guinea‐pig isolated trachealis.
Propranolol (1 μmol 1−1) did not modify the relaxant action of nicorandil but antagonized isoprenaline.
Among K+‐channel inhibitors tested, apamin (0.1 μmol 1−1) and procaine (5 mmol 1−1) did not modify the relaxant action of nicorandil. In contrast, tetraethylammonium (TEA, 8 mmol 1−1) caused five fold antagonism.
Trachealis exposed to K+‐rich (120 mmol 1−1) Krebs solution developed near‐maximal tension. Nicorandil relaxed the K+‐depolarized tissue though its concentration‐effect curve was shifted markedly to the right.
In tissues in which tone was induced by histamine, methylene blue (100 μmol 1−1) antagonized nicorandil and sodium nitroprusside but did not modify the relaxant action of aminophylline.
Intracellular electrophysiological recording showed that nicorandil (1 μmol 1−1) could evoke some relaxation in the absence of electrical changes. Higher concentrations (10–1000 μmol 1−1) reduced the amplitude and frequency of spontaneous electrical slow waves. Nicorandil also caused concentration‐dependent hyperpolarization and relaxation. When the hyperpolarization was sufficiently pronounced slow wave activity was abolished.
TEA (8 mmol 1−1) induced slow waves which were surmounted by a spike potential. TEA slightly reduced the maximal hyperpolarization induced by nicorandil and increased the time required for nicorandil to abolish slow wave discharge.
Procaine (5 mmol 1−1) induced slow waves of relatively low frequency. Sometimes these were surmounted by a spike potential. Procaine markedly reduced the hyperpolarization induced by nicorandil and increased the time required for abolition of slow waves.
In studies of the efflux of 86Rb+ from muscle‐rich strips of trachea, nicorandil (1000 μmol 1−1) increased the efflux rate constant, whereas isoprenaline (1 μmol 1−1) was without effect.
It is concluded that nicorandil‐induced relaxation does not involve the activation of β‐adrenoceptors but is partly attributable to the formation of nitric oxide from the nitrate moiety in its molecular structure. Nicorandil can evoke relaxation in the absence of membrane potential change but towards the upper end of its effective concentration range, nicorandil increases membrane K+ conductance and thereby evokes hyperpolarization of trachealis cells. The K+ channels opened by nicorandil are permeable to 86Rb, insensitive to apamin and TEA but may be inhibited by procaine.
Role of the endothelium on the facilitatory effects of angiotensin I and angiotensin II on noradrenergic transmission in the caudal artery of the rat
Authors: Story D.F. , Ziogas J. 
Published: July 2012

Perfusion of carbogen gas through the lumen of the rat caudal artery abolished the dilator response to acetylcholine (1 μmol 1−1) in artery segments which had been precontracted with noradrenaline (50 nmol 1−1). Hence, it was assumed that gas perfusion was effective in removing the vascular endothelium.
Angiotensin I (30 nmol 1−1) and angiotensin II (10 nmol 1−1) enhanced the responses of artery segments to field stimulation of their sympathetic nerves (0.5 Hz, 10 s). In arteries with an intact endothelium the ability of each peptide to enhance responses to stimulation was the same whether applied through the lumen or to the adventitial surface.
Removal of the endothelium, by gas perfusion, did not significantly alter the facilitatory effects of extraluminally or intraluminally applied angiotensin I or angiotensin II.
The converting enzyme inhibitor enalaprilat was equally effective in inhibiting the facilitatory effect of angiotensin I in the presence and absence of an intact endothelium.
It is concluded that in the rat caudal artery, conversion of angiotensin I to angiotensin II does not depend on an intact endothelium and that the facilitatory effect of angiotensin II on noradrenergic neuroeffector transmission is not modified by, or dependent on, an intact endothelium.
Pharmacological analysis of the interaction between Bay K 8644 and 5‐HT in rabbit aorta
Authors: Barrett V.J. , Leff P. , Martin G.R. , Richardson P.J. 
Published: July 2012

Bay K 8644 potentiated and augmented 5‐hydroxytryptamine (5‐HT)‐induced contractions in the rabbit, isolated aorta preparation, as manifested in leftward shift and increase in the asymptote of 5‐HT E/[A] (effect vs concentration) curves.
The operational model of agonism (Black & Leff, 1983) was used to analyse this interaction and the concomitant effects of irreversible receptor alkylation by phenoxybenzamine. The competitive effects of spiperone in the presence and absence of Bay K 8644 were also examined.
From these analyses it is concluded that Bay K 8644 elicits its potentiating effects by increasing the efficacy of 5‐HT at the 5‐HT2 receptor with no alteration in affinity. This is consistent with the known effect of Bay K 8644 of causing an increase in the functional concentration of plasmalemmal calcium channels coupled to the 5‐HT2 receptors in this preparation.
The positively co‐operative shape of the 5‐HT E/[A] curves obtained in the aorta and the quantitative nature of their potentiation by Bay K 8644 indicated that the coupling of 5‐HT2 receptor occupancy to intracellular calcium concentration is linear and that the co‐operativity resides in the subsequent relation between intracellular calcium and pharmacological effect.
Bay K 8644 may serve as a probe for differentiating between the types of calcium channels that transduce 5‐HT receptor‐mediated effects in different systems. Such information would be useful in the classification of agonist interactions with 5‐HT receptors.
The influence of epithelium on the responsiveness of guinea‐pig isolated trachea
Authors: Holroyde Martin C. 
Published: July 2012

This study was designed to investigate the possibility that tracheal epithelium generates a relaxant factor analogous to the endothelial‐derived relaxant factor (EDRF) of vascular tissue. The absence of such a factor following epithelial damage in diseases such as asthma might help to explain the airway hyperreactivity characteristic of such diseases.
Removal of epithelium by rubbing enhanced the sensitivity of guinea‐pig isolated tracheal chains to 5‐hydroxytryptamine, histamine, acetylcholine, adenosine, isoprenaline and also minimally to KC1. Responses to LaCl3 and electrical field stimulation were not affected. Low concentrations of adenosine produced contractions only in tissues denuded of epithelium.
In the presence of indomethacin 1.4 μM or dithiothreitol (DTT) 1 μM, dose‐response curves to histamine were moved to the left in both control and rubbed tissues, and the maximum response was increased. The difference in sensitivity between tissues with and without epithelium was not affected by indomethacin, but was slightly reduced by DTT. Phenidone (0.1 mM) also increased the maximum responses, but increased the sensitivity only of the tissues with intact epithelium, to the same level as that seen in the tissues denuded of epithelium.
Superfusion cascade studies provided no evidence for the generation of a relaxant factor from tracheal epithelium.
It is suggested that the supersensitivity produced by removal of the epithelium is not due to the removal of a relaxant factor, but rather to the removal of a permeability barrier, allowing a greater concentration of agonist at the level of the underlying smooth muscle.