bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation by endothelium of the responses induced by endothelin‐1 and by some of its analogues in rat isolated aorta
Authors: Topouzis S. , Huggins J.P. , Pelton J.T. , Miller R.C. 
Published: July 2012

The contractile effects of endothelin‐1 and various analogues were studied in rat isolated aortic rings. The potency order of the peptides studied was endothelin‐1 > sarafotoxin S6b > [Ala3,11]endothelin‐1 > [Ala1,15]endothelin‐1. [Ala1,3,11,15]endothelin‐1 was neither agonist nor antagonist.
The concentration of endothelin‐1 required to induce contractions equal to 50% of those induced by 1 μm noradrenaline was reduced from 5.8 nm when the vascular endothelium was present to 1.4 nm after it had been mechanically removed.
Contractions elicited by [Ala3,11]endothelin‐1, [Ala1,15]endothelin‐1 and sarafotoxin S6b were not modulated by the endothelium.
Endothelin‐1 increased the tissue content of guanosine 3′,5′‐cyclic monophosphate (cyclic GMP) in rat aortic segments with endothelium by about 4 fold, suggesting that it increased the release of endothelium‐derived relaxing factor. Sarafotoxin S6b did not reduce, or significantly increase, tissue cyclic GMP levels and therefore had little effect on EDRF release.
The concentration of sodium nitroprusside required to relax half‐maximally aortae denuded of endothelium was 430 nm if the aortae had been precontracted with 10 nm endothelin‐1 and 35 nm if 10 nm sarafotoxin S6b was used as the spasmogen. This indicates that differential sensitivities of the smooth muscle to cyclic GMP cannot explain differences between responses to endothelin‐1 and sarafotoxin S6b in the presence of. endothelium.
It is concluded that endothelin‐1 contractions of rat aorta are modified by the endothelium, probably by enhancing the release of endothelium‐derived relaxing factor (EDRF) and not by affecting the sensitivity of the smooth muscle to EDRF. This suggests that a stimulated release of an adequate amount of EDRF is necessary to modulate contractile responses to these peptides.
Relationship between lipolysis and cyclic AMP generation mediated by atypical β‐adrenoceptors in rat adipocytes
Authors: Hollenga Ch. , Brouwer F. , Zaagsma J. 
Published: July 2012

The nature of the β‐adrenoceptor(s) mediating adenylyl cyclase activation in rat adipocyte ghosts by (−)‐isoprenaline and the lipolytically selective β‐adrenoceptor agonist, BRL 37344, was investigated by use of the β1‐selective antagonist, CGP 20712A. The results were compared with lipolysis in adipocytes.
While in lipolysis BRL 37344 was a full and 10 times more potent agonist than (−)‐isoprenaline, in adenylyl cyclase activation similar pD2 values for both agonists were found. BRL 37344 was only a partial agonist on rat adipocyte adenylyl cyclase, with an intrinsic activity of 0.62.
With CGP 20712A small rightward shifts of the (−)‐isoprenaline concentration‐response curve (CRC) were observed at concentrations up to 10 μm, while at 100 μm and 1 mm clear rightward shifts occurred. The BRL 37344 CRC was not shifted with antagonist concentrations up to 10 μm. Only at 100 μm and 1mm CGP 20712A were rightward shifts observed.
CGP 20712A concentrations of 10 μm and 100 μm depressed the maximum of the (−)‐isoprenaline CRC to 89 and 60%, while the BRL 37344 CRCs retained the control maximum effect (62% of (−)‐isoprenaline). Only at 1 mm CGP 20712A, was the CRC of BRL 37344 depressed, while the (−)‐isoprenaline maximum was diminished further.
It was concluded that as with lipolysis, (−)‐isoprenaline acts both through typical β1‐ and atypical β3‐adrenoceptors for activation of adenylyl cyclase, while BRL 37344 acts solely through atypical β3‐adrenoceptors.
The results also demonstrate that the relationship between adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) and lipolysis is different for BRL 37344 and (−)‐isoprenaline. Although the maximum activation of adenylyl cyclase by BRL 37344 is only 62% of that by (−)‐isoprenaline, the distance between the lipolysis and adenylyl cyclase CRCs is much larger in the case of BRL 37344, indicating a larger transduction reserve for this agonist.
Differences in the K+‐channels opened by cromakalim, acetylcholine and substance P in rat aorta and porcine coronary artery
Authors: Bray Katharine , Quast Ulrich 
Published: July 2012

The effects of acetylcholine and substance P on the efflux of 86Rb+ and 42K+ from rat aorta and pig coronary artery, respectively, were compared with those of the K+ channel opening agent, cromakalim.
In rat aorta preloaded with 86Rb+ and/or 42K+, acetylcholine produced transient, concentration‐dependent increases in the efflux rate coefficients of these tracers (maximum ≅ 35%). These effects were abolished by endothelial cell removal.
Donor/acceptor experiments with rat aorta suggested that at least some of the efflux of 86Rb+ seen in the presence of acetylcholine was not derived from the endothelium, but came from the smooth muscle itself.
Acetylcholine (10 μm)‐induced 86Rb+ efflux was reduced by tetraethylammonium (TEA, 10 mm) to 33% and ouabain (300 μm) to 54% of control. Preincubation with Ba2+ (100 μm) did not significantly inhibit acetylcholine‐induced efflux.
Acetylcholine‐induced 42K+/86Rb+ efflux was unaffected by preincubation with glibenclamide (10 μm). In contrast, the 42K+/86Rb+ efflux induced by cromakalim was inhibited by glibenclamide (50 nm) by 50%.
Acetylcholine (0.3–10 μm)‐induced inhibition of phenylephrine (1 μm)‐induced tone was abolished by endothelial cell removal but unaffected by glibenclamide. Cromakalim‐induced relaxations were endothelium‐independent and were inhibited by glibenclamide in a concentration‐dependent manner.
lG‐monomethyl l‐arginine (l‐NMMA, 250 μm) produced a significant (37 ± 14%) inhibition of acetylcholine‐induced 86Rb+ efflux whereas DG‐monomethyl l‐arginine was without effect. In the tissue bath l‐NMMA inhibited relaxations produced by acetylcholine (0.3–10 μm), but was without effect on responses to cromakalim.
In the pig coronary artery, substance P induced an endothelium‐dependent efflux of 86Rb+ and 42K+, which was unaffected by preincubation with glibenclamide (10 μm) or l‐NMMA (250 μm).
The present study shows that acetylcholine and substance P each open K+‐channels in arterial smooth muscle. However, the insensitivity of the stimulated 86Rb+/42K+ efflux to inhibition by glibenclamide suggests that the K+‐channel opened by these agents is different from the K+‐channel opened by cromakalim. In addition, the inability of l‐NMMA to inhibit fully the acetylcholine‐ and substance P‐stimulated 86Rb+ efflux suggests that in rat aorta and pig coronary artery the endothelium‐derived hyperpolarizing factor(s) (EDHF) is different from endothelium‐derived relaxing factor (EDRF).
Heterogeneity of thromboxane A2 (TP‐) receptors: evidence from antagonist but not agonist potency measurements
Authors: Tymkewycz Paulina M. , Jones R.L. , Wilson N.H. , Marr C.G. 
Published: July 2012

Thromboxane A2 (TP‐) receptors in human, rat and rabbit platelets and in smooth muscle of guinea‐pig trachea, rat aorta and rabbit aorta have been characterized by measurement of the potencies of agonists and antagonists having considerable variations in chemical structure.
On each washed platelet system, eight prostanoids induced maximal irreversible aggregation (full agonists) and the potency ranking was EP 171 > STA2 > 9,11‐azo PGH2 > 9,11‐endoxy‐10a‐homo PGH2 > U‐46619 (standard) > PGH2 = 16‐p‐fluorophenoxy‐ω‐tetranor PGF2α > 16,16‐dimethyl PGF2α. Correlations between the three platelet preparations for both absolute and relative potencies were good. On human platelets, STA2, at concentrations above that required for maximum aggregation, exerted an inhibitory effect which was independent of its interaction with the TP‐receptor.
Five prostanoids, EP 109, EP 167, EP 204, PTA2 and 16,20‐methano PTA2, exhibited partial agonist activity on the platelet and smooth muscle preparations. There was good agreement between absolute potencies on the six preparations; on platelets potency was assessed from shape change measurements, since aggregation, when present, always showed a very shallow concentration‐response relationship. The magnitude of the maximum response induced by each compound decreased in the order listed above, to the extent that 16,20‐methano PTA2 could be treated as a pure antagonist.
With U‐46619 as agonist, the pA2 values of seven antagonists were found to be very similar on human and rat platelets. The potency ranking was EP 169 > AH 23848 > EP 092 > ONO 11120 > EP 115 = 16,20‐methano PTA2 > BM 13177. There was a similar trend on rabbit platelets but pA2 values were 1.0–1.5 log units smaller; the exception was BM 13177 which had similar affinities. The antagonism produced by EP 169 and AH 23848 was surmountable on rabbit platelets but not on human and rat platelets.
None of the antagonists was highly potent on the rabbit aorta (pA2 values < 7.5 by Schild analysis). Affinities on the guinea‐pig trachea and the rat aorta were higher and in the same range as those obtained for human and rat platelets. However the correlations of pA2 values between any pair of smooth muscle preparations and between any pair of platelet/smooth muscle preparations were either weak or not significant (P > 0.05).
The excellent agreement for both full and partial agonist potencies between the six preparations provides no evidence for TP‐receptor subtypes and further suggests that the agonist recognition sites of the TP‐receptors could be very similar, if not identical, in nature. In contrast, the different antagonist affinities found in this and other published studies indicate heterogeneity of TP‐receptors. However, classification into TP1‐, TP2‐receptors, etc. on the basis of the limited antagonist data available does not appear appropriate at this time.
Adenosine‐5′‐O‐(2‐thiodiphosphate) is a potent agonist at P2 purinoceptors mediating insulin secretion from perfused rat pancreas
Authors: Bertrand G. , Chapal J. , Puech R. , Loubatières‐Mariani M.M. 
Published: July 2012

The effects of a P2 purinoceptor agonist, adenosine 5′‐O‐(2‐thiodiphosphate) (ADP‐β‐S) have been studied on insulin secretion and flow rate of the isolated perfused pancreas of the rat.
In the presence of a moderately stimulating glucose concentration (8.3 mm), ADP‐/7‐S (4.95–495 nm) evoked a biphasic insulin response in a concentration‐dependent manner. A comparison of relative potency between ADP‐β‐S and adenosine 5′‐triphosphate (ATP) showed that ADP‐β‐S was 100 times more potent than ATP. On the other hand, in the presence of a non stimulatory glucose concentration (4.2 mm), ADP‐β‐S (165 nm) did not modify the basal insulin secretion.
ADP‐β‐S, at concentrations effective on insulin secretion and also at higher concentrations (1.65 and 16.5 μm), provoked an increase of the pancreatic flow rate in a concentration‐dependent manner.
Our results show that ADP‐β‐S is a potent insulin secretory P2 purinoceptor agonist. As it is resistant to hydrolysis it might be useful in studying the effect of activation of the P2 purinoceptor of β cells on insulin secretion in vivo.
The use of 4‐diphenylacetoxy‐N‐(2‐chloroethyl)‐piperidine (4‐DAMP mustard) for estimating the apparent affinities of some agonists acting at muscarinic receptors in guinea‐pig ileum
Authors: Barlow R.B. , McMillen Louise S. , Veale M.A. 
Published: July 2012

4‐Diphenylacetoxy‐N‐(2‐chloroethyl)‐piperidine (4‐DAMP mustard), which is known to block muscarinic M3 receptors in preference to muscarinic M2 receptors, was used to estimate the apparent affinity constants of some agonists acting at muscarinic receptors in guinea‐pig ileum. Estimates for carbachol and n‐pentyl‐trimethyl ammonium iodide were similar to published values obtained in similar conditions: those for n‐hexyl‐trimethyl ammonium iodide were slightly lower.
The results for the agonists, n‐pentyl‐ and n‐hexyl‐trimethyl ammonium iodides and for the partial agonist, n‐heptyl‐trimethyl ammonium iodide were not as regular as was suggested by Stephenson, though there is an overall increase in apparent affinity with chain length.
Estimates of apparent affinity may be affected by hexamethonium, usually present in experiments on ileum. Its absence had little effect on the results with carbachol but reduced the estimates obtained with n‐pentyl trimethyl ammonium, which has strong nicotinic effects compared with its muscarinic effects. On ileum treated with tetrodotoxin the values for n‐pentyl trimethyl ammonium were similar to those obtained in the presence of hexamethonium (0.28 mm): slightly higher estimates of affinity were obtained in the presence of indomethacin (2.8 μm). The nicotinic effects of n‐pentyl ammonium may involve the release of prostaglandins.
The estimates of apparent affinity did not depend on the method used to calculate them as the ‘null’ method and the ‘operational’ method give similar answers. Estimates of the transducer‐ratio for the partial agonist, n‐heptyl‐trimethyl ammonium iodide, were numerically the same as those of its efficacy.
This work illustrates the use of 4‐DAMP mustard as a tool for measuring the apparent affinity of agonists acting at muscarinic M3 receptors.
Comparison of the effects of several potassium‐channel openers on rat bladder and rat portal vein in vitro
Authors: Edwards G. , Henshaw M. , Miller M. , Weston A.H. 
Published: July 2012

The ability of several K‐channel openers to inhibit KCl‐induced contractions of rat bladder detrusor and spontaneous mechanical activity in rat portal vein was examined.
Lemakalim, pinacidil, Ro 31–6930, RP 49356, P1060 and S 0121 dose‐dependently relaxed rat detrusor, precontracted with 20 mm KCl. With the exception of pinacidil, concentrations of these agents below 30 μm did not inhibit 80 mm KCl‐included contractions. Pinacidil (10 μm) produced a small, but significant (P < 0.05) relaxation of 80 mm KCl‐induced mechanical activity. Minoxidil sulphate and BRL 38226 produced some relaxation of 20 mm but not 80 mm KCl‐induced contractions.
Glibenclamide (0.3–3 μm) antagonized the relaxant effects of lemakalim, pinacidil, Ro 31–6930, RP 49356, P1060 and S 0121 in a competitive manner (pA2 values 6.3–6.6). The effects of minoxidil sulphate and BRL 38226 were fully antagonized by 3 μm glibenclamide.
Lemakalim, pinacidil, S 0121, BRL 38226 and minoxidil sulphate were each approximately 8 times more potent as inhibitors of the spontaneous contractions of rat portal vein than KCl‐induced contractions of the rat detrusor. Minoxidil sulphate was approximately 30 times more potent in the rat portal vein than in the bladder. This may indicate that either minoxidil sulphate is acting at different recognition sites in these two tissues, or that this compound has an additional mechanism of action in the portal vein.
With the exception of minoxidil sulphate, all the compounds tested stimulated 86Rb efflux and 42K efflux from preloaded rat detrusor strips. The stimulated 86Rb efflux was qualitatively but not quantitatively similar to the stimulated 42K efflux. Minoxidil sulphate stimulated 42K efflux from rat portal vein but not from rat bladder.
It is concluded that all the compounds tested cause relaxation of rat detrusor predominantly by K‐channel opening. Selectivity for bladder rather than vascular smooth muscle was not shown by any compound.
Interference of BN 52021, an antagonist of PAF, with different forms of active anaphylaxis in the guinea‐pig: importance of the booster injection
Authors: Desquand Stéphanie , Lefort Jean , Dumarey Claude , Vargaftig B. Boris 
Published: July 2012

BN 52021, an antagonist of platelet activating factor (PAF), was inactive against bronchoconstriction in guinea‐pigs sensitized with low amounts of ovalbumin (OA) injected twice, at a 14 day interval and challenged i.v. 7 days later.
Serum IgG titers increased for 7 weeks after the booster injection at day 14 and returned to low levels at day 96.
Administered by the intratracheal (i.t.) route at 1 mg, BN 52021 failed to inhibit bronchoconstriction induced by the i.t. administration of OA to guinea‐pigs tested 7, 28, 56 and 84 days after the booster injection, even when the titers of circulating IgG had declined with time. BN 52021 was also inactive against bronchoconstriction in guinea‐pigs boosted at day 98 and tested 7 days later and against contractions and thromboxane (Tx) B2 and histamine release induced by OA‐challenged parenchymal lung strips from the boosted guinea‐pigs.
Sensitized unboosted guinea‐pigs displayed reduced IgG serum titers. Used 21 or 70 days after the sensitizing injection, they did develop bronchoconstriction upon the i.t. instillation of OA, which was blocked by BN 52021. The latter also inhibited OA‐induced contractions of lung parenchymal strips from these unboosted guinea‐pigs.
When boosted and non‐boosted guinea‐pigs received OA i.t. and bronchoalveolar lavage fluid was collected 10 min later, the number of eosinophils increased markedly in boosted, but not in non‐boosted guinea‐pigs.
The booster injection of antigen thus modifies the response of the lung and PAF appears to be relevant for antigen‐induced bronchoconstriction in unboosted animals, but loses its major role following the booster injection.
Effects of antagonists on quisqualate and nicotinic receptor‐mediated currents of midbrain neurones in culture
Authors: Bijak M. , Jarolimek W. , Misgeld U. 
Published: July 2012

The action of non‐N‐methyl‐d‐aspartate (non‐NMDA) and nicotinic antagonists on excitatory postsynaptic currents (e.p.s.cs) and on quisqualate (Quis)‐ and nicotine‐gated currents was studied by use of whole‐cell recording in dissociated culture of the rat midbrain.
6‐Cyano‐7‐nitroquinoxaline‐2,3‐dione (CNQX; 0.1 μm) and kynurenic acid (0.1 mm) attenuated network‐generated and miniature e.p.s.cs while mecamylamine (100 μm) and hexamethonium (400 μm) had no effect. Acetylcholine (ACh) enhanced or suppressed e.p.s.cs. The suppressing effect of ACh was blocked by atropine (0.1–10 μm).
ACh (50–1000 μm) and quisqualate (Quis, 0.1–20 μm) induced inward currents with the same reversal potential as e.p.s.cs.
Application of Quis and α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) in a low concentration (0.5 and 5 μm, respectively) evoked a maintained current which was attenuated by CNQX (1 μm) and kynurenic acid (0.5 mm) but not by mecamylamine (100 μm).
Higher concentrations of Quis (5–20 μm) and AMPA (50–100 μm) evoked a transient and a maintained current component. Kynurenic acid (1 mm) reduced the transient but not the maintained component. CNQX (5–10 μm) increased the maintained component without reducing the transient one; 20 μm CNQX reduced both components.
ACh‐induced transient current was mimicked by nicotine and reversibly and dose‐dependently blocked by mecamylamine. Atropine (10 μm), hexamethonium (400 μm) as well as CNQX (100 μm) and kynurenic acid (1 mm) did not affect the current.
Hexamethonium (50–400 μm) voltage‐dependently depressed the maintained current elicited by both Quis and ACh.
In conclusion, although the antagonists examined here seem to discriminate between non‐NMDA and nicotinic receptor‐mediated e.p.s.cs, they vary considerably in respect of their mode of action when tested on Quis, AMPA and ACh‐induced currents.
Peptide N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) activates capsaicin‐sensitive primary afferent nerves in guinea‐pig atria and urinary bladder
Authors: Giuliani Sandro , Santicioli Paolo , Tramontana Manuela , Geppetti Pierangelo , Maggi Carlo Alberto 
Published: July 2012

We have investigated the ability of the N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP) a synthetic analogue of a chemotactic peptide derived from a variety of bacteria, to activate capsaicin‐sensitive primary afferents in the guinea‐pig atria and urinary bladder.
In the isolated, electrically‐driven left atria from reserpine‐pretreated guinea‐pigs (atropine in the bath), FMLP (3 nm–1 μm) produced a biphasic positive inotropic response. The late component of this response was selectively abolished by in vitro capsaicin pretreatment while both the early and late responses were abolished by indomethacin.
The inotropic response to FMLP in the guinea‐pig atria was unaffected by ruthenium red. The late but not the early response was strongly inhibited or abolished by tetrodotoxin (TTX), ω‐conotoxin (CTX) or by the C‐terminal fragment (8–37) of human ω‐calcitonin gene‐related peptide (hCGRP). hCGRP‐(8–37) acts as competitive antagonist at CGRP receptors.
In the guinea‐pig isolated bladder, FMLP (10 nm–10 μm) produced a concentration‐dependent contraction which was unchanged by previous in vitro capsaicin, TTX or CTX pretreatment. The response to low concentrations of FMLP was suppressed by indomethacin, irrespective of the capsaicin pretreatment.
FMLP (10 μm) produced a significant increase in the outflow of CGRP‐like immunoreactivity (CGRP‐LI) from superfused guinea‐pig atria or urinary bladder. CGRP‐LI outflow induced by FMLP was blocked by indomethacin or in vitro capsaicin pretreatment.
These findings indicate that FMLP activates the ‘efferent’ function of capsaicin‐sensitive primary afferents via prostanoid generation. This action could provide a neurogenic contribution to the overall inflammatory response produced by bacteria‐derived peptides in inflamed tissues. In addition the present data indicate that endogenous prostanoids generated during exposure to FMLP produce peptide secretion from sensory nerves via a TTX‐ and CTX‐sensitive but ruthenium red‐resistant mechanism.
Morphine, but not sodium cromoglycate, modulates the release of substance P from capsaicin‐sensitive neurones in the rat trachea in vitro
Authors: Ray N.J. , Jones A.J. , Keen P. 
Published: July 2012

Opioids have been shown to inhibit substance P (SP) release from primary afferent neurones (PAN). In addition, opioid receptors have been identified on PAN of the vagus nerves. Sodium cromoglycate (SCG) decreases the excitability of C‐fibres in the lung of the dog in vivo. We have utilised a multi‐superfusion system to investigate the effect of opioids and SCG on the release of SP from the rat trachea in vitro.
Pretreatment of newborn rats with capsaicin (50 mg kg−1 s.c. at day 1 and 2 of life) resulted in a 93.2 ± 6.3% reduction in tracheal substance P‐like immunoreactivity (SP‐LI) content when determined by radioimmunoassay in the adult.
Exposure to isotonically elevated potassium concentrations (37–90 mm), capsaicin (100 nm–10 μm), and bradykinin (BK; 10 nm–1 μm) but not des‐Arg9‐BK (1 μm) stimulated SP‐LI release by a calcium‐dependent mechanism.
SCG (1 μm and 100 μm) did not affect spontaneous, potassium (60 mm)‐ or BK (1 μm)‐stimulated SP‐LI release.
Morphine (0.1–100 μm) caused dose‐related inhibition of potassium (60 mm)‐stimulated SP‐LI release with the greatest inhibition of 60.4 ± 13.7% at 100 μm. The effect of morphine was not mimicked by the κ‐opioid receptor agonist, U50,488H (10 μm) or the ω‐opioid receptor agonist, Tyr‐(d‐Pen)‐Gly‐Phe‐(d‐Pen) (DPDPE).
The effect of morphine was totally abolished by prior and concomitant exposure to naloxone (100 nm) which had no effect on control release values.
We conclude that opioid receptors, predominantly of the μ‐opioid receptor subtype, inhibit SP‐LI release from PAN in the rat trachea and suggest that centrally inactive μ‐opioid receptor agonists may have therapeutic potential in the treatment of asthma.