bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interaction of parafluorohexahydrosiladiphenidol at muscarinic receptors in vitro
Authors: Eglen R.M. , Michel A.D. , Montgomery W.W. , Kunysz E.A. , Machado C.A. , Whiting R.L. 
Published: July 2012

The antagonistic actions of parafluorohexahydrosiladiphenidol (pFHHSiD) at muscarinic receptors has been studied in cardiac muscle, smooth muscle and cell culture preparations. In this paper, the classification scheme of Doods et al. (1987) is employed. This scheme is based upon differential affinities of muscarinic antagonists. pFHHSiD exhibited high pA2 values at M3 receptors mediating contractions of guinea‐pig ileum and oesophageal muscularis mucosae (7.8 and 8.2 respectively) whereas low values were determined at M2 receptors mediating negative inotropic responses in guinea‐pig atria (6.0). Intermediate pA2 values were determined at M1 receptors mediating contractions of the canine femoral and saphenous veins.
The pA2 values of pFHHSiD at receptors mediating endothelial‐dependent relaxation of rat aortic rings, rabbit jugular vein and canine femoral artery (7.6–7.9) were similar to those determined on the ileum. However, the pA2 values of pFHHSiD at receptors mediating contractions of the guinea‐pig trachea (7.1), which has been previously shown to possess M3 receptors, were different from those determined in the ileum.
The similarity in pA2 values of pFHHSiD between the M3 receptors in guinea‐pig ileum and the receptors mediating endothelial‐dependent relaxations provide further evidence for the role of M3 receptors in this vascular response. Taken together, pA2 values for pFHHSiD range from 7.1 to 8.2, depending upon the M3 preparation used. The selectivity of the compound therefore for the M3 versus the M2 muscarinic receptor ranged from 13 to 163 fold.
At muscarinic receptors mediating stimulation of phosphatidylinositol hydrolysis, pFHHSiD paradoxically displayed a high affinity for the M1 receptor in the SH‐SY5Y cell line (pA2 = 7.9) as well as for the M3 receptor in the human astrocytoma (1321 N1 cell line(pA2 = 7.6). The value at the M1 receptor in SH‐SY5Y cells was greater than was observed at M1 receptors mediating contractions of both the canine saphenous and femoral veins (7.1).
pFHHSiD, therefore, clearly delineated M3 from M2 muscarinic receptors, whilst the separation between M1 and M3 receptors was variable. The reason for the anomalous affinity estimates in some functional studies remains unclear. These data indicate that the pA2 values for pFHHSiD appear to be tissue‐dependent since the M3 selectivity varies according to the preparations studied. As a result the utility of pFHHSiD in muscarinic receptor classification is limited.
Differential effect of zinc on the vertebrate GABAA‐receptor complex
Authors: Smart T.G. , Constanti A. 
Published: July 2012

γ‐Aminobutyric acid (GABA) responses were recorded from rat superior cervical ganglia (SCG) in culture using the whole cell recording technique.
Zinc (50–300 μm) reversibly antagonized the GABA response in embryonic and young post‐natal neurones, while neurones cultured from adult animals were far less sensitive and occasionally resistant to zinc blockade. Cadmium (100–300 μm) also antagonised the GABA response, while barium (100 μm‐2 mm) was ineffective.
The differential blocking effect of zinc on cultured neurones of different ages also occurred in intact SCG tissue.
The GABA log dose‐response curve constructed with foetal or adult cultured neurones was reduced in a non‐competitive manner by zinc. This inhibition was minimally affected by the membrane potential.
The GABA response recorded intracellularly from guinea‐pig pyriform cortical slices was enhanced by zinc (300–500 μm), which occurred concurrently with a decrease in the input conductance of the cell. The enhancement was unaffected by prior blockade of the GABA uptake carrier by 1 mm nipecotic acid. This phenomenon could be reproduced by barium (300 μm) and cadmium (300 μm).
We conclude that the vertebrate neuronal GABAA‐receptor becomes less sensitive to zinc with neural (GABAA‐receptor?) development, and the enhanced GABA response recorded in the CNS is a consequence of the reduction in the input conductance and not due to a direct effect on the receptor complex.
Adrenergic‐cholinergic interactions in left atria: a study using K + channel agonists, antagonist and pertussis toxin
Authors: Ray Abhijit , MacLeod Kathleen M. 
Published: July 2012

The role of activation of potassium conductance in the antagonism by the muscarinic agonist carbachol of positive inotropic responses to α‐ and β‐adrenoceptor stimulation was studied in electrically driven left atrial strips of the rabbit.
The potassium channel antagonist, 4‐aminopyridine, attenuated the direct negative inotropic response to carbachol and the reversal by carbachol of positive inotropic responses to the α‐adrenoceptor agonist phenylephrine (in the presence of timolol). The inhibitory effect of carbachol on positive inotropic responses to the β‐adrenoceptor agonist isoprenaline was much less affected by 4‐aminopyridine.
Pretreatment of rabbits with pertussis toxin also attenuated the direct negative inotropic response to carbachol and the inhibitory effect of carbachol on positive inotropic responses to phenylephrine.
Neither carbachol nor phenylephrine, alone or in combination, had any effect on left atrial adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels.
The potassium channel agonist, pinacidil, exerted a dose‐dependent negative inotropic response in rabbit left atria and reversed positive inotropic responses to phenylephrine and isoprenaline. In the dose‐range tested, pinacidil had a greater inhibitory effect on positive inotropic responses to phenylephrine than on positive inotropic responses to isoprenaline.
Pretreatment of left atria with pinacidil or cromakalim, another potassium channel agonist, antagonized positive inotropic responses to phenylephrine but not to isoprenaline.
These results suggest that activation of potassium conductance plays an important role in the inhibition by carbachol of positive inotropic responses of rabbit left atria to phenylephrine but not to isoprenaline.
Release of atrial natriuretic peptide from rat myocardium in vitro: effect of minoxidil‐induced hypertrophy
Authors: Kinnunen Päivi , Taskinen Tarja , Leppäluoto Juhani , Ruskoaho Heikki 
Published: July 2012

Ventricular hypertrophy is characterized by stimulation of ventricular synthesis of atrial natriuretic peptide (ANP). To examine the role of ventricular ANP levels in the secretion of ANP into the circulation, atrial and ventricular levels of immunoreactive‐ANP (IR‐ANP) as well as ANP messenger RNA (mRNA), and the release of IR‐ANP from isolated perfused hearts, both before and after atrialectomy, were measured simultaneously in control and minoxidil‐treated Wistar‐Kyoto (WKY) and spontaneously hypertensive (SHR) rats.
IR‐ANP levels in the ventricles of untreated, 12 month‐old SHR with severe ventricular hypertrophy were increased when compared to age‐matched WKY rats. Minoxidil treatment for 8 weeks in both strains resulted in a decrease in mean arterial pressure and increases in ventricular weight to body weight ratios, plasma IR‐ANP concentrations (in WKY from 133 ± 20 to 281 ± 34 pg ml−1, P < 0.01; in SHR from 184 ± 38 to 339 ± 61 pg ml−1, P < 0.05), and in ventricular IR‐ANP contents (in WKY: 53%; in SHR: 41%). A highly significant correlation was found between ventricular IR‐ANP content and ventricular weight to body weight ratio (r = 0.59, P < 0.001, n = 26).
When studied in vitro, in isolated perfused heart preparations, the hypertrophied ventricular tissue after atrialectomy secreted more ANP into the perfusate than ventricles of the control hearts; ventricles contributed 28%, 22%, 18% and 15% of the total ANP release to perfusate in the minoxidil‐treated SHR, control SHR, minoxidil‐treated WKY and control WKY, respectively. A significant correlation was found between the IR‐ANP release from ventricles and ventricular weight to body weight ratio (r = 0.56, P < 0.01, n = 24).
These studies demonstrate that the ventricles contribute substantially to the circulating level of ANP, and that the amount released depends on the degree of ventricular hypertrophy.
Hypotensive effects of 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin and 5‐methylurapidil following stereotaxic microinjection into the ventral medulla of the rat
Authors: Valenta Barbara , Singer Ernst A. 
Published: July 2012

The effects of the 5‐HT1a receptor agonists 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) and 5‐methylurapidil (5‐MU) on blood pressure and heart rate were investigated in the anaesthetized normotensive rat after local injection into the ventral medulla (medial part of the area of the B1/B3 cell group).
Both 8‐OH‐DPAT and 5‐MU, decreased arterial blood pressure and heart rate. Local injection of the α1‐adrenoceptor antagonist prazosin did not affect cardiovascular parameters.
Subcutaneous injection of the 5‐HT1a receptor antagonists spiroxatrine or spiperone inhibited the cardiovascular response to 8‐OH‐DPAT and 5‐MU.
Histological examination showed the injection sites which were associated with cardiovascular responses to the agonists to be contained within the medial part of the area of the B1/B3 cell group, corresponding to the region of the nucleus raphe magnus and pallidus. Injections of agonists into adjacent areas had no effect on blood pressure or heart rate.
The results support the hypothesis that activation of somatodendritic 5‐HT1a autoreceptors located on 5‐hydroxytryptaminergic neurones in the ventral medulla of the rat results in a decrease in blood pressure and heart rate. The region of the B1/B3 cell group is suggested as a possible site for the hypotensive action of 5‐HT1a receptor agonists.
Inhibition of neutrophil and eosinophil induced chemotaxis by nedocromil sodium and sodium cromoglycate
Authors: Bruijnzeel P.L.B. , Warringa R.A.J. , Kok P.T.M. , Kreukniet J. 
Published: July 2012

Neutrophils and eosinophils infiltrate the airways in association with the allergen‐induced late phase asthmatic reaction. Mobilization of these cells takes place via lipid‐like and protein‐like chemotactic factors. In this study platelet‐activating factor (PAF), leukotriene B4 (LTB4), zymosan‐activated serum (ZAS) and N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) were used as illustrative examples of both groups. Chemotaxis was studied in human neutrophils and eosinophils. The inhibitory effects of nedocromil sodium and sodium cromoglycate were evaluated.
All chemotactic factors tested attracted neutrophils with the following rank order of activity: ZAS > PAF ≡ FMLP ≡ LTB4. Eosinophils were only mobilized by PAF, LTB4 and ZAS with the following rank order of activity: ZAS > PAF > LTB4.
Nedocromil sodium and sodium cromoglycate were equally active as the PAF antagonist BN 52021 in inhibiting the PAF‐induced chemotaxis of neutrophils (IC50 & 10−8 m). Both drugs were also equally active in inhibiting the chemotaxis of neutrophils induced by ZAS (IC50 ≅ 10−7−10−6 m), FMLP(IC50 ≅ 10−7 m) and LTB4 (IC50 ≅ 10−6 m).
Nedocromil sodium significantly inhibited the chemotaxis of eosinophils induced by PAF (IC50 ≅ 10−6 m) and LTB4 (IC50 ≅ 10−7 m). The inhibitory potency of BN 52021 was similar to that of nedocromil sodium on the PAF‐induced chemotaxis of eosinophils. Sodium cromoglycate was incapable of eliciting significant inhibition of these chemotactic responses. However, sodium cromoglycate significantly inhibited the chemotaxis of eosinophils induced by ZAS (IC50 ≅ 10−7 m), whereas nedocromil sodium was ineffective.
Use‐dependent effects of pirmenol on and conduction in guinea‐pig ventricular myocardium
Authors: Hasegawa Junichi , Hirai Shozo , Noguchi Noriyasu , Hisatome Ichiro , Kotake Hiroshi , Mashiba Hiroto 
Published: July 2012

The use‐dependent effects of pirmenol, a new antiarrhythmic drug, on the maximal rate of rise of the action potential, conduction velocity, and their corresponding recovery kinetics were studied in isolated papillary muscles of guinea‐pig. Standard microelectrode techniques were used to monitor the conduction and action potential characteristics of the muscles.
Pirmenol decreased and the overshoot of action potentials in a dose‐dependent fashion. Also, doses of pirmenol greater than 1 mm abolished the generation of action potentials. Low concentrations of pirmenol (3 and 10 μm) prolonged the action potential duration, while concentrations greater than 0.1 mm shortened it markedly.
The resting block of in the presence of 10 and 30 μm pirmenol was 9.48 ± 3.12 and 20.36 ± 3.61%, and that of conduction velocity 2.87 ± 1.52 and 6.58 ± 2.09%, respectively.
The degree of use‐dependent block induced by 10 and 30 μm pirmenol during 0.2, 1, 2 and 3 Hz stimulations was dose‐ and rate‐dependent.
In the presence of 30 μm pirmenol, mean values of time constants for the onset of the use‐dependent inhibition of and conduction velocity during a 2 Hz stimulation were 1.32 ± 0.15 and 1.28 ± 0.09 s, respectively. The recovery time constants averaged 15.83 ± 2.14 (for ) and 27.80 ± 8.74 (for conduction velocity) s in the presence of 30 μm pirmenol.
These results showed that the characteristics of the use‐dependent inhibition of and conduction velocity induced by pirmenol are similar to those of slow kinetic drugs such as disopyramide rather than of fast ones.
Behavioural evidence for a functional interaction between central 5‐HT2 and 5‐HT1A receptors
Authors: Backus Lisa I. , Sharp Trevor , Grahame‐Smith David G. 
Published: July 2012

The possibility of 5‐HT2 receptor modulation of central 5‐HT1A receptor function has been examined using the 5‐hydroxytryptamine (5‐HT) behavioural syndrome induced by 5‐HT1A receptor active drugs in rats.
The 5‐HT2/5‐HT1C antagonist ritanserin (0.1–2 mg kg−1) increased the 5‐HT behavioural syndrome induced by submaximally effective doses of 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT), 5‐methoxy‐N,N‐dimethyltryptamine (5‐MeODMT) and gepirone.
Pretreatment with the 5‐HT2/5‐HT1C antagonist ICI 170,809 (0.25–5 mg kg−1) also enhanced the behavioural syndrome induced by 8‐OH‐DPAT or 5‐MeODMT.
The 5‐HT2/α1‐adrenoceptor antagonist ketanserin in a low dose (0.25 mg kg−1) significantly increased the 5‐HT behavioural syndrome induced by 8‐OH‐DPAT or 5‐MeODMT, while in a higher dose (2.5 mg kg−1) this drug decreased the response. Experiments with prazosin indicate that the higher dose of ketanserin might reduce the 5‐HT behavioural syndrome through blockade of α1‐adrenoceptors.
Ritanserin and ICI 170,809 had no effect on apomorphine‐induced stereotypy or hyperactivity, indicating that these drugs do not produce non‐specific behavioural activation.
Ritanserin and ICI 170,809 inhibited quipazine‐induced wet dog shakes at doses similar to those enhancing the 5‐HT behavioural syndrome.
We suggest that ritanserin, ICI 170,809 and ketanserin enhance 5‐HT1A agonist‐induced behaviour through blockade of an inhibitory 5‐HT2 receptor regulating or coupled to 5‐HT1A receptor‐mediated function.
Induction of non‐specific airway hyperreactivity by potassium channel blockade in rat isolated trachea
Authors: Chand N. , Diamantis W. , Sofia R.D. 
Published: July 2012

The exposure of rat isolated tracheal segment to the K+‐channel inhibitor tetraethylammonium (TEA, 10 mm) for a period of 10–15 min generally produced little or no contractile response.
Cooling (10°C) provocation alone usually produced small (10 ± 3% acetylcholine maximum) contractile responses.
In the presence of TEA (10 mm, 10–15 min exposure), rat trachea exhibited airway hyperreactivity to acetylcholine, 5‐hydroxytryptamine (5‐HT) and cooling. It also increased the peak tension induced by 5‐HT.
TEA‐induced airway hyperreactivity to cooling was signficantly inhibited in Ca2+‐free Krebs solution suggesting an important role for extracellular Ca2+ influx.
We conclude that the blockade of potassium channels with TEA induces non‐specific airway hyperreactivity to cooling, 5‐HT and acetylcholine in rat isolated tracheal segments.
Evidence for the existence of ‘atypical’β‐adrenoceptors (β3‐adrenoceptors) mediating relaxation in the rat distal colon in vitro
Authors: McLaughlin Daniel P. , MacDonald Allan 
Published: July 2012

Experiments were carried out to characterize the adrenoceptors mediating relaxant responses in the rat distal colon. Three agonists were used: noradrenaline, isoprenaline and the β3‐adrenoceptor agonist BRL 37344. Phentolamine, propranolol and (±)‐cyanopindolol were tested as antagonists. Tone in the rat distal colon was induced with KCl (30–40 mm) as a spasmogen, and relaxations of this KCl‐induced tone produced by the agonists were measured.
Relaxant responses to noradrenaline that were obtained in the presence of propranolol (1 μm) were not antagonized by phentolamine (0.01 to 1 μm). Relaxant responses to isoprenaline that were obtained in the presence of phentolamine (1 μm) were antagonized in a concentration‐dependent manner by propranolol (0.01 to 3 μm), although this antagonism was weak and non‐competitive. Relaxant responses to BRL 37344 that were obtained in the presence of phentolamine (1 μm) were only weakly antagonized by high (1 μm) concentrations of propranolol.
Tachyphylaxis to BRL 37344 was observed, a second concentration‐response curve being shifted to the right by 15 fold. Exposure of the tissues to BRL 37344 (1 μm) between concentration‐response curves also caused rightward shifts in the responses to noradrenaline (18 fold) and isoprenaline (19 fold) but not to papaverine.
In the presence of phentolamine (1 μm) and propranolol (1 μm), the rank order of potency of the agonists was: (−)‐isoprenaline (1.0) ≥ BRL 37344 (0.93) > (−)‐noradrenaline (0.3).
Responses to BRL 37344 in the presence of phentolamine (1 μm) and propranolol (1 μm) were antagonized by (±)‐cyanopindolol (1 μm), with an apparent pA2 value of 6.67. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (±)‐cyanopindolol (0.1 to 10 μm), with the slope of the Schild plot close to unity and a pA2 value of 7.12.
The resistance of the relaxant responses to antagonism by phentolamine and propranolol, along with the relatively high potency of the β3‐adrenoceptor agonist BRL 37344 and the antagonism of ‘resistant’ responses by (±)‐cyanopindolol would suggest that ‘atypical’ β‐adrenoceptors, similar to the β3‐adrenoceptors of rat adipocytes and other tissues, exist in the rat distal colon.
Pinacidil inhibits neuromuscular transmission indirectly in the guinea‐pig and rabbit mesenteric arteries
Authors: Nakashima Mikio , Li Yajun , Seki Narihito , Kuriyama Hirosi 
Published: July 2012

Effects of pinacidil were investigated on neuromuscular transmission in smooth muscle tissues of the rabbit and guinea‐pig mesenteric arteries by both electrophysiological procedures and a bioassay of noradrenaline (NA) outflows.
Pinacidil (over 1 μm) hyperpolarized smooth muscle cell membranes in both tissues, in a concentration dependent manner. Pinacidil hyperpolarized and increased the ionic conductance of smooth muscle membrane more markedly in the rabbit mesenteric artery than in the guinea‐pig. The hyperpolarization induced by pinacidil occurred in the presence or absence of endothelial cells and was blocked by glibenclamide.
Perivascular adrenergic nerve stimulation produced excitatory junction potentials (e.j.ps) and repetitive stimulation produced a facilitation of e.j.ps in both tissues. Pinacidil (over 1 μm) reduced the amplitude and the decay time of e.j.ps to a consistently greater extent in the rabbit mesenteric artery than in the guinea‐pig. However, the facilitation process of e.j.ps was not modified following application of pinacidil (1 μm). The pinacidil‐induced inhibition of e.j.ps was prevented by pretreatment with glibenclamide.
Pinacidil (30 μm) marginally increased the overflows of NA and its metabolite, 3,4‐dihydroxyphenylglycol (DOPEG) released following repetitive perivascular nerve stimulations.
Pinacidil (10 μm) partly inhibited the voltage‐dependent Ca channel, as estimated from the recovery process following removal of pinacidil, of action potentials evoked on e.j.ps.
It is concluded that pinacidil increases ionic conductance and hyperpolarizes smooth muscle cell membranes of the guinea‐pig and rabbit mesenteric arteries and as a consequence, inhibits the neuromuscular transmission process occurring on adrenergic nerve stimulation with no reduction in the amount of released transmitter.
Negative inotropic effects of disopyramide on guinea‐pig papillary muscles
Authors: Kondo Noriaki , Mizukami Masami , Shibata Shoji 
Published: July 2012

The inhibitory effects of disopyramide on electromechanical responses were investigated in guinea‐pig papillary muscles driven by electrical stimuli. Disopyramide up to 10−5 m did not cause a negative inotropic effect, while the maximum upstroke velocity of the action potential (dV/dtmax) was significantly decreased.
At higher concentrations, this drug dose‐dependently inhibited the contraction, and dV/dtmax was further decreased. This inhibition of contraction was accompanied by a depression of the slow action potential in partially depolarized preparations by increasing [K+]o (26 mm).
In preparations pretreated with nifedipine (10−6 m) and ryanodine (10−6 m), the contraction was almost completely inhibited. In such preparations, ouabain (2 × 10−6 m) markedly increased the contraction, probably through the Na+‐Ca2+ exchange mechanism. This contraction was inhibited by disopyramide above 10−8 m, and an almost complete inhibition was caused at 3 × 10−5 m.
A similar inhibitory effect was observed on the contraction increased by the lowering of [Na+]o (36 mm).
These results suggest that disopyramide at high concentrations inhibits Ca influx through slow Ca2+ channels and at low concentrations, it reduces the contraction increased through the Na+‐Ca2+ exchange mechanism. Disopyramide had a greater effect on cardiac contractility mediated by the Na+‐Ca2+ exchange mechanism.