bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for reduction of bradykinin‐induced bronchoconstriction in guinea‐pigs by release of nitric oxide
Authors: Ricciardolo Fabio L.M. , Nadel Jay A. , Yoishihara Shigemi , Geppetti Pierangelo 
Published: July 2012

In this study the influence of nitric oxide (NO) on the bronchoconstriction induced by bradykinin in anaesthetized and artifically ventilated guinea‐pigs pretreated with atropine was investigated.
Aerosol administration of bradykinin (0.1 −1 mm, 40 breaths) caused a dose‐dependent increase in lung resistance (R1): maximum increase in R1 was 2.5 fold the baseline value. Pretreatment with aerosolized NG‐nitro‐1‐arginine methyl ester (1‐NAME) or NG‐monomethyl‐1‐arginine (1‐NMMA) (1 mm, 10 breaths every 5min for 30min), NO synthase inhibitors, markedly increased the bron‐choconstrictor response to bradykinin. 1‐Arginine, but not D‐arginine, (3 mm, 10 breaths every 5 min for 30 min) reversed the hyperresponsiveness to aerosolized bradykinin caused by 1‐NAME and 1‐NMMA.
1‐NAME (1 mm, 10 breaths every 5 min for 30 min) increased the bronchoconstriction induced by intravenous bradykinin (1‐10nmol kg1). 1‐Arginine, but not D‐arginine, (10 breaths every 5 min for 30 min) reversed the hyperresponsiveness to intravenous bradykinin caused by 1‐NAME.
The increase in RL induced by capsaicin, either aerosol (10 μm, 10 breaths) or i.v. (20 nmol kg−1) was not affected by 1‐NAME (1 mm, 10 breaths every 5 min for 30 min). Acute resection of the vagi did not affect the bronchoconstriction evoked by bradykinin in guinea‐pigs, either in the absence or presence of 1‐NAME (1 mm, 10 breaths every 5 min for 30 min).
These results suggest that, irrespective of the route of administration, bradykinin releases NO or a related molecule which exerts a bronchodilator action that opposes the bronchoconstrictor mechanisms activated by bradykinin itself.
The role of myoendothelial cell contact in non‐nitric oxide‐, non‐prostanoid‐mediated endothelium‐dependent relaxation of porcine coronary artery
Authors: Kühberger Elisabeth , Groschner Klaus , Kukovetz Walter R. , Brunner Friedrich 
Published: July 2012

Experiments were designed to analyse the requirement of myoendothelial junctions by bradykinin‐induced endothelium‐dependent relaxations resistant to NG‐nitro‐L‐arginine (L‐NOARG) and indo‐methacin in porcine coronary arteries.
Rings of porcine coronary arteries were contracted with the thromboxane receptor agonist, U46619 and relaxations to bradykinin recorded isometrically. All experiments were performed in the presence of indomethacin. Nitric oxide (NO)‐mediated effects were blocked by the NO synthase inhibitor L‐NOARG (250 μm) and myoendothelial contacts inhibited by treatment with hypertonic solution containing D‐mannitol or sucrose (each 180 μm) or the gap junctional uncoupling agent 1‐heptanol (2 μm). High [K+] solutions (40 μm) were used to probe a possible contribution of endothelium‐derived hyperpolarizing factor (EDHF).
In the presence of endothelium, bradykinin induced concentration‐dependent relaxations with a mean EC50 of 3.2 nm and a maximum response of 95 ± 1% of papaverine‐induced relaxation (control curve).
In the absence of endothelium, bradykinin failed to induce relaxations. Addition of cultured porcine aortic endothelial cells to the organ bath resulted in some relaxation and restored in part the relaxant effect of bradykinin. This endothelial cell‐mediated relaxant effect was completely abolished in the presence of 250 μm L‐NOARG.
Bradykinin‐induced relaxations in endothelium‐preserved rings were only slightly suppressed by L‐NOARG (86% of control). In vessels partially depolarized by high extracellular [K+] (40 μm) relaxation was reduced to 72% of control. In the presence of L‐NOARG, bradykinin failed to relax partially depolarized vessels.
In the presence of 2 mm 1‐heptanol, 180mM mannitol or 180mM sucrose maximum relaxation to bradykinin was reduced to ∼70%, i.e. to the same extent as in the presence of high [K+]. The remaining relaxation was sensitive to blockade by L‐NOARG.
Tissue cyclic GMP content which reflects NO activity, was increased about 4 fold by bradykinin (300 nm). This increase was unaffected by high [K+], heptanol or sucrose but blocked by L‐NOARG.
Our results suggest that non‐nitric oxide‐ and non‐prostanoid‐mediated endothelium‐dependent relaxation of porcine coronary artery requires functionally intact myoendothelial junctions.
Mechanism of the cardiovascular activity of laudanosine: comparison with papaverine and other benzylisoquinolines
Authors: Chuliá Susana , Ivorra M. Dolores , Lugnier Claire , Vila Elisabeth , Noguera M. Antonia , D'Ocon Pilar 
Published: July 2012

The activity of (±)‐laudanosine, a benzyltetrahydroisoquinoline alkaloid, was investigated in pithed rats and rat isolated aorta. Its effects on [3H]‐prazosin, [3H]‐(+)‐cis‐diltiazem and [3H]‐nitrendipine binding to rat cerebral cortical membranes, and on the different molecular forms of cyclic nucleotide phosphodiesterases (PDE) isolated from bovine aorta were investigated.
The dose‐response curve to methoxamine (3–300 μg kg−1, i.v.) in normotensive pithed rats was shifted to the right by (±)‐laudanosine, 3 and 6 mg kg−1.
(±)‐Laudanosine inhibited in a concentration‐dependent manner the contractile responses evoked by noradrenaline (NA 1 μm), depolarizing solution (KC1 80 μm) or depolarizing solution plus phentolamine (10 μm) in rat isolated aorta. The alkaloid appeared to be more potent against NA‐induced contractions.
In Ca2+‐free solution, (±)‐laudanosine (100 μm) inhibited the contraction evoked by NA and did not modify the phasic contractile response evoked by caffeine. The alkaloid did not modify the refilling of the intracellular Ca2+‐stores sensitive to NA or caffeine.
(±)‐Laudanosine inhibited [3H]‐prazosin binding to cortical membranes and also inhibited [3H]‐(+)‐cis‐diltiazem but with a lower potency. [3H]‐nitrendipine binding was not affected by laudanosine.
(±)‐Laudanosine does not have a significant effect on the different forms of PDEs isolated from bovine aorta. In contrast, compounds structurally related to this alkaloid such as papaverine and its derivatives, had a non‐selective or more specific inhibitory effect on these PDE forms. These differences can be explained on the basis of their structural features: the planarity of the isoquinoline ring (papaverine) facilitates the interaction with receptor sites, and the different position of the benzyl group does not modify the activity unless this position leads to the presence of a chiral centre (laudanosine).
These results suggest that (±)‐laudanosine has a selective activity as an α1‐adrenoceptor blocker. Its lack of action on different PDE forms provides us with information about a group of benzylisoquinolines that with small structural changes show a different effect on PDE‐forms isolated from vascular smooth muscle.
Differential sensitivity of 3H‐agonist binding to pre‐ and postsynaptic 5‐HT1A receptors in bovine brain
Authors: Iben Lawrence G. , Mahle Cathy D. , Yocca Frank D. 
Published: July 2012

The full and weak partial 5‐HT1A agonist ligands [3H]‐8‐OH‐DPAT and [3H]‐BMY‐7378 were used to characterize the binding parameters of pre‐ and postsynaptic 5‐HT1A binding sites in bovine dorsal raphe and hippocampal membranes, respectively. The Kd and Bmax values for the individual radioligands were indistinguisable across the regions tested, as were the Ki values generated by a series of agents acting at 5‐hydroxytryptamine (5‐HT) receptors.
The concentration‐dependent allosteric attenuation of [3H]‐8‐OH‐DPAT and [3H]‐BMY‐7378 binding produced by the nonhydrolyzable guanyl nucleotide, Gpp(NH)p, generated similar IC50 values within a particular region; however, these were significantly different between regions. While the maximal attenuation of [3H]‐8‐OH‐DPAT and [3H]‐BMY‐7378 binding was similar in dorsal raphe, Gpp(NH)p produced a significantly greater attenuation of [3H]‐8‐OH‐DPAT binding in hippocampal membranes when compared to [3H]‐BMY–7378. The maximal attentuation of [3H]‐8‐OH‐DPAT binding by Gpp(NHp) in hippocampus was also significantly greater than that seen with either radioligand in dorsal raphe.
Although exposure to Gpp(NH)p had no effect on the affinity constants of either radioligand in either region, it produced a concentration‐dependent reduction in the maximal number of binding sites for both radioligands in both regions. While the percentage reduction in Bmax values were similar for both radioligands in the dorsal raphe, Gpp(NH)p reduced the Bmax of [3H]‐8‐OH‐DPAT in hippocampus significantly more than that of [3H]‐BMY–7378.
These results suggest that while pre‐ and postsynaptic 5‐HT1A receptors may share similar pharmacological recognition properties, a region‐dependent difference in the coupling of the 5‐HT1A receptor to G‐proteins may exist.
Inhibition of nitric oxide synthesis in vascular smooth muscle by retinoids
Authors: Hirokawa K. , O'Shaughnessy K.M. , Ramrakha P. , Wilkins M.R. 
Published: July 2012

These studies examine the effect of retinoids on interleukin 1β (IL‐1β)‐induced nitric oxide synthase (NOS) activity in cultured rat aortic vascular smooth muscle (VSM) cells and isolated rat aortic rings.
All‐trans‐retinoic acid (all‐transM‐RA, 0.1–10 μm) and its active analogues produced concentration‐dependent inhibition of IL‐1β (0.1–10 ng ml−1)‐induced nitrite production in cultured VSM cells. In contrast, the inactive retinoid, Ro 14–6113 (0.1–10 μm), had no effect on IL‐1β‐induced nitrite production.
Since some of the actions of retinoids are mediated by induction of transforming growth factor beta (TGF‐β), its effect on inducible NOS activity in VSM cells was examined. TGF‐β produced concentration‐dependent (0.1–10 ng ml−1) inhibition of IL‐1β‐induced nitrite production and the maximum effect (approximately 90% inhibition) was significantly greater than that seen with all‐trans‐RA (approximately 70% with 10 μm). However, an anti‐TGF‐β antibody (50 μg ml−1) which blocked the effect of exogenous TGF‐β (5 ng ml−1) did not significantly reverse the inhibitory action of all‐trans‐RA (10 μm).
In addition to inhibiting IL‐1β‐induced nitrite production, all‐trans‐RA (10 μm) reduced substantially inducible NOS mRNA and protein levels in IL‐1β‐induced VSM cells (P < 0.01).
Incubation of isolated rat aortic rings with IL‐1 β (10 ng ml−1) caused a progressive resistance of the rings to the vasoconstrictor action of phenylephrine (10 nm to 10 μm). This effect was abolished by the addition of the nitric oxide synthase inhibitor L‐NG‐monomethyl‐L‐arginine (L‐NMMA, 1 μm). All‐trans‐RA (IO μm) also markedly and significantly reversed this IL‐1β‐induced vascular hyporeactivity (P < 0.01).
These data show that all‐trans‐RA and other active retinoids are able to block cytokine‐stimulated expression of inducible NOS in cultured VSM cells and isolated aortic rings.
Different endothelin receptors involved in endothelin‐1‐ and sarafotoxin S6B‐induced contractions of the human isolated coronary artery
Authors: Bax Willem A. , Aghai Zohara , VAN Tricht Corina L.J. , Wassenaar Claes , Saxena Pramod R. 
Published: July 2012

Endothelin receptors, that mediate contraction of the human isolated coronary artery, were characterized by use of a number of agonists and antagonists. Contraction induced by the non‐selective agonists, endothelin (ET)‐1 and sarafotoxin S6b, was compared in endothelium‐intact and endothelium‐denuded ring segments. The effects of ET‐1 and BQ‐123 (an ETA receptor antagonist) were investigated both in ring segments and in spirally cut strips. Lastly, the effect of phosphoramidon was studied on contraction induced by big‐ET‐1.
The order of agonist potency (pD2) in endothelium‐intact coronary artery ring segments was: ET‐1 (8.27) ≅sarafotoxin S6b (8.16)>big‐ET‐1 (<7.1)≅ET‐3 (<6.9). [Ala1,3,11,15]ET‐1 (ETB receptor agonist) caused significant contraction only at 1 μm, whereas 0.3 μm big‐ET‐3 had no effect. Removal of the endothelium in ring segments did not affect the contractile response to ET‐1 or to sarafotoxin S6b.
After a full concentration‐response curve had been obtained to ET‐1 or sarafotoxin S6b, further contractions of the endothelium‐intact coronary artery segments could only be achieved by applying ET‐1 in segments exposed to sarafotoxin S6b, and not the reverse.
BQ‐123 (0.1 μm) antagonized contractions of endothelium‐intact ring segments induced by sarafotoxin S6b (pKB 7.86). Only 10 μm BQ‐123 antagonized contractions induced by ET‐1 (pKB 5.75). FR139317 was also more potent against sarafotoxin S6b (pKB 8.24‐8.47) than against ET‐1 (pKB 6.11). [Ala1,3,11,15]ET‐1 (1 μm) had no effect on the contractile response to ET‐1 or to sarafotoxin S6b.
In strip preparations with intact endothelium, the pD2 of ET‐1 increased to 9.04 ± 0.16 (vs. 8.50 ± 0.07 in rings), and BQ‐123 (1 μm) caused a rightward shift of the ET‐1 induced concentration‐response curve (pKB 6.62 vs. 5.75 in rings).
Contractile responses to big‐ET‐1 of endothelium‐intact coronary artery segments were attenuated in the presence of phosphoramidon (100 μm), indicating conversion of big‐ET‐1 to ET‐1 within the coronary artery segment.
The present study indicates that ET‐1 and sarafotoxin S6b contract the human isolated coronary artery via different receptors, which can probably be best characterized as subtypes of the ETA receptor. Furthermore, it is demonstrated that the type of preparation (ring or strip) may affect the potency of ET‐1 as an agonist and of BQ‐123 as an antagonist.
Spinal cord SP release and hyperalgesia in monoarthritic rats: involvement of the GABAB receptor system
Authors: Malcangio Marzia , Bowery Norman G. 
Published: July 2012

Monoarthritis was induced in Lewis rats by interdermal injection in the left hind paw of a suspension of Mycobacterium tubercolusis in mineral oil (500 μg 100 μ1−1). Controls were injected with 100 μ1 mineral oil.
Withdrawal latencies to thermal stimuli of the inflamed paw, the contralateral and both paws of control rats were measured at daily intervals after injection by the plantar test.
After detection of the pain threshold, rat spinal cords were removed and horizontal dorsal slices were mounted in a 3‐compartment bath to measure electrically‐evoked release of substance P‐like immunoreactivity (SP‐LI).
The inflamed paw of monoarthritic rats exhibited a lower pain threshold to thermal stimuli than the contralateral paw of the same animals and both paws of control rats. Inflamed paw hyperalgesia was maximal two days after injection, and declined gradually between 7 to 21 days with no evidence of excitability of withdrawal reflexes after 28 days.
During the 28 days study, monoarthritic rats gained less weight than control rats.
Electrical stimulation of the dorsal roots attached to rat isolated spinal cord slices induced a significant increase (174 ± 18% of basal outflow which was 30.3 fmol 8 ml−1 n = 5) in SP‐LI release.
One‐week after induction of inflammation no differences in the amount of SP‐LI released from the spinal cord of incomplete Freund's adjuvant‐treated rats (IFA) and Freund's adjuvant‐treated rats (CFA) were detected. Two weeks after, CFA spinal cord tended to release more SP‐LI than IFA cords and, 21 days after injection, the spinal cord of CFA rats released significantly more peptide than IFA rats (17.8 ± 2.8 fmol ml−1, n = 12 and 6.9 ± 3.2 fmol ml−1, n = 9, respectively).
Twenty‐one days after treatment, the evoked release from monoarthritic rat spinal cords was increased by 263 ± 42% (n = 3) in the presence of the GABAB receptor antagonist, CGP 36742 (100 μm) which also significantly potentiated monoarthritis‐induced hyperalgesia up to 45min after injection (100mg kg−1, i.p.).
These findings may provide a basis for a novel approach to chronic pain therapy but also an explanation for the lack of analgesia produced by the GABAB agonist, baclofen, in chronic as compared to acute pain.
S14080, a peripheral analgesic acting by release of an endogenous circulating opioid‐like substance
Authors: Ferreira Sérgio H. , Lorenzetti Berenice B. , Devissaguet Michelle , Lesieur Daniel , Tsouderos Yannis 
Published: July 2012

The oral administration of a benzothiazolinone derivative (benzoyl‐6 dihydro‐2,3 benzothiazole), S14080, caused dose‐dependent antinociception in the rat paw pressure test, which represents a model of mechanical hyperalgesia. S14080 had no significant effect on the inflammatory oedema induced by carrageenin or on the tail flick test, nor did it possess a notable antipyretic effect.
Post‐treatment with S14080 dose‐dependently antagonized the hyperalgesia induced by prostaglandin E2, bradykinin, dopamine and by the hyperalgesic cytokines reported to be released by carrageenin (tumour necrosis factor α, interleukin‐1 and interleukin‐8).
The blockade of prostaglandin E2‐induced paw hyperalgesia by oral pretreatment of the rats with S14080 was abolished by prior intraplantar administration of either naloxone or NorBNI which are non‐specific and specific κ opioid antagonists, respectively.
Adrenalectomy abolished the oral antinociceptive effect of S14080.
Five consecutive daily injections of S14080 did not produce tolerance such as that seen with the central antinociceptive action of morphine.
As with peripherally acting opiates, the antinociceptive activity of S14080 was abolished by the intraplantar injection of agents which inhibit either arginine synthetase (NG‐monomethyl‐l‐arginine) or the activation of guanylate cyclase (methylene blue).
We conclude that S14080 is a new type of peripheral antinociceptive which, in rats, acts mainly by releasing an endogenous, opioid‐like substance from the adrenal glands.
Angiotensin‐converting enzyme (ACE) inhibitor transport in human intestinal epithelial (Caco‐2) cells
Authors: Thwaites David T. , Cavet Megan , Hirst Barry H. , Simmons Nicholas L. 
Published: July 2012

The role of proton‐linked solute transport in the absorption of the angiotensin‐converting enzyme (ACE) inhibitors captopril, enalapril maleate and lisinopril has been investigated in human intestinal epithelial (Caco‐2) cell monolayers.
In Caco‐2 cell monolayers the transepithelial apical‐to‐basal transport and intracellular accumulation (across the apical membrane) of the hydrolysis‐resistant dipeptide, glycylsarcosine (Gly‐Sar), were stimulated by acidification (pH 6.0) of the apical environment. In contrast, transport and intracellular accumulation of the angiotensin‐converting enzyme (ACE) inhibitor, lisinopril, were low (lower than the paracellular marker mannitol) and were not stimulated by apical acidification. Furthermore, [14C]‐lisinopril transport showed little reduction when excess unlabelled lisinopril (20 mm) was added.
pH‐dependent [14C]‐Gly‐Sar transport was inhibited by the orally‐active ACE inhibitors, enalapril maleate and captopril (both at 20 mm). Lisinopril (20 mm) had a relatively small inhibitory effect on [14C]‐Gly‐Sar transport. pH‐dependent [3H]‐proline transport was not inhibited by captopril, enalapril maleate or lisinopril.
Experiments with BCECF[2′,7′,‐bis(2‐carboxyethyl)‐5(6)‐carboxyfluorescein]‐loaded Caco‐2 cells demonstrate that dipeptide transport across the apical membrane is associated with proton flow into the cell. The dipeptide, carnosine (β‐alanyl‐l‐histidine) and the ACE inhibitors, enalapril maleate and captopril, all lowered intracellular pH when perfused at the apical surface of Caco‐2 cell monolayers. However, lisinopril was without effect.
The effects of enalapril maleate and captopril on [14C]‐Gly‐Sar transport and pHi suggest that these two ACE inhibitors share the H+‐coupled mechanism involved in dipeptide transport. The absence of pH‐dependent [14C]‐lisinopril transport, the relatively small inhibitory effect on [14C]‐Gly‐Sar transport, and the absence of lisinopril‐induced pHi changes, all suggest that lisinopril is a poor substrate for the di/tripeptide carrier in Caco‐2 cells. These observations are consistent with the greater oral availability and time‐dependent absorption profile of enalapril maleate and captopril, compared to lisinopril.
Sensitization by calyculin A of brain capillary endothelial cells to endothelin‐1
Authors: Vigne Paul , Breittmayer Jean Philippe , Frelin Christian 
Published: July 2012

Cultured brain capillary endothelial cells of the rat respond to endothelin‐1 (ET‐1) by an increased activity of the Na+,K+,2Cl−, cotransporter and a mobilization of intracellular Ca2+ stores.
Calyculin A (1–30 nm), but not okadaic acid, sensitizes up to 100 fold the Na+,K+,2Cl− cotransporter to the action of ET‐1.
Calyculin A (30 nm) does not modify the binding properties of ET‐1 to ETA receptors.
Calyculin A (30 nm) inhibits ET‐1 induced intracellular Ca2+ mobilization.
It is concluded that inhibition of protein phosphatase 1 selectively modifies the repertoire of intracellular actions of ET‐1 and favours actions that are unrelated to the phospholipase C signalling cascade.
Regulation of transepithelial ion transport by two different purinoceptors in the apical membrane of canine kidney (MDCK) cells
Authors: Zegarra‐Moran Olga , Romeo Giovanni , Galietta Luis J.V. 
Published: July 2012

The effect of extracellular nucleotides on the transepithelial ion transport of Madin Darby canine kidney cells (MDCK) was investigated. Cells were grown up to confluency on permeable supports and the short circuit current (Isc) was measured with an Ussing chamber‐like mini‐perfusion system.
Apical ATP stimulated a biphasic Isc increase consisting of a first rapid and transient peak followed by a broader one.
The first peak evoked by ATP was reversibly blocked by basilen blue (BB) in a concentration‐dependent fashion, with an EC50 of 7.5 μm.
The P2Y receptor agonist, 2‐methylthioATP (2‐MeSATP) caused a single transient Isc increase that was completely blocked by pretreatment with BB. On the contrary, the P2x agonist, α,β‐methylene ATP (α,β‐meATP) was almost completely ineffective on Isc. UTP essentially induced a monophasic response the time‐course of which resembled that of the second peak stimulated by ATP. The agonist potency order was 2‐MeSATP ≥ ATP >> UTP, α<β‐meATP for the first peak and UTP ≥ ATP > 2‐MeSATP > α,β‐meATP for the second peak.
Monolayer incubation with the membrane permeable calcium chelator [bis‐o‐aminophenoxy)‐ethane‐N,N,N′,N′,‐tetraacetic acid, tetra(acetoximethyl)‐ester] (BAPTA/AM) inhibited the ATP‐evoked first peak.
The non‐hydrolyzable ATP analogue, adenosine‐5′‐O‐(3‐thio)‐trisphosphate (ATP‐γ‐S) elicited a biphasic response similar to that of ATP. The P1 receptor agonist, 2‐chloroadenosine and CGS‐21680, were almost unable to induce an Isc increase. These results rule out the involvement of ATP hydrolysis and P1 receptor activation as responsible for Isc increase.
Inhibition of prostaglandins synthesis by indomethacin abolished the second ATP‐evoked peak.
Chloride replacement with gluconate on both sides of the epithelium completely inhibited the second peak induced by ATP but only reduced the amplitude of the first spike.
The results suggest that ATP stimulates Isc increase by two mechanisms. The first one is mediated by a P2Y receptor and by intracellular calcium increase. The second induces prostaglandin synthesis probably through a P2U receptor activation.