bluuebunny/crossref_metadata_2025_split huggingface dataset:
Different cardiovascular profiles of three melanocortins in conscious rats; evidence for antagonism between γ2‐MSH and ACTH‐(1–24)
Authors: Van Bergen Patricia , Kleijne Jeroen A. , De Wildt Dick J. , Versteeg Dirk H. G. 
Published: August 2006

We investigated the effects of [Nle4,d‐Phe7]α‐melanocyte‐stimulating hormone (NDP‐MSH), adrenocorticotropin‐(124) (ACTH‐(124)) and γ2‐MSH, three melanocortins with different agonist selectivity for the five cloned melanocortin receptors, on blood pressure and heart rate in conscious, freely moving rats following intravenous administration.
As was previously found by other investigators as well as by us, γ2‐MSH, a peptide suggested to be an agonist with selectivity for the melanocortin MC3 receptor, caused a dose‐dependent, short lasting pressor response in combination with a tachycardia. Despite the fact that NDP‐MSH is a potent agonist of various melanocortin receptor subtypes, among which the melanocortin MC3 receptor, it did not affect blood pressure or heart rate, when administered i.v. in doses of up to 1000 nmol kg−1.
ACTH‐(124) caused a dose‐dependent decrease in blood pressure in combination with a dose‐dependent increase in heart rate in a dose‐range from 15 to 500 nmol kg−1. The cardiovascular effects of ACTH‐(124) were independent of the presence of the adrenals.
Pretreatment with ACTH‐(124) caused a pronounced, dose‐dependent parallel shift to the right of the dose‐response curve for the pressor and tachycardiac effects of γ2‐MSH. The antagonistic effect of ACTH‐(124) was already apparent following a dose of this peptide as low as 10 nmol kg−1, which when given alone had no intrinsic hypotensive activity.
These results form further support for the notion that it is not via activation of one of the as yet cloned melanocortin receptors that γ‐MSH‐like peptides increase blood pressure and heart rate. The cardiovascular effects of ACTH‐(124) seem not to be mediated by the adrenal melanocortin MC2 receptors, for which ACTH‐(124) is a selective agonist, or by adrenal catecholamines.
There appears to be a functional antagonism between ACTH‐(124) and γ2‐MSH, two melanocortins derived from a common precursor, with respect to their effect on blood pressure and heart rate. Whether this antagonism plays a (patho)physiological role remains to be shown.

British Journal of Pharmacology (1997) 120, 1561–1567; doi:10.1038/sj.bjp.0701065
Effects of σ ligands on the nociceptin/orphanin FQ receptor co‐expressed with the G‐protein‐activated K+ channel in Xenopus oocytes
Authors: Kobayashi Toru , Ikeda Kazutaka , Togashi Shunji , Itoh Noboru , Kumanishi Toshiro 
Published: August 2006

Taking advantage of the functional coupling of the nociceptin/orphanin FQ receptor with the G‐protein‐activated inwardly rectifying K+ (GIRK) channel, we investigated the effects of various σ ligands on the nociceptin/orphanin FQ receptor in Xenopus oocytes co‐injected with the cloned nociceptin/orphanin FQ receptor and GIRK1 mRNAs. Carbetapentane and rimcazole, which induced no current response at 100 μm, reversibly suppressed the inward K+ current responses induced by nociceptin in a concentration‐dependent manner, and the IC50 values (μm) for these compounds were 9.0 and 12.6, respectively. (±)‐N‐allylnormetazocine, (+)‐cyclazocine, (+)‐3‐(3‐hydroxyphenyl)‐N‐(1‐propyl)piperidine and 1,3‐di‐(2‐tolyl)guanidine, at 100 μm, had no effect on the receptor. These results suggest that carbetapentane and rimcazole act as antagonists at the nociceptin/orphanin FQ receptor and may be involved in pain regulation.British Journal of Pharmacology (1997) 120, 986–987; doi:10.1038/sj.bjp.0701068
Potentiation by nitric oxide of the ATP‐sensitive K+ current induced by K+ channel openers in guinea‐pig ventricular cells
Authors: Shinbo Atsushi , Iijima Toshihiko 
Published: August 2006

Modulation by nitric oxide (NO) of the ATP‐sensitive K+ channel (KATP) current (IK (ATP)) was investigated in single ventricular cells dissociated from guinea‐pig hearts. IK (ATP) was induced by 5‐amino‐N‐[2‐(2‐chlorophenyl)ethyl]‐N′‐cyano‐3‐pyridinecarboxamidine (KRN4884) and cromakalim.
In the whole‐cell patch clamp configuration, KRN4884 (0.13 μm) increased the outward current in a concentration‐dependent manner with an EC50 value of 0.48 μm. This current was completely antagonized by glibenclamide (1 μm).
IK (ATP) induced by either KRN4884 (0.3 μm) or cromakalim (10 μm) was significantly enhanced by the additional application of a NO donor (±)‐(E)‐ethyl‐2‐[(E)‐hydroxyimino]‐5‐nitro‐3‐hexeneamide (NOR3, 0.1 and 1 mm).
The potentiating effect was observed only when NOR3 solution was prepared just before experiments, when release of NO was considered to be on‐going. The effect was significantly eliminated in the presence of the NO scavenger oxyhaemoglobin (310 μm). Also, oxidative metabolites of NO, such as NO2− or NO3−, were without effect.
8‐Bromo‐guanosine‐3′ : 5′‐cyclic monophosphate (8‐Br‐cyclic GMP, 0.10.5 mm) significantly decreased IK (ATP) induced by KRN4884.
In cell‐attached patches, NOR3 (1 mm) potentiated the KRN4884‐induced IK (ATP) in a way similar to that seen in whole‐cell recordings. By contrast, NOR3 (1 mm) did not enhance the current in either inside‐out or outside‐out patches.
These results indicate that NO potentiates the action of K+ channel openers on the KATP through a mechanism which remains to be determined.

British Journal of Pharmacology (1997) 120, 1568–1574; doi:10.1038/sj.bjp.0701069
Dissociation of lipopolysaccharide‐mediated induction of nitric oxide synthase and inhibition of DNA synthesis in RAW 264.7 macrophages and rat aortic smooth muscle cells
Authors: Paul Andrew , Bryant Clare , Lawson Mark F. , Chilvers Edwin R. , Plevin Robin 
Published: August 2006

The active component of endotoxin, lipopolysaccharide (LPS), inhibited basal DNA synthesis in both RAW 264.7 macrophages (IC50 0.05±0.03 μg ml−1) and rat aortic smooth muscle cells (RASMC) (IC50 9.7±0.4 μg ml−1).
In both cell types, serum differentially affected LPS‐stimulated inhibition of DNA synthesis. In RAW 264.7 macrophages the presence of serum reduced the IC50 for LPS‐stimulated inhibition of DNA synthesis (1.4±0.85 ng ml−1). However, in RASMC serum stimulated DNA synthesis and further increased the IC50 value for LPS‐stimulated inhibition of thymidine incorporation (57.3±7.8 μg ml−1).
LPS also stimulated the induction of nitric oxide synthase (NOS) in RAW 264.7 macrophages with maximal expression at concentrations of 13 μg ml−1. This was wholly dependent upon the presence of serum. In RASMC LPS alone, up to concentrations of 100 μg ml−1, did not induce nitric oxide synthase and required co‐incubation with the direct activator of adenylyl cyclase, forskolin. Under these conditions stimulated expression of NOS was inhibited by the presence of serum.
Incubation with the nitric oxide synthase inhibitors Nω‐nitro‐l‐arginine methyl ester (l‐NAME) and l‐canavanine did not reverse the inhibition of [3H]‐thymidine incorporation in response to LPS but prevented the formation of nitrite in both cell types.
These results indicate that the effects of LPS upon cell growth are independent of the induction of the 130 kDa isoform of nitric oxide synthase and nitric oxide formation in both RAW 264.7 macrophages and RASMC.

British Journal of Pharmacology (1997) 120, 1439–1444; doi:10.1038/sj.bjp.0701070
Differential effects of ω‐conotoxin GVIA on cholinergic and non‐cholinergic secretomotor neurones in the guinea‐pig small intestine
Authors: Vremec Melinda A , Bornstein Joel C , Wright Christine E , Humphrey Andrea 
Published: August 2006

Ussing chambers were used to study the effects of the specific N‐type Ca2+ channel antagonist, ω‐conotoxin GVIA, on neurally evoked secretion across isolated submucosa/mucosa preparations from the small intestine of the guinea‐pig.
Cholinergic and non‐cholinergic neurones were stimulated with 10 μM dimethylphenylpiperazinium (DMPP). Non‐cholinergic secretomotor neurones were preferentially stimulated with 100 nM 5‐hydroxytryptamine (5‐HT), while cholinergic secretomotor neurones were preferentially stimulated with 3 μM 5‐HT in the presence of the 5‐HT2 receptor antagonist ketanserin (30 nM).
ω‐Conotoxin GVIA (1 nM–1 μM) depressed the secretion evoked by DMPP in a concentration‐dependent manner, but a substantial residual response was observed. Hyoscine (100 nM) significantly depressed secretion evoked by DMPP, but did not prevent further depression of secretion by ω‐conotoxin GVIA.
The toxin was substantially more effective when the non‐cholinergic secretomotor neurones were preferentially activated with 100 nM 5‐HT, with a decrease in the response of more than 75% of the control value in the presence of 1 μM ω‐conotoxin GVIA.
ω‐Conotoxin GVIA (1 μM) was relatively ineffective against secretion evoked by preferential activation of cholinergic secretomotor neurones with 3 μM 5‐HT in the presence of 30 nM ketanserin, inhibiting the response by less than 33%. However, this inhibition was significant. Both 100 nM hyoscine and 300 nM tetrodotoxin abolished this effect of ω‐conotoxin GVIA.
It is concluded that N‐type Ca2+ channels play a major role in transmitter release from non‐cholinergic secretomotor neurones, but are not important for release from cholinergic secretomotor neurones in the guinea‐pig small intestine.

British Journal of Pharmacology (1997) 121, 232–236; doi:10.1038/sj.bjp.0701071
Effects of KRN4884, a novel pyridinecarboxamidine type KATP channel opener, on serum triglyceride levels in rats
Authors: Yokoyama Takashi , Izumi Hideakira , Endoh Megumi , Izawa Toshio , Ogawa Nobuyuki , Okada Yuji 
Published: August 2006

The effects of KRN4884, a novel pyridinecarboxamidine type KATP channel opener, on serum triglyceride levels were investigated in Sprague‐Dawley rats.
Oral administration of KRN4884 (3 mg kg−1) for 10 days caused a significant reduction in serum triglyceride levels, which was comparable to that of clofibrate (160 mg kg−1). Reduction in serum triglyceride levels by KRN4884 and clofibrate were accompanied by a reduction in triglyceride levels both in chylomicron and in very low density lipoprotein. KRN4884 treatment did not affect serum concentrations of total cholesterol and phospholipid, but did increase free fatty acid levels. Clofibrate reduced total cholesterol, phospholipid and free fatty acid levels.
Administration of clofibrate significantly decreased triglyceride secretion rate as measured by the Triton WR‐1339 injection procedure, while KRN4884 did not.
Rats receiving KRN4884 exhibited an increase in lipoprotein lipase (LPL) activity both in adipose tissue and in skeletal muscle. There was an inverse correlation between serum triglyceride levels and tissue LPL activities. KRN4884 did not change hepatic triglyceride lipase (HTGL) activity. Clofibrate affected neither LPL nor HTGL activities.
It is concluded that administration of KRN4884 results in reduced serum triglyceride levels which may be due to the enhancement of LPL activity in peripheral tissues.

British Journal of Pharmacology (1997) 120, 1471–1476; doi:10.1038/sj.bjp.0701077
The isoquinoline derivative KN‐62 a potent antagonist of the P2Z‐receptor of human lymphocytes
Authors: Gargett Caroline E. , Wiley James S. 
Published: August 2006

Extracellular adenosine 5′‐triphosphate (ATP) is an agonist for a P2Z receptor on human lymphocytes which mediates opening of a cation‐selective ion channel, activation of phospholipase D and shedding of the adhesion molecule, L‐selectin, from the cell surface. The isoquinolinesulphonamides, KN‐62, (1‐[N, O‐bis(5‐isoquinolinesulphonyl)‐N‐methyl‐L‐tyrosyl]‐ 4‐phenylpiperazine), a selective antagonist of Ca2+/calmodulin‐dependent protein kinase II (CaMKII), and KN‐04, (N‐[1‐[N‐methyl‐p‐(5 isoquinoline sulphonyl)benzyl]‐2‐(4 phenylpiperazine)ethyl]‐5‐isoquinolinesulphonamide) an inactive analogue, were used to investigate the possible role of CaMKII in these diverse effects of extracellular ATP.
KN‐62 potently antagonized ATP‐stimulated Ba2+ influx into fura‐2 loaded human lymphocytes with an IC50 of 12.7±1.5 nm (n=3) and complete inhibition of the flux at a concentration of 500 nm. Similarly, KN‐62 inhibited ATP‐stimulated ethidium+ uptake, measured by time resolved flow cytometry, with an IC50 of 13.1±2.6 nm (n=4) and complete inhibition of the flux at 500 nm.
KN‐04 antagonized ATP‐stimulated Ba2+ influx with an IC50 of 17.3±2.7 nm (n=3). Similarly, KN‐04 inhibited ATP‐stimulated ethidium+ uptake with an IC50 of 37.2±8.9 nm (n=4). Both fluxes were completely inhibited at 500 nm KN‐04.
ATP‐stimulated phospholipase D activity, measured in [3H]‐oleic acid‐labelled lymphocytes by the transphosphatidylation reaction, was antagonized by KN‐62 and KN‐04, with 50% inhibition at 5.9±1.2 and 9.7±2.8 nm (n=3), respectively. Both KN‐62 and KN‐04 inhibited ATP‐stimulated shedding of L‐selectin, measured by flow cytometric analysis of cell surface L‐selectin, with IC50 values of 31.5±4.5 and 78.7±10.8 nm (n=3), respectively. Neither of the isoquinolinesulphonamides (500 nm) inhibited phorbol ester‐ or ionomycin‐stimulated phospholipase D activity or phorbol ester‐induced shedding of L‐selectin.
The inhibitory effect of KN‐62 or KN‐04 on P2Z‐mediated responses was slow in onset (5 min) and only partially reversed by washing the cells.
Both KN‐62 and KN‐04 (at 500 nm) had no effect on uridine 5′‐triphosphate (UTP)‐stimulated Ca2+ transients in fura‐2 loaded human neutrophils, a response which is mediated by the P2Y2 receptor.
Thus, KN‐62 and KN‐04 are potent antagonists of the P2Z receptor and at nanomolar concentrations inhibit all known responses mediated by the P2Z receptor of human lymphocytes. In contrast, KN‐62 and KN‐04 had no effect on responses mediated by the P2Y2 receptor of neutrophils. Moreover, since KN‐62 and KN‐04 are almost equipotent, the P2Z‐mediated responses do not involve CaMKII, but indicate that the isoquinolinesulphonamides are potent and direct inhibitors of the P2Z‐receptor.

British Journal of Pharmacology (1997) 120, 1483–1490; doi:10.1038/sj.bjp.0701081
Paradoxical action of the cannabinoid WIN 55,212‐2 in stimulated and basal cyclic AMP accumulation in rat globus pallidus slices
Authors: Maneuf Yannick P. , Brotchie Jonathan M. 
Published: August 2006

The effects of the synthetic cannabinoid WIN 55,212‐2 on forskolin‐stimulated and basal adenosine 3′ : 5′‐cyclic monophosphate (cyclic AMP) accumulation in globus pallidus slices were investigated. WIN 55,212‐2 caused a concentration‐dependent decrease in forskolin‐stimulated cyclic AMP accumulation in globus pallidus slices (maximum inhibition 36% for 30 μm). This effect was blocked by the cannabinoid receptor antagonist SR 141716A (100 μm). WIN 55,212‐2 alone caused a concentration‐dependent increase in cyclic AMP levels in unstimulated slices (maximum increase 52.6% for 100 μm). This effect was also blocked by SR 141716A (100 μm). In either forskolin‐stimulated or unstimulated conditions SR 1417161A (100 μm) did not affect cyclic AMP levels.British Journal of Pharmacology (1997) 120, 1397–1398; doi:10.1038/sj.bjp.0701101
The effect of okadaic acid on non‐adrenergic non‐cholinergic contraction in guinea‐pig isolated bronchus
Authors: Harrison S , Spina D , Page C P 
Published: August 2006

We have investigated the role of phosphatases in modulating contractile responses to electrical field stimulation (EFS), methacholine, substance P and capsaicin in guinea‐pig isolated main bronchus by use of the phosphatase 1 and 2A inhibitor okadaic acid.
Non‐adrenergic non‐cholinergic (eNANC) contractile responses were elicited by EFS (3 Hz, 20 s, 0.5 ms max. voltage) in the guinea‐pig isolated main bronchus in the presence of the non‐selective muscarinic antagonist, atropine (1 μM), the non‐selective β‐adrenoceptor antagonist, propranolol (1 μM), the neutral endopeptidase inhibitor thiorphan (10 μM) and the cyclo‐oxygenase inhibitor, indomethacin (5 μM). Okadaic acid significantly attenuated eNANC contractile responses (% inhibition) elicited by EFS (0.01 μM, 15.2±26.9%; 0.03 μM, 30.4±13.9%; 0.01 μM, 39.8±5.1%; 0.3 μM, 59.5±8.7%; 1 μM 77.8±7.8%; P<0.05, n=4). In contrast, the inactive analogue 1‐Nor okadaone (0.3 μM) failed to attenuate significantly eNANC contractile responses (% inhibition elicited by 1‐Nor okadaone, −1.25±8.5% vs dimethylsulphoxide (DMSO), −13.5±21.5%; P>0.05, n=4).
Cholinergic contractile responses were elicited by EFS (1–30 Hz, 10 s, 0.5 ms max. voltage) in guinea‐pig isolated bronchus in the presence of the nitric oxide synthase inhibitor, Nω‐nitro‐L‐arginine methyl ester (L‐NAME, 30 μM). Okadaic acid failed to attenuate significantly the contractile (% methacholine Emax) response elicited by EFS at all frequencies tested compared with the control (1 Hz, control, 22±7.9% vs okadaic acid, 18±7.7%; 3 Hz, control, 26±6.9% vs okadaic acid, 27±9.1%; 10 Hz, control, 36±7.6% vs okadaic acid, 33±8.9%; 30 Hz, control, 50±7.6% vs okadaic acid, 42±14%; P>0.05, n=4).
Okadaic acid (0.3 μM) failed to alter significantly the contractile potency (pD2) to capsaicin (okadaic acid, 9.0±0.5, vs DMSO, 9.2±0.4; P>0.05 n=6), substance P (okadaic acid, 7.6±0.3 vs DMSO, 8.2±0.2; P>0.05 n=7) or methacholine (okadaic acid, 6.4±0.2 vs DMSO, 6.4±0.3; P>0.05 n=4).
Okadaic acid (0.01–1 μM) did not appear to reverse substance P‐induced tone. The maximal relaxant response (% reversal of substance P‐induced tone) mediated by okadaic acid (1 μM) was 33±11.7% (n=4), this was not significantly different from the DMSO (0.8%) or a time‐dependent fall in tone of 34.3±23.1% (n=4) and 33±15.8% (n=4), respectively. Okadaic acid (0.3 μM) failed to augment isoprenaline‐induced relaxation repsonses in substance P contracted bronchus (okadaic acid, 6.5±0.4 vs DMSO, 5.9±0.3; P>0.05, n=9).
These results indicate that protein phosphatases appear to regulate the release of sensory neuropeptides from airway sensory nerves in response to electrical field stimulation.

British Journal of Pharmacology (1997) 121, 181–186; doi:10.1038/sj.bjp.0701114
KATP‐channel on the somata of spiny neurones in rat caudate nucleus: regulation by drugs and nucleotides
Authors: Schwanstecher Christina , Bassen Dagmar 
Published: August 2006

The aim of the present study was to characterize the pharmacological properties of the adenosine 5′‐triphosphate(ATP)‐sensitive K+ channel (KATP‐channel) on the somata of spiny neurones in rat caudate nucleus and to compare them with those of β‐cells. For that purpose we tested the effects of several KATP‐channel‐inhibiting and ‐activating drugs on the opening activity of the KATP‐channel in caudate nucleus by use of the patch‐clamp technique. In addition, the modulation of drug responses by cytosolic nucleotides was examined.
When KATP‐channels in caudate nucleus were activated in cell‐attached patches by inhibition of mitochondrial energy production, meglitinide (a benzoic acid derivative), Hoe36320 (a sulphonylurea of low lipophilicity) and glipizide reduced KATP‐channel activity half‐maximally at 0.4 μM, 0.4 μM and about 0.5 nM, respectively.
In inside‐out patches (presence of 0.7 mM free Mg2+ at the cytoplasmic membrane side), tolbutamide (0.1 mM) caused only partial inhibition of KATP‐channels in the absence of cytosolic nucleotides but complete inhibition in the simultaneous presence of the channel‐activating nucleotide guanosine 5′‐diphosphate (GDP; 1 mM) and the channel‐inhibiting nucleotide adenylyl‐imidodiphosphate (AMP‐PNP; 0.2 mM).
Diazoxide (0.3 mM) strongly increased channel activity in the presence of ATP (0.1 mM) or GDP (0.03 mM), but was ineffective in the presence of AMP‐PNP (0.1 mM). In the absence of cytosolic nucleotides diazoxide even decreased channel activity.
In the presence of 0.1 mM ATP, diazoxide activated KATP‐channels half‐maximally at 38 μM.
When KATP‐channel activity was inhibited by 0.1 mM ATP, (−)‐pinacidil (0.5 mM) elicited a slight activation of KATP‐channels in caudate nucleus, whereas (+)‐pinacidil (0.5 mM) and lemakalim (0.3 mM) were ineffective.
Since our data indicate similar control by drugs and nucleotides of KATP‐channels in the somata of spiny neurones and pancreatic β‐cells, we conclude that the high affinity sulphonylurea receptors of these tissues are probably closely related.

British Journal of Pharmacology (1997) 121, 193–198; doi:10.1038/sj.bjp.0701120
Antinociceptive and immunosuppressive effects of opiate drugs: a structure‐related activity study
Authors: Sacerdote Paola , Manfredi Barbara , Mantegazza Paolo , Panerai Alberto E. 
Published: August 2006

Although it is well known that morphine induces significant immunosuppression, the potential immunosuppressive activity of morphine derived drugs commonly used in the treatment of pain (codeine, hydromorphone, oxycodone) has never been evaluated.
We evaluated in the mouse the effect of the natural opiates (morphine and codeine) and synthetic derivatives (hydromorphone, oxycodone, nalorphine, naloxone and naltrexone) on antinociceptive thresholds and immune parameters (splenocyte proliferation, Natural Killer (NK) cell activity and interleukin‐2 (IL‐2) production).
Morphine displayed a potent immunosuppressive effect that was not dose‐related to the antinociceptive effect, codeine possessed a weak antinociceptive effect and limited immunosuppressive activity; nalorphine, a μ‐antagonist and κ‐agonist, exerted a potent immunosuppressive effect, but had very weak antinociceptive activity. The pure κ‐antagonist nor‐BNI antagonized the antinociceptive, but not the immunosuppresive effect of nalorphine.
Hydromorphone and oxycodone, potent antinociceptive drugs, were devoid of immunosuppressive effects.
The pure antagonists naloxone and naltrexone potentiated immune responses.
Our data indicate that the C6 carbonyl substitution, together with the presence of a C7‐8 single bond potentiates the antinociceptive effect, but abolishes immunosuppression (hydromorphone and oxycodone).
The single substitution of an allyl on the piperidinic ring resulted in a molecule that antagonized the antinociceptive effect but maintained the immunosuppressive effect.
Molecules that carry modifications of C6, the C7‐8 bond and C14, together with an allyl or caboxymethyl group on the piperidinic ring antagonized both the antinociceptive and the immunosuppressive effect of opiates and were themselves immunostimulants.

British Journal of Pharmacology (1997) 121, 834–840; doi:10.1038/sj.bjp.0701138