bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of stimulatory GTP‐binding protein (Gs) in reduced β‐adrenoceptor coupling in the femoral artery of spontaneously hypertensive rats
Authors: Asano Masahisa , Masuzawa Kaoru , Matsuda Tomohiro 
Published: July 2012

Arterial relaxant responses to β‐adrenoceptor agonists are decreased in spontaneously hypertensive rats (SHR) when compared with normotensive Wistar‐Kyoto rats (WKY). To establish which component of the β‐adrenoceptor · adenylate cyclase (AC) system is impaired in the SHR arteries, effects of two activators of AC ‐ cholera toxin (CTX) and forskolin ‐ and of dibutyryl cyclic AMP (db cyclic AMP) were compared between strips of femoral arteries isolated from 13 week‐old SHR and age‐matched WKY.
In the absence of timolol, a β‐adrenoceptor antagonist, contractile responses of the strips to noradrenaline (NA) were significantly greater in the SHR than in the WKY. Timolol augmented the contractile responses to NA to a smaller extent in the SHR than in the WKY.
After blockade by timolol of β‐adrenoceptors, contractile responses of the strips to NA through the activation of α‐adrenoceptors were not significantly different between the two strains.
Pre‐treatment of the strips with CTX, an activator of the stimulatory GTP‐binding protein (Gs), produced a slow‐onset and long‐lived antagonism of the α‐adrenoceptor‐mediated contractions. The antagonism was much smaller in the SHR than in the WKY.
The dose‐response curves of the strips from both strains for α‐adrenoceptor stimulation with NA determined after pretreatment with CTX were comparable to those determined in the absence of timolol.
Forskolin, an activator of the catalytic subunit of AC, and DB cyclic AMP also antagonized the α‐adrenoceptor‐mediated contractions. However, these antagonisms were not significantly different between the two strains.
Isobutyl methylxanthine (IBMX), an inhibitor of cyclic AMP phosphodiesterase, produced a similar antagonism of the α‐adrenoceptor‐mediated contractions between the two strains.
These results suggest that a reduced function of Gs is the main factor responsible for the decreased responsiveness to β‐adrenoceptor stimulation in the SHR femoral artery.
Selective modulation by membrane potential of the interaction of some calcium entry blockers with calcium channels in rat mesenteric artery
Authors: Morel Nicole , Godfraind Théophile 
Published: July 2012

The effects of flunarizine, (+)‐PN 200‐110 and nifedipine on [3 H]‐(+)‐PN 200‐110 specific binding were investigated in intact rat mesenteric arteries bathed in physiological solution or in KCl‐depolarizing solution, and in a membrane fraction from rat mesenteric arteries.
Unlabelled dihydropyridines, (+)‐PN 200‐110 and nifedipine, inhibited [3 H]‐(+)‐PN 200‐110 specific binding concentration‐dependently in polarized as well as in depolarized intact arteries. The Ki value of (+)‐PN 200‐110 was decreased in arteries bathed in KCl‐depolarizing solution compared to arteries bathed in physiological solution, while the Ki value of nifedipine was not significantly changed. Ki values measured in depolarized arteries were close to the IC50 values (concentrations inhibiting by 50% the KCl‐contraction of rat mesenteric artery).
Flunarizine (10−6 M) was unable to displace the specific binding of [3 H]‐(+)‐PN 200‐110 in intact arteries bathed in physiological solution. At 10−7 M‐10−6 M, it inhibited the binding in depolarized arteries, suggesting that prolonged depolarization is required for the interaction of flunarizine with the dihydropyridine receptor.
In a membrane fraction isolated from rat mesenteric arteries, (+)‐PN 200‐110, nifedipine and flunarizine were all able to displace completely the specific binding of [3 H]‐(+)‐PN 200‐110. Displacement curves were parallel and Hill coefficients were close to unity. Ki values were close to the values obtained in depolarized intact arteries.
These results revealed a good correlation between the data obtained from binding tests and from pharmacological studies for dihydropyridine calcium entry blocking drugs, taking into account the time‐dependence associated with their action on KCl‐contraction compared to their binding properties. There was an important discrepancy between the concentrations of flunarizine active in binding studies and those active in pharmacological studies, which could be accounted for by the existence of multiple binding sites for calcium entry blockers in calcium channels.
A quantitative study of the actions of excitatory amino acids and antagonists in rat hippocampal slices
Authors: Blake J.F. , Brown M.W. , Collingridge G.L. 
Published: July 2012

A quantitative pharmacological investigation of the actions of excitatory amino acids on hippocampal CA1 neurones has been made using a new slice preparation developed for grease gap recording; d.c. potential was measured across a grease barrier placed between alvear fibres and the bathing medium.
In Mg2+‐free perfusate, N‐methyl‐D‐aspartate (NMDA, 1–100 μM), quisqualate (1–500 μM), kainate (1–200 μM) and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA, 1–100 μM) caused dose‐dependent depolarizations.
The dose‐response relationships were fitted to logistic expressions. The maximum responses to AMPA, NMDA and kainate were similar; their respective EC50 values were 5, 13 and 23 μM. Quisqualate had a smaller maximum; its EC50 value was 10 μM. The slopes of the dose‐response relationships were different for the 4 agonists; the order of steepness of the slopes was NMDA > AMPA > kainate > quisqualate.
Similar amino acid‐induced depolarizations were observed in slices of just the CA1 region or in whole slices bathed in tetrodotoxin. Isolated alvear fibres, however, were insensitive to the excitatory amino acids.
D‐2‐Amino‐5‐phosphonovalerate (APV, 50 μM) selectively and reversibly antagonized responses induced by NMDA (apparent pA2 = 5.21).
Kynurenic acid (1 mM) reversibly depressed responses to the three agonists tested. The doseratios for antagonism of AMPA, kainate and quisqualate were 6.9, 5.6 and 4.6 respectively.
This preparation has a different sensitivity profile to agonists from those of previously reported preparations of spinal cord, neocortex and cerebellum. The greater sensitivity to NMDA may be due to the higher density of NMDA receptors in the hippocampus. The effects of the antagonists, APV and kynurenate, are similar to those found in other brain areas.
Noradrenaline (gamma) and ATP responses of innervated and non‐innervated rat cerebral arteries
Authors: Edwards F.R. , Hards Daphne , Hirst G.D.S. , Silverberg G.D. 
Published: July 2012

The distribution of sympathetic adrenergic nerves on the rat middle cerebral artery and on the arterioles which originated from it was determined by use of gloxylic histochemistry.
Whereas the middle cerebral artery and proximal arterioles arising from this artery received a sympathetic innervation, the distal regions of the same arterioles were devoid of innervation.
The arteries and arterioles which were innervated were depolarized by noradrenaline in the combined presence of α‐ and β‐adrenoceptor antagonists. Those which were not innervated were not depolarized by noradrenaline.
ATP depolarized all arteries and arterioles examined.
These observations are discussed with respect to the similarities and differences between γ‐adrenoceptors and P2 purinoceptors.
Interactions of drugs acting on central dopamine receptors and cholinoceptors on yawning responses in the rat induced by apomorphine, bromocriptine or physostigmine
Authors: Zarrindast M.R. , Poursoltan M. 
Published: July 2012

Yawning was induced by subcutaneous (s.c.) injection of low doses of apomorphine to rats. This effect decreased with increasing doses of the drug.
Intraperitoneal (i.p.) pretreatment of animals with sulpiride (D2‐receptor blocker) reduced the frequency of the yawns induced by apomorphine, while SCH 23390 (D1‐receptor blocker, s.c.) pretreatment increased the small number of yawns which was induced by higher doses of apomorphine. Administration of SCH 23390 alone to rats also produced a low degree of yawning.
Apomorphine‐induced yawning was decreased in animals treated with SK&F 38393 (D1 ‐agonist, i.p.), atropine (i.p.) or theophylline (i.p.).
Intraperitoneal injection of bromocriptine (D2‐agonist) in rats also induced dose‐dependent yawning. The effect was decreased in animals pretreated with sulpiride, while SCH 23390 pretreatment did not change bromocriptine‐induced yawning significantly. Pretreatment of animals with SK&F 38393, atropine or theophylline reduced the number of yawns induced by bromocriptine.
Physostigmine (i.p.) but not neostigmine (i.p.) also induced yawning. The effect was antagonized by atropine or theophylline but not by sulpiride. Administration of SK&F 38393 decreased yawning induced by physostigmine. This inhibitory influence of SK&F 38393 was reduced by SCH 23390 in pretreated animals. Treatment of animals with SCH 23390 or bromocriptine increased the frequency of yawns induced by physostigmine.
It is concluded that D2‐receptor activation elicits yawning through influence on cholinergic mechanisms, whereas D1‐receptor stimulation decreases yawning behaviour by a negative influence on the cholinergic system.
Effects of hydroxyethyl rutosides upon the permeability of single capillaries in the frog mesentery
Authors: Blumberg Sara , Clough Geraldine , Michel Charles 
Published: July 2012

We have investigated the effects of a standardised mixture of hydroxyethyl rutosides (HR) upon the permeability of the walls of single capillaries and venules of the frog mesentery.
In each experiment a single vessel was perfused via a micropipette with frog Ringer solutions containing bovine serum albumin (10 mg ml−1) and Ficoll 70 (40 mg ml−1) first in the absence of HR and then with HR added to the perfusate. The permeability of the vessel walls was assessed during each perfusion by using a development of the Landis micro‐occlusion technique to estimate their hydraulic permeability (Lp) and the effective osmotic pressure (σΔπ) exerted across them by the perfusate macromolecules.
Measurements were made both in vessels which appeared to be healthy and in vessels showing signs of stasis or inflammation before perfusion.
HR at concentrations of 1.0, 0.1 and 0.01 mg ml−1 reduced hydraulic permeability to approximately half of its value in the absence of HR. It increased σδπ to macromolecules at concentrations of 10, 1.0, 0.1, 0.01 and 0.001 mg ml−1. The effects of HR upon permeability were not reversed within 10 min of perfusion with an HR‐free solution.
Ultrastructural examination of a number of vessels in which initial high values of permeability were reduced to values within the normal range of permeabilities by HR, showed clear signs of damage to the endothelium, with large gaps between adjacent endothelial cells.
These observations suggest that HR does reduce microvascular permeability both in healthy vessels and vessels showing signs of inflammation. The reduction in permeability of inflamed vessels does not appear to be the result of closure of the gaps between adjacent endothelial cells.
Mechanisms of positive inotropic effects and delayed relaxation produced by DPI 201–106 in mammalian working myocardium: effects on intracellular calcium handling
Authors: Kihara Yasuki , Gwathmey Judith K. , Grossman William , Morgan James P. 
Published: July 2012

We used the bioluminescent protein aequorin, which emits light when it combines with Ca2+, to test the hypothesis that the inotropic and lusitropic actions of DPI 201–106 are due to changes in intracellular Ca2+ handling in papillary muscles from ferrets and guinea‐pigs.
DPI 201–106 increased peak isometric tension (T) in a dose‐dependent manner, with an 83% increase in T as the concentration of DPI 201–106 was increased to 1 × 10−5 m; however, peak [Ca2+]i did not increase significantly until the concentration of DPI 201–106 reached 3 × 10−6 m, suggesting a sensitization of the contractile apparatus to Ca2+.
Tetrodotoxin (1 × 10−6m), which did not reduce the tension response significantly before DPI 201–106, decreased both [Ca2+]i and T in the presence of 1 × 10−5m DPI 201–106, suggesting involvement of a sodium channel activation mechanism; however, tetrodotoxin did not completely reverse the calcium sensitization.
The shift of the [Ca2+]i versus T relationship was not observed in the presence of another sodium channel agonist, veratridine (3 × 10−7‐1 × 10−6m).
In the guinea‐pig, DPI 201–106 markedly prolonged relaxation of tension (increase of 60% in the time from peak to 50% tension regression), which was accompanied by the appearance of a second component in the aequorin light signal; effects on relaxation were less prominent in the ferret.
Tension prolongation and the second component of the [Ca2+]i transient in the guinea‐pig were exacerbated by increased [Ca2+]o and decreased by tetrodotoxin. Ryanodine (3 × 10−7 m) markedly diminished the calcium transient in controls and the initial component of the calcium transient in the presence of DPI 201–106, but had only a modest effect on the second component.
We conclude that although sodium agonism plays a role, sensitization of the contractile apparatus to Ca2+ is an important mechanism in the positive inotropic action of DPI 201–106.
The negative lusitropic action of DPI 201–106 varies between ferret and guinea‐pig, possibly reflecting differences between these two species in subcellular Ca2+ handling.
Role of endothelium in hypoxic contraction of canine basilar artery
Authors: Elliott D.A. , Ong B.Y. , Bruni J.E. , Bose D. 
Published: July 2012

Reversible contraction of canine basilar artery, produced by hypoxia, persisted after mechanical and chemical removal of the endothelium. The removal of endothelium was confirmed by scanning electron microscopy as well as by the abolition or reversal of the relaxant response to acetylcholine or arginine8‐vasopressin.
Hydroquinone, believed to block selectively endothelium‐mediated relaxation, also preferentially attenuated hypoxic contractions even in the absence of endothelium but did not reduce responses to 5‐hydroxytryptamine (5‐HT) or high external potassium.
Contractions induced by red blood cell haemolysate, which occur independently of the endothelium, were also selectively attenuated by hydroquinone.
Contractions caused by hypoxia were inhibited by pretreatment with adenosine or by its application after contraction had developed.
Hypoxic contraction in canine basilar artery may result partly from a direct effect on smooth muscle as well as through the endothelium.
Hydroquinone may have an additional locus of action in smooth muscle cells besides its well known effect on the endothelium.
Effects of 5‐hydroxytryptamine on human isolated placental chorionic arteries and veins
Authors: Reviriego Jesús , Marín Jesús 
Published: July 2012

Effects of 5‐hydroxytrypamine (5‐HT) on cylindrical segments of human chorionic arteries and veins were investigated. Concentrations of 5‐HT (up to 3 × 10−6 m) produced concentration‐dependent contractions; higher concentrations induced a reduction of the maximal response. These responses were antagonized by methysergide and ketanserin in a non‐competitive manner. The contractions elicited by low 5‐HT concentrations were more affected by methysergide (10−7m) than by ketanserin (10−7m). Ketanserin apparently increased the responses to high 5‐HT concentrations in veins. Arteries appeared to be more sensitive to both drugs than veins. Single concentrations of 5‐HT elicited transient contractions in both kinds of vessel.
Marked tachyphylaxis was seen in segments exposed to high concentrations of 5‐HT or in which a concentration‐response curve was determined.
Contractions induced by 5‐HT were reduced in a Ca2+‐free medium. Veins were more affected by the Ca2+ antagonists, nifedipine (10−7m), nicardipine (10−5m) and diltiazem (10−5m) than arteries.
5‐HT (10−6m) enhanced 45Ca2+ uptake in those vessels in which a concentration‐response curve had not been previously determined. In veins, this increase was reduced by the three Ca2+ antagonists.
The results indicate that 5‐HT responses in these vessels were greatly dependent on extracellular Ca2+. A type of 5‐HT1‐receptor may mediate responses to low 5‐HT concentrations, while higher concentrations may activate 5‐HT2‐receptors. 5‐HT may desensitize the latter by interconversion between a high affinity and low affinity state, as suggested by others, a change prevented in part by ketanserin.
The distribution of γ‐adrenoceptors and P2 purinoceptors in mesenteric arteries and veins of the guinea‐pig
Authors: Hirst G.D.S. , Jobling P. 
Published: July 2012

Membrane potential changes and contractions were recorded from mesenteric arteries and veins of the guinea‐pig, during perivascular nerve stimulation or application of noradrenaline or adenosine triphosphate (ATP).
After α‐adrenoceptor blockade, noradrenaline activated low affinity adrenoceptors (γ‐adrenoceptors) causing depolarization and arterial contraction only in the presence of an inhibitor of catecholamine uptake.
Noradrenaline did not cause depolarization or contraction of the vein after α‐adrenoceptor blockade even after catecholamine uptake was blocked.
Adenosine triphosphate caused depolarization and contraction of both arteries and veins. These responses were abolished by α‐,β‐,methylene adenosine triphosphate (Me‐ATP).
Me‐ATP abolished rapid excitatory junction potentials (e.j.ps) caused by perivascular nerve stimulation of arteries but had no effect on arterial responses mediated by γ‐adrenoceptors.
In veins, perivascular nerve stimulation evoked slow e.j.ps which persisted in the presence of Me‐ATP but were abolished after blockade of α‐adrenoceptors.
The observations indicate that P2 purinoceptors are present on both mesenteric artery and vein whilst γ‐adrenoceptors are localized near the neuromuscular junction of the artery. However γ‐adrenoceptors do not appear to be directly involved in the generation of arterial e.j.ps.
α1‐Adrenoceptor antagonist activity of novel pyrimidine derivatives (SHI437 and IK29) in rabbit aorta and trigone of the bladder
Authors: Azuma Hiroshi , Sugimoto‐Tokushima Mineko , Tanaka Kumi , Ikenoue Yoshiaki , Ito Shigeru , Ishikawa Masayuki 
Published: July 2012

In the rabbit isolated aorta and trigone of the bladder, noradrenaline, phenylephrine and clonidine elicited concentration‐dependent contractions, which may be caused through activation of postsynaptic α1‐adrenoceptors.
SHI437, IK29, prazosin and yohimbine competitively antagonized the contractile responses induced by noradrenaline in the aorta and trigone. The pA2 values of SHI437, IK29, prazosin and yohimbine were 7.35 ± 0.09, 7.47 ± 0.10, 8.55 ± 0.02 and 6.28 ± 0.05 in the aorta, and 8.07 ± 0.04, 8.30 ± 0.03, 8.22 + 0.04 and 6.46 ± 0.04 in the trigone, respectively.
SHI437, IK29, prazosin and yohimbine also possessed competitive α2‐adrenoceptor blocking properties, judging from their antagonism of the clonidine‐induced inhibitory effect on the twitch responses in the electrically stimulated vas deferens of the rat. The pA2 values of SHI437, IK29, prazosin and yohimbine were determined to be 4.76 ± 0.02, 4.74 ± 0.02, 5.06 ± 0.03 and 7.86 ± 0.04, respectively.
SHI437, IK29 and prazosin inhibited the contractile responses elicited by transmural electrical stimulation without affecting the evoked 3H‐overflow from the [3H]‐noradrenaline‐preloaded rabbit aorta. Yohimbine augmented the contractile responses and 3H‐overflow.
SHI437 and IK29 at a concentration sufficient to inhibit noradrenaline‐induced contraction failed to attenuate the contractile responses of aorta to KCl, 5‐hydroxytryptamine and prostaglandin F2α, and of the trigone to acetylcholine and histamine.
The present results suggest that SHI437 and IK29 are highly selective α1‐adrenoceptor antagonists, especially in the trigone of the bladder.
Methylene blue but not changes in cyclic GMP inhibits resting and bradykinin‐stimulated production of prostacyclin by pig aortic endothelial cells
Authors: Martin William , Drazan Kveta M. , Newby Andrew C. 
Published: July 2012

Primary cultures of pig aortic endothelial cells produced 6‐keto‐prostaglandin F1α (6‐keto PGF1α), the stable breakdown product of prostacyclin, both in the resting state and in response to bradykinin. The rise in 6‐keto‐PGF1α production induced by bradykinin (1–100 nm) was concentration‐dependent.
Treating endothelial cells with the inhibitor of soluble guanylate cyclase, methylene blue (0.1–20 μm) produced an irreversible reduction in resting and bradykinin (0.1 μm)‐stimulated production of 6‐keto‐PGF1α with an IC50 of 0.5 ± 0.1 μm. Treating endothelial cells with haemoglobin (10 μm) had no effect on resting or bradykinin (0.1 μm)‐stimulated production of 6‐keto‐PGF1α.
Two stimuli that elevate the level of guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) in endothelial cells, 8‐bromo cyclic GMP (30 μm) and atriopeptin II (0.1 μm), each had no effect on resting or bradykinin (0.1 μm)‐stimulated production of 6‐keto‐PGF1α. Furthermore, treating endothelial cells with either 8‐bromo cyclic GMP (30 μm) or atriopeptin II (0.1 μm) had no effect on the ability of methylene blue (20 μm) to inhibit resting or bradykinin (0.1 μm)‐stimulated production of 6‐keto‐PGF1α.
Adding arachidonic acid (1 μm) to endothelial cells led to a marked stimulation of 6‐keto‐PGF1α production. Treating cells with either methylene blue (20 μm) or the cyclo‐oxygenase inhibitor, flurbiprofen (10 μm), inhibited both resting and arachidonic acid (1 μm)‐induced production of 6‐keto‐PGF1α.
In pig aortic endothelial cells methylene blue appears to block prostacyclin production by a mechanism independent of inhibition of soluble guanylate cyclase. Care should be exercised when using methylene blue as a selective inhibitor of endothelium‐derived relaxing factor due to its additional ability to block production of the other endothelium‐derived vasodilator, prostacyclin.
Interactions between the tachykinins and calcitonin gene‐related peptide lead to the modulation of oedema formation and blood flow in rat skin
Authors: Brain S.D. , Williams T.J. 
Published: July 2012

The mechanisms involved in tachykinin‐induced oedema were investigated in rat skin and interactions between the tachykinins and calcitonin gene‐related peptide (CGRP) were studied.
Intradermal injections of the tachykinins, substance P, neurokinin A and neurokinin B, stimulated local oedema formation which was in each case potentiated by co‐injection of the vasodilator CGRP. Oedema induced by substance P, in the presence and absence of CGRP, was significantly inhibited by pretreatment of rats with a combination of the histamine H1 antagonist, mepyramine, and the 5‐hydroxytryptamine antagonist, methysergide. Oedema induced by neurokinin A or B was not inhibited by this pretreatment.
Intradermally‐injected CGRP induced a long lasting increase in local blood flow, which was measured with a laser Doppler blood flow meter. The simultaneous injection of substance P, but not of the structurally‐related neurokinins, caused a loss of the prolonged vasodilator activity of CGRP.
These results show that oedema induced by substance P is partially dependent on mast cell amines and that only substance P causes a loss of the prolonged vasodilator activity of CGRP.
We suggest that the ability of substance P to prevent the persistent vasodilator activity of CGRP may be a direct consequence of substance P‐induced activation of mast cells.