British Journal of Pharmacology
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The SK3/K<sub>Ca</sub>2.3 potassium channel is a new cellular target for edelfosine BACKGROUND AND PURPOSE The 1‐O‐octadecyl‐2‐O‐methyl‐sn‐glycero‐3‐phosphocholine (edelfosine) is an ether‐linked phospholipid with promising anti‐cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function.EXPERIMENTAL APPROACH Using cell migration‐proliferation assays, patch clamp, spectrofluorimetry and 125 I‐Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA‐MB‐435s cells, mediated by the small conductance Ca2+ ‐activated K+ channel, SK3/KCa 2.3.KEY RESULTS Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/KCa 2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit 125 I‐Apamin binding to this SKCa channel; rather, it reduced the calcium sensitivity of SK3/KCa 2.3 channel and dramatically decreased intracellular Ca2+ concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SKCa channel blockers. In contrast, K+ channel openers prevented edelfosine‐induced anti‐migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA‐MB‐435s cell migration. In contrast, transient expression of SK3/KCa 2.3 protein in a SK3/KCa 2.3‐deficient cell line increased cell migration and made these cells responsive to edelfosine.CONCLUSIONS AND IMPLICATIONS Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/KCa 2.3 channels and provide insights into the future development of a new class of migration‐targeted, anti‐cancer agents.
British Journal of Pharmacology - Tập 162 Số 2 - Trang 464-479 - 2011
New, long‐acting, potent bradykinin antagonists
Three new bradykinin (BK) antagonists, d ‐Arg0 ‐Hyp3 ‐Thi5 ‐d ‐Tic7 ‐Oic8 ‐BK (compound I), d ‐Arg0 ‐Hyp3 ‐d ‐Tic7 ‐Oic8 ‐BK (compound II), and Arg(Tos)1 ‐Hyp3 ‐Thi5 ‐d ‐Tic7 ‐Oic8 ‐BK (compound III), were tested against the effects of BK in 9 bioassay preparations including visceral smooth muscles, vasoconstriction, plasma protein extravasation, release of prostaglandin E2 , bronchoconstriction, and stimulation of afferent C‐fibre nociceptors. In some of these tests the effects of the new compounds were compared with those of the antagonist d ‐Arg0 ‐Hyp2 ‐Thi5,8 ‐d ‐Phe7 ‐BK (compound IV), described by Stewart & Vavrek (1987). For all bioassays the general rank order of potency of the compounds was found to be I > II > III ≫ IV. The new antagonists were long‐acting; in some bioassays their effects outlasted the duration of the experiment. The inhibitory effects of the new BK antagonists were specific for BK; actions of noradrenaline, angiotensin II, acetylcholine or histamine were unaffected by the antagonists. They did not stimulate the release of histamine or prostaglandins. An agonistic effect was observed only with very high concentrations of compounds I and II in the plasma protein extravasation test. The long duration of action of the new BK antagonists is probably due to a high and long‐lasting affinity to the BK receptors. A high resistance of the antagonists to enzymatic destruction may be another reason. The new BK antagonists will be valuable tools for the investigation of the pathophysiological role of BK. In addition they may offer a potential for therapeutic applications.
British Journal of Pharmacology - Tập 102 Số 2 - Trang 297-304 - 1991
LOCAL KALLIKREIN AND TRYPSIN RESPONSES IN THE RAT
Locally administered commercial hog pancreatic kallikrein (Depot‐Glumorin) and bovine pancreatic tyrpsin both increased vascular permeability in the skin and paws of rats. By the use of numerous antagonists and enzyme inhibitors, this vascular response was found to be the result not of kinin formation but of a direct action mostly on histamine receptors. Highly purified kallikrein did not increase vascular permeability in rats, suggesting either that the effect was due to an impurity in the commercial preparation or that a structural change in the enzyme occurred on purification. Soya bean trypsin inhibitor prevented the trypsin response when both were injected locally. On intraperitoneal injection, the inhibitor was effective only against local kallikrein. The kallikrein inhibitor, aprotinin (Trasylol), was not effective against local kallikrein but it reduced the trypsin response when both were injected locally.
British Journal of Pharmacology - Tập 69 Số 4 - Trang 625-629 - 1980
Inhibition by antihistamines of the vascular permeability increase induced by bradykinin
Mepyramine and triprolidine hydrochloride have a marked inhibitory effect on the local increase of vascular permeability induced by bradykinin. The anti‐bradykinin effect of both antihistamines was species dependent, being evident in rabbits, rats and mice but not in guinea‐pigs.
British Journal of Pharmacology - Tập 34 Số 2 - Trang 330-336 - 1968
Interactions between the tachykinins and calcitonin gene‐related peptide lead to the modulation of oedema formation and blood flow in rat skin
The mechanisms involved in tachykinin‐induced oedema were investigated in rat skin and interactions between the tachykinins and calcitonin gene‐related peptide (CGRP) were studied. Intradermal injections of the tachykinins, substance P, neurokinin A and neurokinin B, stimulated local oedema formation which was in each case potentiated by co‐injection of the vasodilator CGRP. Oedema induced by substance P, in the presence and absence of CGRP, was significantly inhibited by pretreatment of rats with a combination of the histamine H1 antagonist, mepyramine, and the 5‐hydroxytryptamine antagonist, methysergide. Oedema induced by neurokinin A or B was not inhibited by this pretreatment. Intradermally‐injected CGRP induced a long lasting increase in local blood flow, which was measured with a laser Doppler blood flow meter. The simultaneous injection of substance P, but not of the structurally‐related neurokinins, caused a loss of the prolonged vasodilator activity of CGRP. These results show that oedema induced by substance P is partially dependent on mast cell amines and that only substance P causes a loss of the prolonged vasodilator activity of CGRP. We suggest that the ability of substance P to prevent the persistent vasodilator activity of CGRP may be a direct consequence of substance P‐induced activation of mast cells.
British Journal of Pharmacology - Tập 97 Số 1 - Trang 77-82 - 1989
Hoe 140 a new potent and long acting bradykinin‐antagonist: <i>in vivo</i> studies
The potency, duration of action and tolerability of Hoe 140, a novel and highly potent bradykinin (BK) antagonist in vitro , has been tested in different in vivo models and compared with the well‐known BK antagonist d ‐Arg‐[Hyp2 , Thi5,8 , d ‐Phe7 ]BK. Hoe 140 is highly potent and long acting in inhibiting BK‐induced hypotensive responses in the rat. Four hours after s.c. administration of 20 nmol kg−1 , inhibition still amounted to 60% whereas the effect of 200 nmol kg−1 of d ‐Arg‐[Hyp2 , Thi5,8 , d ‐Phe7 ]BK was not significant. BK‐induced bronchoconstriction in guinea‐pigs was strongly inhibited by Hoe 140. The magnitude and duration of inhibition confirmed the findings obtained in the blood pressure experiments in the rat. Carrageenin‐induced inflammatory oedema of the rat paw was considerably inhibited at i.v. doses between 0.1 and 1 mg kg−1 . In conscious dogs, intravenous doses of 0.01 and 0.1 mg kg−1 of Hoe 140 and d ‐Arg‐[Hyp2 , Thi5,8 , d ‐Phe7 ]BK were well tolerated. At doses of 1 mg kg−1 adverse effects occurred that were attributed to the residual BK agonistic activity of both compounds. Hoe 140 has been shown to be a highly potent and long acting BK antagonist in vivo in different animal species and models. This makes it appropriate to investigate further the physiological and pathophysiological role of BK.
British Journal of Pharmacology - Tập 102 Số 3 - Trang 774-777 - 1991
Plasma protein extravasation induced by mammalian tachykinins in rat skin: influence of anaesthetic agents and an acetylcholine antagonist
The effect of mammalian tachykinins on plasma protein extravasation was assessed in the rat dorsal skin. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) increased vascular permeability in a dose‐related manner with a threshold dose of about 0.07 pmol in sodium pentobarbitone‐anaesthetized animals. Plasma protein extravasation induced by the tachykinins was 100–500 times less in magnitude in animals anaesthetized with urethane. Plasma protein extravasation induced by SP (66 pmol) was significantly reduced (63%; P < 0.001) by atropine (a muscarinic inhibitor) while that induced by NKA or NKB was unaffected by the inhibitor suggesting that a cholinergic component might only be involved in the vascular permeability elicited by SP. The rank order of potency for the tachykinins on plasma protein extravasation was: NKB > SP > NKA (in absence of atropine) and NKB > NKA > SP (in presence of atropine), suggesting that this vascular response is mediated by a SP‐E‐receptor type. The amplitudes of the plasma protein extravasation induced by NKB and its hydrophilic analogue [Arg° ]NKB were similar, indicating that the lipophilic features of the native peptide cannot account for its potent biological activity. Plasma protein extravasation was enhanced by the SP analogue [d ‐Pro4 , Lys6 , d ‐Trp7,9,10 , Phe11 ] SP (4–11), thus showing the limitation of such SP analogues (antagonists) for characterizing the tachykinin receptors involved in vascular permeability.
British Journal of Pharmacology - Tập 91 Số 2 - Trang 265-273 - 1987
Hoe 140 a new potent and long acting bradykinin‐antagonist: <i>in vitro</i> studies
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 × 10−9 mol l−1 and a K I 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 10−4 mol 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.
British Journal of Pharmacology - Tập 102 Số 3 - Trang 769-773 - 1991
Effects of the bradykinin antagonist B4310 on smooth muscles and blood pressure in the rat, and its enzymatic degradation
Six competitive bradykinin (Bk) antagonists were tested for their agonistic properties on the rat uterus. Five of these peptides showed agonistic effects only at concentrations at least two orders of magnitude higher than those of bradykinin. The antagonistic potency of Lys‐Lys‐3‐Hyp‐5,8‐Thi‐7‐DPhe‐Bk (B4310) in the rat uterus (pA2 = 7.24) and in the rat duodenum (pA2 = 7.31) was very similar to that determined in an earlier study for the antagonism of the bradykinin‐induced stimulation of the trigeminal nerve in the rabbit iris sphincter muscle preparation (pA2 = 7.59). The fall in mean arterial blood pressure induced by i.a. injections of bradykinin was greatly reduced during an i.a. infusion of B4310, but not 10 min thereafter, which indicates a rapid inactivation of B4310 in vivo . Bacitracin possibly interferes with the enzymatic cleavage of B4310 but seems to have no effect on the degradation of bradykinin. An i.a. infusion of captopril greatly enhanced the potency of bradykinin in inducing a fall in arterial blood pressure, confirming the important role of angiotensin converting enzyme in the cleavage of bradykinin. However, the design of this experiment did not allow conclusions about the effect of captopril on the degradation of B4310. B4310 incubated with rat lung tissue disappeared from the incubation medium within a few minutes, i.e. as fast as bradykinin, which explains its short duration of action in vivo . Captopril partially inhibited the cleavage of both bradykinin and B4310. The present results show that the bradykinin antagonists available at present are useful tools for the investigation of the biological role of bradykinin. However, the susceptibility to enzymatic degradation may limit their usefulness in animal experiments or in clinical studies.
British Journal of Pharmacology - Tập 96 Số 3 - Trang 531-538 - 1989
Effects of LY274614, a competitive NMDA receptor antagonist, on the micturition reflex in the urethane‐anaesthetized rat
The effects of 3 competitive N‐methyl‐d ‐aspartate (NMDA) receptor antagonists, LY274614, LY233536 and LY235723, on the micturition reflex and external urethral sphincter EMG activity, were examined either under isovolumetric conditions or during continuous filling cystometry in urethane‐anaesthetized (1.2 g kg−1 , s.c.) rats. Intravenous administration of LY274614 (3–30 mg kg−1 ) inhibited in a dose‐dependent fashion both bladder and sphincter activity in the intact rats. In addition, the volume threshold for inducing micturition was increased and voided volume was decreased. Intrathecal administration of LY274614 (0.06–30 μg) similarly inhibited bladder and sphincter activity during cystometry in intact rats. In chronic spinal cord (T6 −T8 ) transected rats LY274614 (0.1–30 mg kg−1 , i.v.) did not alter bladder activity under isovolumetric conditions but decreased the amplitude of micturition contractions and sphincter EMG activity during cystometry at a dose of 10–30 mg kg−1 . The inhibitory effects of i.v. administration of LY274614, on bladder and sphincter activity induced by infusion of chemical irritant (0.1 % acetic acid) or saline, were similar; except that a slightly larger dose was needed to inhibit sphincter activity during acetic acid infusion. Peak amplitude of micturition contractions recovered to 50% of control 3 h following i.v. (30 mg kg−1 ) or i.t. (6 μg) administration of LY274614. Two other chemically related NMDA antagonists, LY233536 and LY235723 produced similar but less potent effects than LY274614 when given i.v. These data indicate that glutamatergic transmitter mechanisms at the level of the spinal cord are important in modulating bladder activity in the intact animal, but that these mechanisms do not contribute to bladder reflexes in the chronic spinal rat. These mechanisms may, however, contribute to sphincter activity in both intact or chronic spinal rats.
British Journal of Pharmacology - Tập 110 Số 1 - Trang 77-86 - 1993
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