bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hoe 140 a new potent and long acting bradykinin‐antagonist: in vitro studies
Authors: Hock F.J. , Wirth K. , Albus U. , Linz W. , Gerhards H.J. , Wiemer G. , Henke St. , Breipohl G. , König W. , Knolle J. , Schölkens B.A. 
Published: July 2012

Hoe 140 (d‐Arg‐[Hyp3, Thi5, d‐Tic7, Oic8]bradykinin) is a new bradykinin (BK)‐antagonist. It was tested in several in vitro assays and compared with d‐Arg‐[Hyp2, Thi5,8,d‐Phe7]BK.
In receptor binding studies in guinea‐pig ileum preparations, Hoe 140 showed an IC50 of 1.07 × 10−9mol l−1 and a KI value of 7.98 × 10−10 mol l−1.
In isolated organ preparations Hoe 140 and d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK inhibited bradykinin‐induced contractions concentration dependently, with IC50‐values in the guinea‐pig ileum preparation of 1.1 × 10−8 mol l−1 and 3 × 10−5 mol l−1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 × 10−9 mol l−1 for Hoe 140. d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK showed an IC50 of 4.0 × 10−6 mol l−1. The IC50 values in the guinea‐pig isolated pulmonary artery were 5.4 × 10−9 mol l−1 and 6.4 × 10−6 mol l−1, respectively. In the rabbit aorta no inhibitory effects on Des‐Arg9‐BK induced contractions were observed.
In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10−8 mol l−1) bradykinin‐induced endothelium‐derived relaxing factor (EDRF) release and the bradykinin‐induced increase in cytosolic free calcium (IC50 = 10−9 mol l−1).
Hoe 140 (10−7 mol l−1) totally suppressed the bradykinin‐induced (10−8 to 10−4mol l−1) prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK (10−7 mol l−1) showed a weaker antagonism.
Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than d‐Arg‐[Hyp2, Thi5,8, d‐Phe7]BK.
Human vascular smooth muscle cells inhibit platelet aggregation when incubated with glyceryl trinitrate: evidence for generation of nitric oxide
Authors: Benjamin Nigel , Dutton Jane A.E. , Ritter James M. 
Published: July 2012

The effect on platelet aggregation of glyceryl trinitrate in the presence of cultured vascular smooth muscle cells was determined turbidometrically. U46619 (a thromboxane mimetic) was used as agonist and experiments were performed in the presence of aspirin. Inorganic nitrite production from glyceryl trinitrate by vascular smooth muscle cells was also measured, to provide an indirect index of nitric oxide synthesis.
The combination of vascular smooth muscle cells together with glyceryl trinitrate, at concentrations that had little effect individually, profoundly inhibited platelet aggregation.
The inhibitory effect on platelet aggregation of vascular smooth muscle cells together with glyceryl trinitrate was markedly attenuated by haemoglobin, an inhibitor of nitric oxide.
These results show that vascular smooth muscle cells inhibit platelet aggregation when exposed to glyceryl trinitrate and suggest that this is due to generation of nitric oxide from glyceryl trinitrate by vascular smooth muscle.
Evidence for facilitatory and inhibitory muscarinic receptors on postganglionic sympathetic nerves in mouse isolated atria
Authors: Costa Mary , Majewski Henryk 
Published: July 2012

McNeil A 343 (10 μm‐30 μm) enhanced the fractional stimulation‐induced (S‐I) outflow of radioactivity from mouse isolated atria which had been incubated with [3H]‐noradrenaline. The enhancing effect of McNeil A 343 was not altered by hexamethonium (300 μm) suggesting that it was not due to an action at nicotinic receptors. It is also unlikely that McNeil A 343 enhanced the S‐I outflow of radioactivity in mouse atria by blocking neuronal reuptake of noradrenaline since the effect persisted in the presence of cocaine (30 μm).
The facilitatory effect of McNeil A 343 on the S‐I outflow of radioactivity was attenuated by atropine (0.3 μm), pirenzepine (0.2 μm or 1.0 μm), dicyclomine (1.0 μm) and methoctramine (1.0 μm) and was thus due to activation of muscarinic receptors.
In contrast to the effect of McNeil A 343, another muscarinic receptor agonist, carbachol (3.0 μm) significantly decreased the S‐I outflow of radioactivity. The receptors through which McNeil A 343 acts to enhance the S‐I outflow of radioactivity appear to be distinct from inhibitory prejunctional muscarinic receptors. The relatively M1‐selective antagonist, pirenzepine (0.2 μm), attenuated the facilitatory effect of McNeil A 343 whereas a higher concentration (1.0 μm) was required to block the inhibitory effect of carbachol. Conversely, the relatively M2‐selective antagonist, methoctramine (0.1 μm), blocked the inhibitory effect of carbachol but a higher concentration of methoctramine (1.0 μm) was required to block the facilitatory effects of McNeil A 343. These results tentatively ascribe facilitatory muscarinic receptors as belonging to the M1 subtype and inhibitory muscarinic receptors as belonging to the M2 subtype.
The non‐selective muscarinic receptor antagonist, atropine, enhanced the S‐I outflow of radioactivity, suggesting that there was tonic activation of inhibitory prejunctional muscarinic receptors by endogenous acetylcholine released from parasympathetic nerves. However, pirenzepine (0.03 μm–1.0 μm) did not decrease the S‐I outflow of radioactivity, suggesting that under the conditions of the present study, facilitatory muscarinic receptors are not tonically activated by endogenous acetylcholine.
Characterization of the 5‐HT receptor mediating endothelium‐dependent relaxation in porcine vena cava
Authors: Sumner M.J. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT) relaxes rings of neonatal porcine isolated vena cava by both an endothelium‐dependent and an endothelium‐independent mechanism. The receptor mediating the latter response has been shown to be a 5‐HT1‐like receptor (positively coupled to adenylyl cyclase) located on the vascular smooth muscle. The features of the endothelium‐dependent response to 5‐HT in this preparation are now described.
In ring preparations contracted with the stable thromboxane‐A2‐mimetic, U‐46619 (10 nm), and in the presence of the 5‐HT2 receptor antagonist ketanserin (1 μm), low concentrations of 5‐HT (1–100 nm) evoked an endothelium‐dependent, rapid, ‘spike‐like’ relaxation. Higher concentrations of 5‐HT (0.1–10 μm) elicited a more sustained, but endothelium‐independent relaxation.
Relaxation induced by low concentrations (1–100 nm) of 5‐HT was abolished by endothelium removal, and was markedly (but not totally) inhibited by the guanylate cyclase inhibitor, methylene blue (10 μm) or by the inhibitor of endothelium‐derived nitric oxide (NO) synthesis, l‐NG‐monomethylarginine (l‐NMMA; 100–500 μm).
The endothelium‐dependent response to 5‐HT was mimicked by α‐methyl‐5‐HT, 5‐methoxytryptamine, tryptamine and 2‐methyl‐5‐HT, but not by sumatriptan or 8‐hydroxy‐di‐n‐propylaminotetralin (8‐OH‐DPAT) at concentrations up to 10 μm. In contrast, relaxation evoked by 5‐carboxamidotryptamine (5‐CT) was endothelium‐independent.
The endothelium‐dependent relaxation induced by 5‐HT or α‐methyl‐5‐HT was antagonized by methysergide, methiothepin, cyproheptadine and metergoline, but not by ketanserin, spiperone, ondansetron, verapamil, cyanopindolol, mesulergine, ICS 205–930, or indomethacin.
These results suggest that the endothelium‐dependent relaxation of porcine vena cava induced by 5‐HT is largely mediated by the release of NO (although other endothelium‐derived relaxing factors may also be involved) and that 5‐HT is acting at a receptor which is not ‘5‐HT1‐like’, 5‐HT2, 5‐HT3 or 5‐HT4 and is not comparable to recognised 5‐HT receptor ligand binding sites. The characteristics of this receptor are discussed in relation to the endothelial 5‐HT receptor types in other blood vessels.
The diverse effects of cromakalim on tension and 86Rb efflux in canine arterial smooth muscle
Authors: Masuzawa Kaoru , Matsuda Tomohiro , Asano Masahisa 
Published: July 2012

To characterize further the K+ channels opened by cromakalim in arterial smooth muscle, the effects of cromakalim on tension and 86Rb efflux were compared in endothelium‐denuded strips of coronary, mesenteric and middle cerebral (MC) arteries of the dog.
Cromakalim relaxed strips precontracted with 20.9 mm K+. The maximum relaxation induced by cromakalim varied in the arteries used; 94% in the coronary artery, 60% in the mesenteric artery and only 38% in the MC artery. Cromakalim failed to relax arterial strips precontracted with 65.9 mm K+.
When the effects of cromakalim on 86Rb efflux were determined in 20.9 mm K+‐contracted strips, cromakalim‐induced relaxations were accompanied by a large increase in 86Rb efflux in the coronary artery, by a small increase in the mesenteric artery but by an apparent decrease in the MC artery.
When 10−7m nifedipine was added to 20.9 mm K+‐contracted strips, to inactivate Ca2+‐activated K+ (KCa) channels, cromakalim produced a greater increase (measured from the point at which cromakalim was administered) in 86Rb efflux than in the absence of nifedipine, suggesting that the effects of cromakalim on 86Rb efflux from the 20.9 mm K+‐contracted strips may be the resultant of two opposing effects: an increased 86Rb efflux perhaps due to the opening of ATP‐sensitive K+ (KATP) channels, and a decreased efflux due to the closing of KCa channels.
After the inactivation of KCa channels in 20.9 mm K+‐contracted strips, the cromakalim‐induced increase in 86Rb efflux measured as area under the curve was eight times greater in the coronary artery than in the MC artery. The increase in 86Rb efflux in the mesenteric artery was intermediate between these extremes.
Cromakalim also increased the 86Rb efflux from 65.9 mm K+‐contracted strips. This increase was not augmented by the addition of nifedipine. Under these conditions, a similar variation in efflux response (as area under the curve) for cromakalim was noted in the arteries used.
The relaxant responses of each artery to cromakalim were competitively antagonized by glibenclamide, a blocker of KATP channels. The cromakalim‐induced increase in 86Rb efflux was also inhibited by glibenclamide.
These results suggest that cromakalim‐opened K+ channels in the three arteries may differ in terms of their frequency of occurrence in the plasmalemma, their permeability to 86Rb and their ability to modulate tension development. On the other hand, the activities of KCa and voltage‐sensitive K+ channels, estimated from the effects of nifedipine, were similar in the three arteries.
Putative neurotrophic factors and functional recovery from peripheral nerve damage in the rat
Authors: Van der Zee Catharina E.E.M. , Brakkee Jan H. , Gispen Willem Hendrik 
Published: July 2012

In rats, recovery of sensory‐motor function following a crush lesion of the sciatic or tibial nerve was monitored by measuring foot reflex withdrawal from a local noxious stimulation of the foot sole.
Putative neurotrophic compounds were tested on this functional recovery model: melanocortins (peptides derived from ACTH (corticotropin) and α‐MSH (melanotropin)), gangliosides and nimodipine were effective whereas isaxonine and TRH (thyrotropin releasing hormone) were not.
Structure‐activity studies with melanocortins revealed a similar effectiveness of α‐MSH, [N‐Leu4, d‐Phe7]‐α‐MSH, desacetyl‐α‐MSH and the ACTH4–9 analogue ORG 2766, questioning the validity of the previously suggested notion that the melanotrophic properties of these peptides are responsible for their neurotrophic effect.
As recovery of function after peripheral nerve damage follows a similar time course in hypophysectomized (five days post operation) and sham‐operated rats, effective melanocortin therapy does not mimic an endogenous peptide signal in the repair process from pituitary origin.
Subcutaneous treatment with ORG 2766 (7.5 μg kg−1 48 h−1) facilitates recovery of function following peripheral nerve damage in young (6–7 weeks old), mature (5 month old) and old (20 month old) rats.
In view of the diversity in structure of the effective neurotrophic factors and the complexity of nerve repair, the present data support the notion that peripheral nerve repair may be facilitated by different humoral factors likely to be active on different aspects of the recovery process.
The role of nitric oxide in inhibitory non‐adrenergic non‐cholinergic neurotransmission in the canine lower oesophageal sphincter
Authors: De Man Joris G. , Pelckmans Paul A. , Boeckxstaens Guy E. , Bult Hidde , Oosterbosch Luc , Herman Arnold G. , Van Maercke Yvan M. 
Published: July 2012

The role of nitric oxide (NO) in non‐adrenergic non‐cholinergic (NANC) neurotransmission was studied on circular muscle strips of the canine lower oesophageal sphincter (LOS). Electrical field stimulation evoked frequency‐dependent relaxations, which were resistant to adrenergic and cholinergic blockade and abolished by tetrodotoxin.
Exogenous administration of NO induced concentration‐dependent and tetrodotoxin‐resistant relaxations which mimicked those in response to electrical stimulation.
NG‐nitro‐l‐arginine (l‐NNA), a stereospecific inhibitor of NO‐biosynthesis, inhibited the relaxations induced by electrical stimulation but not those by exogenous NO or vasoactive intestinal polypeptide (VIP).
The effect of l‐NNA was prevented by l‐arginine, the precursor of the NO biosynthesis but not by its enantiomer d‐arginine.
Haemoglobin abolished the NO‐induced responses and reduced those evoked by electrical stimulation.
Cumulative administration of VIP induced concentration‐dependent relaxations, which were slow in onset and sustained. A complete relaxation to VIP was not achieved and the relaxations were not affected by l‐NNA.
In conclusion, our results provide evidence that NANC relaxations are mediated by NO, suggesting NO or a NO releasing substance as the final inhibitory NANC neurotransmitter in the canine LOS.
Characterization of P2X‐ and P2Y‐purinoceptors in the rabbit hepatic arterial vasculature
Authors: Ralevic V. , Mathie R.T. , Alexander B. , Burnstock G. 
Published: July 2012

Responses to adenosine 5′‐triphosphate (ATP) and its agonists were studied in the isolated liver of the rabbit dually perfused through the hepatic artery and the portal vein.
In the hepatic arterial vascular bed at basal tone, ATP and its agonists elicited vasoconstrictor responses with the rank order of potency α,β‐methylene ATP > 2‐methylthio ATP > ATP, consistent with their action at the P2X‐purinoceptor.
When tone was raised with noradrenaline (10−5 m), vasodilator responses were produced with ATP and 2‐methylthio ATP; α,β‐methylene ATP produced only further constriction. The rank order of vasodilator potency was 2‐methylthio ATP > ATP ≫ α,β‐methylene ATP, consistent with their action at the P2Y‐purinoceptor.
Methylene blue (10−5 m) antagonized vasodilator responses to acetylcholine and ATP, but not those to adenosine or sodium nitroprusside. Addition of 8‐phenyltheophylline (10−5 m) antagonized responses to adenosine but not those to sodium nitroprusside. Responses to ATP remaining after antagonism with methylene blue were not further antagonized by 8‐phenyltheophylline.
These results present evidence for discrete P2X‐ and P2Y‐purinoceptors in the rabbit hepatic arterial bed which mediate vasoconstrictor and vasodilator responses respectively.
Vasodilatation produced by ATP was entirely due to direct action at the P2Y‐purinoceptor, and not at a P1‐purinoceptor following breakdown to adenosine. The antagonism of these responses by methylene blue is consistent with the view that vasodilatation by ATP takes place largely via endothelial P2Y‐purinoceptors that lead to release of endothelium‐derived relaxing factor. However, we cannot exclude the possibility that P2Y‐purinoceptors located on the vascular smooth muscle play a contributory role in ATP‐induced vasodilatation.
Endothelins: vasoconstrictor effects and localization in canine cerebral arteries
Authors: Saito A. , Shiba R. , Yanagisawa M. , Masaki T. , Kimura S. , Yamada K. , Mima T. , Shigeno T. , Goto K. 
Published: July 2012

The vascular effects of endothelin and localization of endothelin‐like immunoreactivity were characterized in isolated cerebral arteries of dogs.
Endothelin‐like immunoreactivity was detected in a few populations of endothelial cells of dog basilar artery.
Endothelin‐1, endothelin‐2 and endothelin‐3 contracted isolated ring preparations of cerebral arteries in a dose‐dependent manner independently of the presence of endothelium. The ED50 values (and 95% confidence intervals) for the contraction were 411 pm (242–697 pm) and 478 pm (295–776 pm) for endothelin‐1 and endothelin‐2, respectively. Endothelin‐3 induced vascular contraction at a higher concentration (ED50 = 26.5 nm, 95% confidence interval = 15.7–45.7 nm).
The increases in tone induced by endothelin‐1 and endothelin‐2 did not return to the resting level after repeated washings, while a rinse with Krebs solution reversed the vasoconstrictor response to endothelin‐3. The endothelins did not cause any vasodilator response in arteries precontracted with uridine 5′‐triphosphate even in the presence of intact endothelial cells.
NiCl2 (1 mm) attenuated the contractions induced by endothelin‐3 (10–300 nm) and those to relatively low doses (1 nm) but not higher doses (10–100 nm) of endothelin‐1 and endothelin‐2. The contractions in response to endothelin‐1, endothelin‐2 and endothelin‐3 were greatly attenuated in Ca2+‐free solutions although high concentrations of endothelin‐1 and endothelin‐2 still evoked contractions.
These results suggest that the vasoconstriction induced by endothelin‐3 and lower doses of endothelin‐1 and endothelin‐2, largely depends on the influx of Ca2+ ions. The apparent insensitivity to Ni2+ shows that additional distinct mechanisms also operate in the vasoconstrictor responses to high concentrations of endothelin‐1 and endothelin‐2.
The presence of endothelin‐like immunoreactivity in endothelial cells suggests that endothelin is a potential endogenous spasmogen.
Increased flow‐induced ATP release from isolated vascular endothelial cells but not smooth muscle cells
Authors: Bodin Philippe , Bailey Doreen , Burnstock Geoffrey 
Published: July 2012

Freshly harvested smooth muscle cells and endothelial cells isolated from the rabbit aorta were perfused (0.5 ml min−1) and stimulated twice by an increase of flow rate (3.0 ml min−1) in order to compare their ability to release adenosine 5′‐triphosphate (ATP).
In smooth muscle cells, the basal release of ATP (0.0265 ± 0.0033 pmol ml−1 per 106 cells) was not increased during periods of increased flow (P = 0.2).
In endothelial cells, the concentration of ATP in the perfusate during periods of low flow (0.0335 ± 0.0038 pmol ml−1 per 106 cells) was significantly increased by 14 times and 5 times during the first and second periods of increased flow, respectively.
The release of ATP by endothelial cells did not appear to be caused by the lysis of cells during the period of increased flow because it can be reproduced several times and because there was no difference between lactate dehydrogenase activity in perfused cells and that in non‐perfused cells.
These results show that, of the two major cell types of the vascular wall, only endothelial cells react to shear stress by releasing ATP.
The effect of inhibitors of the l‐arginine/nitric oxide pathway on endotoxin‐induced loss of vascular responsiveness in anaesthetized rats
Authors: Gray Gillian A. , Schott Cathy , Julou‐Schaeffer Géraldine , Fleming Ingrid , Parratt James R. , Stoclet Jean‐Claude 
Published: July 2012

The effects on blood pressure and on pressor responses to noradrenaline (NA), of NG‐monomethyl‐l‐arginine (l‐NMMA) and NG‐nitro‐l‐arginine methyl ester (l‐NAME), inhibitors of the l‐arginine/nitric oxide pathway, were investigated in anaesthetized rats receiving an infusion of bacterial endotoxin (E. coli lipopolysaccharide, LPS).
Infusion of LPS (10 mg kg−1 h−1) for 50min had no effect on mean arterial blood pressure (MABP) but induced a reduction in responsiveness to noradrenaline (100 ng–1 μg kg−1). l‐NMMA (30 mg kg−1), but not d‐NMMA, caused an increase in MABP of approximately 30 mmHg and restored responses to NA. This effect was reversed by l‐ but not d‐arginine (100 mg kg−1).
In LPS‐treated rats, blood pressure responses to NA were only marginally increased by the cyclooxygenase inhibitor, indomethacin (5 mg kg−1). l‐NAME (1 mg kg−1) caused a similar increase in MABP and restored pressor responses to NA both in the presence and absence of indomethacin.
Co‐infusion of vasopressin (100 ng kg−1, for 10 min) with LPS (10 mg kg−1 h−1) in order to reproduce the hypertensive effect of l‐NMMA and l‐NAME increased pressor responsiveness to 100 and 300 ng kg−1 NA but not to 1 μg kg−1 NA.
Infusion of sodium nitroprusside (30 μg kg−1 min−1) decreased responsiveness to NA even when the hypotension was corrected by co‐infusion of vasopressin (50 ng kg−1 min−1).
These results demonstrate that the restoration of vascular responsiveness to NA in LPS‐treated anaesthetized rats by inhibitors of the l‐arginine/nitric oxide pathway is stereospecific and reversible. Furthermore, the experiments involving indomethacin suggest that although cyclo‐oxygenase products of arachidonic acid may contribute to the development of LPS‐induced hyporeactivity, the effect of l‐NAME is unlikely to involve inhibition of the cyclo‐oxygenase pathway. Comparison of NA responsiveness during vasopressin and l‐NMMA/l‐NAME‐induced hypertension shows that increasing the blood pressure may modify LPS‐induced hyporeactivity, but cannot account for the complete restoration of responses to NA by l‐NMMA and l‐NAME. These observations suggest that activation of nitric oxide formation from l‐arginine makes a direct contribution to the production of vascular hyporeactivity by LPS in vivo.
Effect of capsaicin on PAF‐induced bronchial hyperresponsiveness and pulmonary cell accumulation in the rabbit
Authors: Spina D. , McKenniff M.G. , Coyle A.J. , Seeds E.A.M. , Tramontana M. , Perretti F. , Manzini S. , Page C.P. 
Published: July 2012

Platelet activating factor (PAF), but not the carrier molecule bovine serum albumin (BSA) induced bronchoconstriction in the anaesthetized rabbit. This bronchoconstriction was not altered by prior treatment with capsaicin.
Rabbits demonstrated increased airways responsiveness to histamine 24 h after exposure to PAF but not to BSA. PAF failed to increase airways responsiveness to histamine in animals pretreated with capsaicin (80 mg kg−1).
A significant increase in inflammatory cells was obtained in bronchoalveolar lavage (BAL) 24 h after PAF exposure in vehicle‐treated rabbits. This was associated with an increase in the numbers of neutrophils and eosinophils. Capsaicin treatment inhibited the PAF‐induced influx of inflammatory cells found in BAL, although this was not associated with an inhibition of PAF‐induced pulmonary eosinophilia.
Capsaicin‐induced motor effects were modest in epithelium‐intact rabbit bronchial preparations, but were significantly enhanced in epithelium‐denuded preparations in the presence of thiorphan. The contractile response to capsaicin was significantly inhibited in tissues exposed to a consecutive dose of capsaicin. Furthermore, ruthenium red abolished capsaicin‐induced contraction in epithelium‐denuded preparations.
Tissue content of calcitonin gene‐related peptide‐like immunoreactivity and substance P‐like immunoreactivity was not reduced in bronchus and iris obtained from capsaicin‐treated rabbits, although capsaicin‐induced contractile responses in rabbit bronchus obtained from animals previously treated with capsaicin were significantly reduced. Furthermore, airway responses to histamine, methacholine and electrical field stimulation in vitro, were not altered by pretreatment of rabbits in vivo for 3 days with capsaicin.
In conclusion, PAF‐induced airways responsiveness and pulmonary cell accumulation is inhibited by in vivo capsaicin pretreatment in the rabbit, via a mechanism that may not involve depletion of sensory neuropeptides.