bluuebunny/crossref_metadata_2025_split huggingface dataset:
The mechanisms of enhancement and inhibition of field stimulation responses of guinea‐pig vas deferens by prostacyclin analogues
Authors: Tam Fiona S F , Chan Kam‐ming , Bourreau Jean‐Pierre , Jones Robert L 
Published: August 2006

In the guinea‐pig isolated vas deferens preparation bathed in Tyrode's solution, the prostacyclin analogues, cicaprost, TEI‐9063, iloprost, taprostene and benzodioxane‐prostacyclin, enhanced twitch responses to submaximal electrical field stimulation (20%‐EFS). The high potency of cicaprost (EC150=1.3 nM) and the relative potencies of the analogues (equi‐effective molar ratios=1.0, 0.85, 1.6, 17 and 82, respectively) suggest the involvement of a prostacyclin (IP‐) receptor.
Maximum enhancement induced by cicaprost in 2.5 mM K+ Krebs‐Henseleit solution was similar to that in Tyrode solution (2.7 mM K+), but was progressively reduced as the K+ concentration was increased to 3.9, 5.9 and 11.9 mM. There was also a greater tendency for the other prostacyclin analogues to inhibit EFS responses in 5.9 mM standard K+ Krebs‐Henseleit solution; this may be attributed to their agonist actions on presynaptic EP3‐receptors resulting in inhibition of transmitter release.
The EFS enhancing action of cicaprost was not affected by the α1‐adrenoceptor antagonist prazosin (100 and 1000 nM). Cicaprost (20 and 200 nM) did not affect contractile responses of the vas deferens to either ATP (5 μM) or α,β‐methylene ATP (1 μM) in the presence of tetrodotoxin (TTX, 100 nM). In addition, enhancement by cicaprost of responses to higher concentrations of ATP (30 and 300 μM) in the absence of TTX, as shown previously by others, was not seen. Prostaglandin E2 (PGE2, 10 nM) and another prostacyclin analogue TEI‐3356 (20 nM) enhanced purinoceptor agonist responses. Unexpectedly, TTX (0.1 and 1 μM) partially inhibited contractions elicited by 10–1000 μM ATP; contractions elicited by 1–3 μM ATP were unaffected. Further studies are required to establish whether a pre‐ or post‐synaptic mechanism is involved.
In a separate series of experiments, cicaprost (5–250 nM), TEI‐9063 (3–300 nM), 4‐aminopyridine (10–100 μM) and tetraethylammonium (100–1000 μM) enhanced both 20%‐EFS responses and the accompanying overflow of noradrenaline to a similar extent. In further experiments with the EP1‐receptor antagonist AH 6809, TEI‐3356 (1.0–100 nM) and the EP3‐receptor agonist, sulprostone (0.1–1.0 nM) inhibited both maximal EFS responses and noradrenaline overflow, thus confirming previous reports of the high activity of TEI‐3356 at the EP3‐receptor. Cicaprost had no significant effect on noradrenaline overflow at 10 and 100 nM, but produced a modest inhibition at 640 nM.
In conclusion, our studies show that prostacyclin analogues (particularly TEI‐3356) can inhibit EFS responses of the guinea‐pig vas deferens by acting as agonists at presynaptic EP3‐receptors. Prostacyclin analogues (particularly cicaprost and TEI‐9063) can also enhance EFS responses through activation of IP‐receptors. The mechanism of the enhancement has not been rigorously established but from our results we favour a presynaptic action to increase transmitter release.
ACE inhibitor potentiation of bradykinin‐induced venoconstriction
Authors: Hecker Markus , Blaukat Andree , Bara Agnieszka T , Müller‐Esterl Werner , Busse Rudi 
Published: August 2006

Angiotensin‐converting enzyme (ACE) inhibitors exert their cardiovascular effects not only by preventing the formation of angiotensin II (AII), but also by promoting the accumulation of bradykinin in or at the vessel wall. In addition, certain ACE inhibitors have been shown to augment the vasodilator response to bradykinin, presumably by an interaction at the level of the B2 receptor. We have investigated whether this is a specific effect of the ACE inhibitor class of compounds in isolated endothelium‐denuded segments of the rabbit jugular vein where bradykinin elicits a constrictor response which is exclusively mediated by activation of the B2 receptor.
Moexiprilat and ramiprilat ( 3 nM) enhanced the constrictor response to bradykinin three to four fold. Captopril and enalaprilat were less active by approximately one and quinaprilat by two orders of magnitude. Moexiprilat and ramiprilat, on the other hand, had no effect on the constrictor response to AII or the dilator response to acetylcholine.
The bradykinin‐potentiating effect of the ACE inhibitors was not mimicked by inhibitors of amino‐, carboxy‐, metallo‐ or serine peptidases or the synthetic ACE substrate, hippuryl‐L‐histidyl‐L‐leucine, at a concentration which almost abolished the residual ACE activity in the vessel wall. In contrast, angiotensin‐(1–7) (10 μM), an angiotensin I metabolite, significantly enhanced the constrictor response to bradykinin.
Ramiprilat did not alter the binding of [3H]‐bradykinin to a membrane fraction prepared from endothelium‐denuded rabbit jugular veins or to cultured fibroblasts, and there was no ACE inhibitor‐sensitive, bradykinin‐induced cleavage of the B2 receptor in cultured endothelial cells.
These findings demonstrate that ACE inhibitors selectively potentiate the B2 receptor‐mediated vascular effects of bradykinin. Their relative efficacy appears to be independent of their ACE‐inhibiting properties and might be related to differences in molecule structure. Moreover, the potentiation of the biological activity of bradykinin by this class of compounds does not seem to be mediated by a shift in affinity of the B2 receptor or a prevention of its desensitization, but may involve an increase in the intrinsic activity of unoccupied B2 receptor molecules.
Stellettamide‐A, a novel inhibitor of calmodulin, isolated from a marine sponge
Authors: Abe Yoshinori , Saito Shin‐ya , Hori Masatoshi , Ozaki Hiroshi , Fusetani Nobuhiro , Karaki Hideaki 
Published: August 2006

Stellettamide A (ST‐A), a novel marine toxin isolated from a marine sponge, inhibited high K+(72.7 mM)‐induced contraction in the smooth muscle of guinea‐pig taenia coli with an IC50 of 88 μM.
In the taenia permeabilized with Triton X‐100, ST‐A inhibited Ca2+ (3 and 10 μM)‐induced contractions with an IC50 of 46 μM for 3 μM Ca2+ and 105 μM for 10 μM Ca2+. In the permeabilized taenia, calyculin‐A (300 nM), a potent inhibitor of type‐1 and type‐2A phosphatases, induced sustained contraction in the absence of Ca2+. ST‐A had no effect on this contraction.
ST‐A inhibited Mg2+‐ATPase activity in native actomyosin prepared from chicken gizzard with an IC50 of 25 μM.
In a reconstituted smooth muscle contractile system containing calmodulin, myosin light chain (MLC) and MLC kinase, ST‐A inhibited MLC phosphorylation with an IC50 of 152 μM. The inhibitory effect of ST‐A was antagonized by increasing the concentration of calmodulin.
ST‐A inhibited calmodulin activity, assessed by Ca2+/calmodulin‐dependent enzymes, (Ca2+‐Mg2+)‐ATPase of erythrocyte membrane, with an IC50 of 100 μM and phosphodiesterase prepared from bovine cardiac muscle with an IC50 of 52 μM. The inhibitory effect on phosphodiesterase activity was antagonized by increasing the calmodulin concentration.
Interaction between ST‐A and calmodulin was demonstrated by instantaneous quenching of the intrinsic tyrosine fluorescence of calmodulin by ST‐A (3–300 μM). Similar results were obtained in the presence or absence of Ca2+ suggesting that ST‐A binds to calmodulin and that Ca2+ is not essential for the binding of ST‐A to calmodulin.
These results suggest that ST‐A, isolated from marine metabolites, is a novel inhibitor of calmodulin.
The involvement of tumour necrosis factor‐α in the protective effects of 17β oestradiol in splanchnic ischaemia‐reperfusion injury
Authors: Squadrito Francesco , Altavilla Domenica , Squadrito Giovanni , Campo Giuseppe M. , Arlotta Mariarita , Arcoraci Vincenzo , Minutoli Letteria , Saitta Antonino , Caputi Achille P. 
Published: August 2006

Tumour necrosis factor‐α (TNF‐α) is a cytokine that is implicated in the pathogenesis of ischaemic states and atherosclerosis. We tested the hypothesis that the vasoprotective effects of the oestrogens may be mediated in vivo by inhibition of the formation of TNF‐α.
Anaesthetized rats, subjected to total occlusion of the superior mesenteric artery and the coeliac trunk for 45 min developed a severe shock state resulting in a fatal outcome within 75–90 min after the release of occlusion. Sham‐operated animals were used as controls.
Splanchnic artery occlusion (SAO) shocked rats had a marked hypotension, enhanced levels of TNF‐α in serum and macrophages, leukopenia and increased ileal leukocyte accumulation, studied by means of myeloperoxidase activity (MPO). Furthermore, aortae from SAO rats showed a marked hyporeactivity to phenylephrine (PE, 1 nM–10 μM), reduced responsiveness to acetylcholine (ACh, 10 nM–10 μM) and an increased staining for intercellular adhesion molecule‐1 (ICAM‐1).
In vivo administration of 17β oestradiol (500 μg kg−1, i.m., three hours before the induction of SAO) increased survival rate (100%, 4 h after SAO), enhanced mean arterial blood pressure; reduced serum TNF‐α (25±5 u ml−1 vs 379±16 u ml−1), ameliorated leukopaenia and reduced ileal MPO (0.7±0.02 u 10−3 g−1 tissue vs 4.2±0.4 u 10−3 g−1 tissue). Furthermore aortae from SAO rats treated with 17β oestradiol exhibited a greater contractile response to phenylephrine, improved responsiveness to ACh and a blunted staining of ICAM‐1. Finally 17β oestradiol, added in vitro to peritoneal macrophages collected from untreated SAO rats, significantly reduced TNF‐α production.
Our results suggest that inhibition of TNF‐αin vivo may explain, at least in part, the vasoprotective effects of oestrogens.

British Journal of Pharmacology (1997) 121, 1782–1788; doi:10.1038/sj.bjp.0701288
Effects of Ca2+ channel blocker neurotoxins on transmitter release and presynaptic currents at the mouse neuromuscular junction
Authors: Katz Eleonora , Protti Darío A. , Ferro Pablo A. , Rosato Siri Marcelo D. , Uchitel Osvaldo D. 
Published: August 2006

The effects of the voltage‐dependent calcium channel (VDCC) blockers ω‐agatoxin IVA (ω‐AgaIVA), ω‐conotoxin GVIA (ω‐CgTx), ω‐conotoxin MVIIC (ω‐MVIIC) and ω‐conotoxin MVIID (ω‐MVIID) were evaluated on transmitter release in the mouse diaphragm preparation. The effects of ω‐AgaIVA and ω‐MVIIC were also evaluated on the perineurial calcium and calcium‐dependent potassium currents, ICa and IK(Ca), respectively, in the mouse levator auris preparation.
The P‐ and Q‐type VDCC blocker ω‐AgaIVA (100 nM) and P‐ Q‐ and N‐type channel blockers ω‐MVIIC (1 μM) and ω‐MVIID (3 μM) strongly reduced transmitter release (>80–90% blockade) whereas the selective N‐type channel blocker ω‐CgTx (5 μM) was ineffective.
The process of release was much more sensitive to ω‐MVIIC (IC50=39 nM) than to ω‐MVIID (IC50=1.4 μM). After almost completely blocking transmitter release (quantal content ∼0.3% of its control value) with 3 μMω‐MVIIC, elevating the external [Ca2+] from 2 to 10 mM induced an increase of ∼20 fold on the quantal content of the endplate potential (e.p.p.) (from 0.2±0.04 to 4.8±1.4).
Nerve‐evoked transmitter release in a low Ca2+‐high Mg2+ medium (low release probability, quantal content = 2±0.1) had the same sensitivity to ω‐AgaIVA (IC50=16.8 nM) as that in normal saline solutions. In addition, K+‐evoked transmitter release was also highly sensitive to the action of this toxin (IC50=11.5 nM; 100 nM >95% blockade). The action of ω‐AgaIVA on transmitter release could be reversed by toxin washout if the experiments were carried out at 31–33°C. Conversely, the effect of ω‐AgaIVA persisted even after two hours of toxin washout at room temperature.
Both the calcium and calcium‐dependent potassium presynaptic currents, ICa and IK(Ca), respectively, were highly sensitive to low concentrations (10–30 nM) of ω‐AgaIVA. The ICa and the IK(Ca) were also strongly reduced by 1 μMω‐MVIIC. The most marked difference between the action of these two toxins was the long incubation times required to achieve maximal effects with ω‐MVIIC.
In summary these results provide more evidence that synaptic transmission at the mammalian neuromuscular junction is mediated by Ca2+ entry through P‐ and/or Q‐type calcium channels.

British Journal of Pharmacology (1997) 121, 1531–1540; doi:10.1038/sj.bjp.0701290
Influence of AMPA/kainate receptors on extracellular 5‐hydroxytryptamine in rat midbrain raphe and forebrain
Authors: Tao Rui , Ma Zhiyuan , Auerbach Sidney B. 
Published: August 2006

The regulation of 5‐hydroxytryptamine (5‐HT) release by excitatory amino acid (EAA) receptors was examined by use of microdialysis in the CNS of freely behaving rats. Extracellular 5‐HT was measured in the dorsal raphe nucleus (DRN), median raphe nucleus (MRN), nucleus accumbens, hypothalamus, frontal cortex, dorsal and ventral hippocampus.
Local infusion of kainate produced increases in extracellular 5‐HT in the DRN and MRN. Kainate infusion into forebrain sites had a less potent effect.
In further studies of the DRN and nucleus accumbens, kainate‐induced increases in extracellular 5‐HT were blocked by the EAA receptor antagonists, kynurenate and 6,7‐dinitroquinoxaline‐2,3‐dione (DNQX).
The effect of infusing kainate into the DRN or nucleus accumbens was attenuated or abolished by tetrodotoxin (TTX), suggesting that the increase in extracellular 5‐HT is dependent on 5‐HT neuronal activity. In contrast, ibotenate‐induced lesion of intrinsic neurones did not attenuate the effect of infusing kainate into the nucleus accumbens. Thus, the effect of kainate in the nucleus accumbens does not depend on intrinsic neurones.
Infusion of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolaproprionate (AMPA) into the DRN and nucleus accumbens induced nonsignificant changes in extracellular 5‐HT. Cyclothiazide and diazoxide, which attenuate receptor desensitization, greatly enhanced the effect of AMPA on 5‐HT in the DRN, but not in the nucleus accumbens.
In conclusion, AMPA/kainate receptors regulate 5‐HT in the raphe and in forebrain sites.

British Journal of Pharmacology (1997) 121, 1707–1715; doi:10.1038/sj.bjp.0701292
Characterization of the Ca2+ responses evoked by ATP and other nucleotides in mammalian brain astrocytes
Authors: Centemeri Carlo , Bolego Chiara , Abbracchio Maria P. , Cattabeni Flaminio , Puglisi Lina , Burnstock Geoffrey , Nicosia Simonetta 
Published: August 2006

This study was aimed at characterizing ATP‐induced rises in cytosolic free calcium ion, [Ca2+]i, in a population of rat striatal astrocytes loaded with the fluorescent Ca2+ probe Fura2, by means of fluorescence spectrometry.
ATP triggered a fast and transient elevation of [Ca2+]i in a concentration‐dependent manner. The responses of the purine analogues 2‐methylthio‐ATP (2‐meSATP), adenosine‐5′‐O‐(2‐thiodiphosphate) (ADPβS), as well as uridine‐5′‐triphosphate (UTP) resembled that of ATP, while α,β‐methylene‐ATP (α,β‐meATP) and β,γ‐methylene‐ATP (β,γ‐meATP) were totally ineffective.
Suramin (50 μM) had only a minor effect on the ATP response, whereas pyridoxal phosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) (5 μM) significantly depressed the maximum response.
Extracellular Ca2+ did not contribute to the observed [Ca2+]i rise: removing calcium from the extracellular medium (with 1 mM EGTA) or blocking its influx by means of either Ni2+ (1 mM) or Mn2+ (1 mM) did not modify the nucleotide responses.
Furthermore, after preincubation with 10 μM thapsigargin, the nucleotide‐evoked [Ca2+]i increments were completely abolished. In contrast, 10 mM caffeine did not affect the responses, suggesting that thapsigargin‐, but not caffeine/ryanodine‐sensitive stores are involved.
Both application of the G‐protein blocker guanosine‐5′‐O‐(2‐thiodiphosphate) (GDPβS) (1 mM) and preincubation with pertussis toxin (PTx) (350 ng ml−1) partially inhibited the nucleotide‐mediated responses. Moreover, the phospholipase C (PLC) inhibitor U‐73122, but not its inactive stereoisomer U‐73343 (5 μM), significantly reduced the ATP‐evoked [Ca2+]i rise.
In conclusion, our results suggest that, in rat striatal astrocytes, ATP‐elicited elevation of [Ca2+]i is due solely to release from intracellular stores and is mediated by a G‐protein‐linked P2Y receptor, partially sensitive to PTx and coupled to PLC.

British Journal of Pharmacology (1997) 121, 1700–1706; doi:10.1038/sj.bjp.0701293
Characterization of the signalling pathways involved in ATP and basic fibroblast growth factor‐induced astrogliosis
Authors: Bolego Chiara , Ceruti Stefania , Brambilla Roberta , Puglisi Lina , Cattabeni Flaminio , Burnstock Geoffrey , Abbracchio Maria P. 
Published: August 2006

A brief challenge of rat astrocytes with either α,β‐methyleneATP (α,β‐meATP) or basic fibroblast growth factor (bFGF) resulted, three days later, in morphological differentiation of cells, as shown by marked elongation of astrocytic processes. The P2 receptor antagonist suramin prevented α,β‐meATP‐ but not bFGF‐induced astrocytic elongation. Similar effects on astrocytic elongation were also observed with ATP and other P2 receptor agonists (β,γmeATP, ADPβS, 2meSATP and, to a lesser extent, UTP).
Pertussis toxin completely abolished α,β‐meATP‐ but not bFGF‐induced effects. No effects were exerted by α,β‐meATP on cyclic AMP production; similarly, neomycin had no effects on elongation of processes induced by the purine analogue, suggesting that adenylyl cyclase and phospholipase C are probably not involved in α,β‐meATP‐induced effects (see also the accompanying paper by Centemeri et al., 1997). The tyrosine‐kinase inhibitor genistein greatly reduced bFGF‐ but not α,β‐meATP‐induced astrocytic elongation.
Challenge of cultures with α,β‐meATP rapidly and concentration‐dependently increased [3H]‐arachidonic acid (AA) release from cells, suggesting that activation of phospholipase A2 (PLA2) may be involved in the long‐term functional effects evoked by purine analogues. Consistently, exogenously added AA markedly elongated astrocytic processes. Moreover, various PLA2 inhibitors (e.g. mepacrine and dexamethasone) prevented both the early α,β‐meATP‐induced [3H]‐AA release and/or the associated long‐term morphological changes, without affecting the astrocytic elongation induced by bFGF. Finally, the protein kinase C (PKC) inhibitor H7 fully abolished α,β‐meATP‐ but not bFGF‐induced effects.
Both α,β‐meATP and bFGF rapidly and transiently induced the nuclear accumulation of Fos and Jun. Both c‐fos and c‐jun induction by the purine analogue could be fully prevented by pretreatment with suramin. In contrast, the effects of bFGF were unaffected by this P2 receptor antagonist.
It was concluded that α,β‐meATP‐ and bFGF‐morphological differentiation of astrocytes occurs via independent transductional pathways. For the purine analogue, signalling involves a Gi/Go protein‐coupled P2Y‐receptor which may be linked to activation of PLA2 (involvement of an arachidonate‐sensitive PKC is speculated); for bFGF, a tyrosine kinase receptor is involved. Both pathways merge on some common intracellular target, as suggested by induction of primary response genes, which in turn may regulate late response genes mediating long‐term phenotypic changes of astroglial cells.
These findings implicate P2 receptors as novel targets for the pharmacological regulation of reactive astrogliosis, which has intriguing implications in nervous system diseases characterized by degenerative events.

British Journal of Pharmacology (1997) 121, 1692–1699; doi:10.1038/sj.bjp.0701294
Evidence that the substance P‐induced enhancement of pacemaking in lymphatics of the guinea‐pig mesentery occurs through endothelial release of thromboxane A2
Authors: Rayner Sharyn E. , Van Helden Dirk F. 
Published: August 2006

In vitro studies were performed to examine the mechanisms underlying substance P‐induced enhancement of constriction rate in guinea‐pig mesenteric lymphatic vessels.
Substance P caused an endothelium‐dependent increase in lymphatic constriction frequency which was first significant at a concentration of 1 nM (115±3% of control, n=11) with 1 μM, the highest concentration tested, increasing the rate to 153±4% of control (n=9).
Repetitive 5 min applications of substance P (1 μM) caused tachyphylaxis with tissue responsiveness tending to decrease (by an average of 23%) and significantly decreasing (by 72%) for application at intervals of 30 and 10 min, respectively.
The competitive antagonist of tachykinin receptors, spantide (5 μM) and the specific NK1 receptor antagonist, WIN51708 (10 μM) both prevented the enhancement of constriction rate induced by 1 μM substance P.
Endothelial cells loaded with the Ca2+ sensing fluophore, fluo 3/AM did not display a detectable change in [Ca2+]i upon application of 1 μM substance P.
Inhibition of nitric oxide synthase by NG nitro‐L‐arginine (L‐NOARG; 100 μM) had no significant effect on the response induced by 1 μM substance P.
The enhancement of constriction rate induced by 1 μM substance P was prevented by the cyclo‐oxygenase inhibitor, indomethacin (3 μM), the thromboxane A2 synthase inhibitor, imidazole (50 μM), and the thromboxane A2 receptor antagonist, SQ29548 (0.3 μM).
The stable analogue of thromboxane A2, U46619 (0.1 μM) significantly increased the constriction rate of lymphangions with or without endothelium, an effect which was prevented by SQ29548 (0.3 μM).
Treatment with pertussis toxin (PTx; 100 ng ml−1) completely abolished the response to 1 μM substance P without inhibiting either the perfusion‐induced constriction or the U46619‐induced enhancement of constriction rate.
Application of the phospholipase A2 inhibitor, antiflammin‐1 (1 nM) prevented the enhancement of lymphatic pumping induced by substance P (1 μM), without inhibiting the response to either U46619 (0.1 μM) or acetylcholine (10 μM).
The data support the hypothesis that the substance P‐induced increase in pumping rate is mediated via the endothelium through NK1 receptors coupled by a PTx sensitive G‐protein to phospholipase A2 and resulting in generation of the arachidonic acid metabolite, thromboxane A2, this serving as the diffusible activator.

British Journal of Pharmacology (1997) 121, 1589–1596; doi:10.1038/sj.bjp.0701306
Hypoglycaemic effects of the novel antidiabetic agent repaglinide in rats and dogs
Authors: Mark Michael , Grell Wolfgang 
Published: August 2006

Repaglinide, a novel compound with a nonsulphonylurea structure, is currently being clinically tested as a therapeutic agent. In the present study, the hypoglycaemic effects of repaglinide in rats and dogs were investigated.
Whereas the R‐enantiomer, AG‐EE 624 ZW, showed only weak hypoglycaemic activity, the S‐enantiomer, repaglinide, turned out to be a potent hypoglycaemic compound in rats after oral as well as after intravenous administration. Only 50% of the dose of repaglinide was needed to be equieffective with the racemic mixture AG‐EE 388 ZW. The corresponding ED50 values calculated for the effects after 120 min p.a. (intravenous administration) were 3.4 μg kg−1 (repaglinide) and 6 μg kg−1 (AG‐EE 388 ZW).
When compared to glimepiride or glibenclamide, repaglinide displayed a 18 to 25 times higher potency in fasted rats. The ED50 values calculated for the effects after 120 min p.a. (oral administration) were 10 μg kg−1 (repaglinide), 182 μg kg−1 (glimepiride) and 255 μg kg−1 (glibenclamide).
In glucose loaded rats (0.5, 1.0, 2.0 and 3.0 g kg−1 glucose, p.o.) repaglinide exerted a very strong antihyperglycaemic activity which was even more pronounced than under normoglycaemic conditions. So for a reduction in blood glucose of 1 mmol l−1, 10.3, 9.3, 7.0 8.4 and 7.2 μg kg−1 repaglinide were needed after glucose loads of 0.0, 0.5, 1.0, 2.0 and 3.0 g kg−1, respectively.
In beagle dogs repaglinide again showed a pronounced hypoglycaemic effect (ED50 28.3 μg kg−1) which lasted for up to 24 h. However, insulin levels were only transiently increased.
The in vivo data presented are well supported by recently published in vitro findings. From its activity profile, repaglinide appears to be a promising new therapeutic agent.

British Journal of Pharmacology (1997) 121, 1597–1604; doi:10.1038/sj.bjp.0701307