bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelium‐independent relaxation of aortic rings by the nitric oxide synthase inhibitor diphenyleneiodonium
Authors: Dodd‐o Jeffrey M , Zheng Gemin , Silverman Howard S , Lakatta Edward G , Ziegelstein Roy C 
Published: August 2006

The flavoprotein binder diphenyleneiodonium (DPI) is a potent, irreversible inhibitor of nitric oxide synthase (NOS), but produces only a transient pressor response following systemic administration to animals, despite evidence of persistent NOS inhibition. To characterize further the effects of DPI on vascular tone, isometric tension was recorded from rat isolated aortic rings mounted between steel wires in an organ bath.
The NOS inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME, 1 mm) initiated an additional contraction of prostaglandin F2α‐preconstricted rings with endothelium which was sustained throughout the period of l‐NAME exposure (+234±39% at 15 min). In contrast, addition of DPI (5 μm) to rings with endothelium produced a transient initial contraction (+111±27% at 2 min) followed by a more sustained relaxation (−27±19% at 15 min, P<0.001 vs l‐NAME).
The contraction to DPI was also observed in rings without endothelium, was abolished by l‐NAME pretreatment, and was unaffected by the α‐adrenoreceptor inhibitor prazosin. Relaxation in response to DPI was not inhibited by endothelium removal or by pretreatment with either l‐NAME or with the ATP‐sensitive potassium channel blocker glibenclamide.
The endothelium‐independent relaxation to DPI was inhibited at 23°C and its time course was delayed by pretreatment with the guanylate cyclase inhibitor methylene blue.
Thus, in addition to a transient initial contraction due to NOS inhibition, DPI produces an endothelium‐independent, temperature‐dependent relaxation which appears in part due to activation of guanylate cyclase. This relaxant effect of DPI may explain the transient nature of its pressor effect in vivo despite sustained NOS inhibition.

British Journal of Pharmacology (1997) 120, 857–864; doi:10.1038/sj.bjp.0701014
Effects of 1,25‐dihydroxyvitamin D3 and its 20‐epi analogues (MC 1288, MC 1301, KH 1060), on clonal keratinocyte growth: evidence for differentiation of keratinocyte stem cells and analysis of the modulatory effects of cytokines
Authors: Gniadecki Robert 
Published: August 2006

Keratinocytes are functionally divided into stem cells, transit amplifying cells and terminally differentiated cells. In a hyperproliferative skin disease, psoriasis, increased mitotic activity of the stem cells is chiefly responsible for epidermal hyperplasia. The effects of 1,25dihydroxyvitamin D3 (1,25(OH)2D3) and potent vitamin D3 analogues (MC 1288: 20‐epi‐1,25(OH)2D3, MC 1301: 20‐epi‐24a‐homo‐26,27‐dimethyl‐1,25(OH)2D3, KH 1060: 20‐epi‐22‐oxa‐24a‐homo‐26,27‐dimethyl‐1,25(OH)2D3) on the stem cells were investigated.
Stem cells were identified retrospectively as those giving rise to large keratinocyte colonies in culture (holoclones). 1,25(OH)2D3 (10−8–10−6 m) suppressed formation of holoclones by stimulating the progenitor cell differentiation into the phenotype expressing differentiation markers (keratins K1/K10 and involucrin).
20‐Epi vitamin D3 analogues were more potent than 1,25(OH)2D3 in inhibiting the clonal keratinocyte growth. This activity correlated with the ability to induce cell differentiation (KH 1060>MC 1301>MC 1288>1,25(OH)2D3).
Cytokines modulated the effects of 1,25(OH)2D3 on clonal growth. One of the following cytokines (epidermal growth factor, transforming growth factor α, interleukin‐1α, interleukin‐1β, interleukin‐6, interleukin‐8) was required for 1,25(OH)2D3 to suppress clonal growth and induce cell differentiation. In contrast, keratinocyte growth factor and insulin‐like growth factor I attenuated the effects of 1,25(OH)2D3.
In conclusion, 1,25(OH)2D3 and 20‐epi vitamin D3 analogues suppress clonal growth by directly inducing the differentiation of progenitor cells. It is conceivable that stimulation of stem cells differentiation is a major mechanism of action of vitamin D3 compounds in psoriasis. Balance between different types of cytokines in psoriatic epidermis may be an important factor determining the clinical effect of vitamin D‐based therapy.

British Journal of Pharmacology (1997) 120, 1119–1127; doi:10.1038/sj.bjp.0701015
Negative modulation of nitric oxide production by neurotensin as a putative mechanism of the diuretic action of SR 48692 in rats
Authors: Croci Tiziano , Landi Marco , Gully Danielle , Maffrand Jean‐Pierre , Le Fur Gérard , Manara Luciano 
Published: August 2006

We investigated the effect of the non‐peptide neurotensin (NT) antagonist SR 48692 on renal function in rats and the involvement of nitric oxide (NO) in the diuretic action of this compound.
In fed animals, SR 48692 dose‐dependently (0.5 to 12.5 mg kg−1, p.o., 0.03 to 1 mg kg−1, i.p. and 0.1 to 1 μg/rat, i.c.v.) increased urine output and urinary excretion of Na+, K+ and Cl− and reduced urine osmolality. The diuretic activity was also evident in water‐deprived, fasted animals and in fasted, water‐loaded rats.
NT (0.1 μg/rat, i.c.v.) had no effect on urine output in fed rats, but reduced the diuretic action of SR 48692 (1 μg/rat, i.c.v.). The opposite result was obtained in fasted, water‐loaded animals: NT dose‐dependently (0.01 and 0.1 μg/rat, i.c.v.) inhibited diuresis and this effect was significantly inhibited by i.c.v. SR 48692. In this experimental condition, SR 48692 did not further increase the on‐going diuresis.
The NO synthesis inhibitor Nω‐nitro‐l‐arginine methyl ester (l‐NAME; 30 mg kg−1, i.p.) alone had no effect on urine output in fed rats but prevented the diuretic action of i.c.v. or i.p. SR 48692; l‐arginine (1 g kg−1, i.p.) but not d‐arginine (1 g kg−1, i.p.) restored the SR 48692‐dependent increase in diuresis. l‐NAME had no effect on furosemide‐stimulated diuresis.
Systemically administered l‐NAME or i.c.v. NT in fasted, water‐loaded rats significantly reduced water diuresis but this effect was no longer seen in animals given i.p. l‐arginine. Rats receiving i.c.v. NT, whose diuresis was significantly reduced, also excreted less nitrates and nitrites in urine.
Increased diuresis after central or systemic administration of SR 48692 to fed rats was paralleled by increased urinary excretion of nitrates and nitrites, this being consistent with peripheral enhancement of NO production after NT‐receptor blockade by SR 48692. The increase in diuresis after furosemide also involved an increase of nitrates and nitrites in urine, but this effect was about half that attained with an equipotent diuretic dose of SR 48692.
In fed rats, the NO donor isosorbide‐dinitrate, reduced systolic blood pressure (unlike SR 48692 which did not affect blood pressure) but also dose‐dependently (1 and 5 mg kg−1, i.p.) stimulated urine output.
The overall effects of SR 48692 strongly support a link between the actions of endogenous NT, AVP and peripheral NO production in the modulation of renal excretion of water, Na+, K+ and Cl−.

British Journal of Pharmacology (1997) 120, 1312–1318; doi:10.1038/sj.bjp.0701016
Suppression of neointimal thickening by a newly developed HMG‐CoA reductase inhibitor, BAYw6228, and its inhibitory effect on vascular smooth muscle cell growth
Authors: Igarashi Masahiko , Takeda Yuki , Mori Seijiro , Ishibashi Naoko , Komatsu Eiichi , Takahashi Kentaro , Fuse Tsunekazu , Yamamura Mikako , Kubo Kazuki , Sugiyama Yasuo , Saito Yasushi 
Published: August 2006

The aim of this study was to determine whether BAYw6228 (BAYw), a newly developed 3‐hydroxy‐3‐methylglutaryl‐CoA (HMG‐CoA) reductase inhibitor, could suppress an atherogenic process such as intimal thickening by a mechanism other than lowering the level of serum cholesterol.
First, we evaluated the in vitro effect of BAYw on the proliferation of vascular smooth muscle cells (SMC) from various species: Sprague‐Dawley (SD) rats, New Zealand (NZ) white rabbits, intimal cells from Watanabe hereditary hyperlipidemic (WHHL) rabbit and SMC from the new‐born human aorta. The increasing rate of total protein content of these cells was inhibited by the addition of BAYw in a dose‐dependent fashion. In the presence of 2% foetal calf serum (FCS), the value of IC50 was 1.0 μm in SD rats. 2.1 μm in NZ white rabbits, and 0.3 μm in WHHL rabbits. With human SMC, the value was 0.02 μm in the presence of 10% FCS and 0.2 μm with a mixture of growth factors.
Based on these above in vitro findings, we next examined the in vivo effect of the agent to determine whether it could suppress rabbit intimal thickening induced by balloon catheterization. A balloon catheter was inserted from a peripheral branch of the left external carotid artery to the aorta to denude the endothelium of the left common carotid artery in Japanese white rabbits. After 12 days they were divided into control and BAYw groups. The former were subcutaneously injected with saline and the latter with BAYw 1 mg kg−1 day−1. Two days after the beginning of treatment, a second balloon injury was performed to the previously injured left common carotid artery in both groups. After another two weeks, the left common carotid artery was removed and variously stained. Although the total serum cholesterol in the BAYw group was significantly lower than in the control (P<0.05), the difference was not enough to affect intimal thickening. In addition, the BAYw group had a smaller intima/media ratio than the control group, decreasing to 45% of control (P<0.05). By anti‐α smooth muscle actin antibody staining, these intimal thickening areas were entirely occupied by SMCs, and their amount was attenuated by BAYw. By anti‐rabbit macrophage antibody (RAM 11) staining, the number of positive cells in the intimal thickening was markedly decreased in the BAYw group compared to control (P<0.01).
These results indicate that BAYw has an inhibitory effect on intimal thickening by attenuating intimal SMC proliferation and infiltration of macrophages, suggesting that BAYw could be effective in the prevention of the progression of atherosclerotic plaque‐like restenosis after angioplasty.

British Journal of Pharmacology (1997) 120, 1172–1178; doi:10.1038/sj.bjp.0701018
Inhibition of the constitutive activity of human 5‐HT1A receptors by the inverse agonist, spiperone but not the neutral antagonist, WAY 100,635
Authors: Newman‐Tancredi Adrian , Conte Caroline , Chaput Christine , Spedding Michael , Millan Mark J 
Published: August 2006

At recombinant human 5‐hydroxytryptamine (5‐HT)5‐HT1A receptors expressed in Chinese hamster ovary cells (CHO‐5‐HT1A), 5‐carboxamidotryptamine (5‐CT), acted as a full agonist (relative to 5‐HT=100%) for stimulation of receptor‐mediated [35S]‐GTPγS (guanylyl 5′‐[γ‐thio]‐tryphosphate) binding. In contrast, spiperone inhibited basal [35S]‐GTPγS binding by 30.2% (IC50=55.5 nm) in CHO‐5‐HT1A membranes but not in control untransfected membranes. The antagonist, N‐{2‐[4‐(2‐methoxyphenyl)‐1‐piperazinyl]ethyl}‐N‐(2‐pyridinyl)‐cyclohexane‐carboxamide (WAY 100,635), blocked both 5‐CT‐induced stimulation and spiperone‐induced inhibition of [35S]‐GTPγS binding without itself modifying [35S]‐GTPγS binding. It is concluded that, in this heterologous expression system, 5‐HT1A receptors display ‘constitutive’ activation of G‐proteins and that spiperone displays inverse agonist activity whereas WAY 100,635 acts as a ‘neutral’ antagonist at this site.British Journal of Pharmacology (1997) 120, 737–739; doi:10.1038/sj.bjp.0701025
Receptor subtypes Y1 and Y5 are involved in the renal effects of neuropeptide Y
Authors: Bischoff Angela , Avramidis Prodromos , Erdbrügger Wilhelm , Münter Klaus , Michel Martin C. 
Published: August 2006

Systemic infusion of neuropeptide Y (NPY) reduces renal blood flow and can concomitantly increase diuresis, natriuresis and calciuresis in anaesthetized rats. The present study was designed to investigate whether the apparently contradictory NPY effects on renal blood flow and urine formation and composition are mediated by distinct NPY receptor subtypes.
NPY and its analogues, peptide YY (PYY), [Leu31, Pro34]NPY and NPY1336, were infused in incremental doses of 0.3, 1 and 3 μg kg−1 min−1 for 45 min each and the results compared to those obtained in vehicle‐infused rats. Renal blood flow was monitored in 15 min intervals, while urine excretion and composition were determined in 15 min collection periods. Plasma renin activity and aldosterone concentrations were measured at the end of the final infusion period.
Relative to vehicle NPY, PYY and [Leu31, Pro34]NPY dose‐dependently reduced renal blood flow and increased diuresis, natriuresis and calciuresis with roughly similar potency; NPY1336 slightly but significantly increased renal blood flow but had no effect on diuresis, natriuresis and calciuresis. None of the peptides significantly affected endogenous creatinine clearance or kaliuresis.
Plasma renin activity was significantly reduced by PYY. Quantitatively similar reductions were observed with NPY and [Leu31, Pro34]NPY but failed to reach statistical significance with the given number of experiments. NPY1336 did not reduce plasma renin activity. None of the peptides significantly affected plasma aldosterone concentrations.
In another series of experiments infusion of PYY336 (2 μg kg−1 min−1 for 120 min) did not reduce renal blood flow but significantly enhancd diuresis and natriuresis to a similar extent as the NPY 2 μg kg−1 min−1.
In a final series of experiments the Y1‐selective antagonist, BIBP 3226 (1 or 10 μg kg−1 min−1) dose‐dependently antagonized reductions of renal blood flow elicited by bolus injections of NPY (0.130 μg kg−1). BIBP 3226 (10 μg kg−1 min−1) also inhibited the effects of a 120 min infusion of NPY (2 μg kg−1 min−1) on renal blood flow but had only minor inhibitory effects on enhancements of diuresis and did not significantly affect enhancements of natriuresis.
We conclude that NPY reduces renal blood via a classical Y1 subtype of NPY receptor. In contrast enhancements of diuresis, natriuresis and calciuresis occur via a distinct subtype which resembles the receptor that mediates NPY‐induced enhancement of food intake.

British Journal of Pharmacology (1997) 120, 1335–1343; doi:10.1038/sj.bjp.0701028
Antiproliferative effects of PCA‐4230, a new antithrombotic drug, in vascular smooth muscle cells
Authors: Del Rio Marcela , Sunkel Carlos , Larcher Fernando , Pilar Ortega M. 
Published: August 2006

In the present study we examined the effects of PCA‐4230, a novel antithrombotic agent, on the growth of cultured A10 vascular smooth muscle cells (rat aorta).
The action of PCA‐4230 on cell proliferation and on serum‐induced DNA synthesis was determined by measuring the cell number and the incorporation of the thymidine analogue 5‐bromo‐2′‐deoxyuridine (BrdU), respectively.
PCA‐4230 reversibly inhibited vascular smooth muscle cell proliferation. The increase in cell number was significantly reduced in the presence of 1 and 50 μm PCA‐4230.
DNA synthesis was concentration‐dependently inhibited by PCA‐4230 (0.5 to 50 μm) in A10 cells that were synchronized by 48 h serum starvation and then re‐stimulated by serum repletion, with an IC50 value of 13 μm. However, serum‐induced DNA synthesis in bovine aortic endothelial cells was not significantly affected by PCA‐4230. In addition, PCA‐4230 (50 μm) caused a significant drop in PDGF‐BB‐mediated BrdU incorporation in A10 cells.
The effect of PCA‐4230 on serum‐induced DNA synthesis was compared to that elicited by nifedipine, another dihydropyridine‐class inhibitor of vascular smooth muscle proliferation. PCA‐4230 (10 μm) elicited a degree of inhibition similar to that of nifedipine at equimolar concentration.
To define the nature of the cell proliferation inhibition, an evaluation of cell cycle progression was undertaken. Flow cytometry studies of DNA content in synchronized cells revealed a block of the serum‐inducible cell cycle progression. This inhibitory effect was markedly reduced when PCA‐4230 was added 2 h after serum repletion.
Accordingly, PCA‐4230 (50 μm) caused a 95 and 90% decrease in the elevation of c‐fos and c‐jun proto‐oncogenes expression as evaluated by Northern blot analysis of mRNA induced early after serum addition.
The present results indicate that PCA‐4230 inhibits vascular smooth muscle cell proliferation, in culture, by altering the cell cycle progression. Flow cytometric studies of DNA content and the down regulation of c‐fos and c‐jun proto‐oncogenes, suggest that the drug is acting at the early G0/G1 transition phase. PCA‐4230 may hold promising potential for the prevention of structural abnormalities of blood vessels associated with atherosclerosis and vascular diseases.

British Journal of Pharmacology (1997) 120, 1360–1366; doi:10.1038/sj.bjp.0701035
Functional and molecular evidence for β1‐, β2‐ and β3‐adrenoceptors in human colon
Authors: Roberts S. J. , Papaioannou M. , Evans B. A. , Summers R. J. 
Published: August 2006

Relaxation of carbachol pre‐contracted human colonic muscle to (–)‐isoprenaline was examined in circular, longitudinal and taenia coli preparations to determine the β‐adrenoceptor subtypes involved. β1‐, β2‐ and β3‐Adrenoceptor mRNAs were also measured in colonic muscle and mucosa.
(–)‐Isoprenaline caused relaxation of longitudinal smooth muscle preparations with pEC50=7.39±0.12, and this response was inhibited by both propranolol (0.1 μm, pKB 8.55±0.12) and the selective β1‐antagonist, CGP 20712A (0.1 μm, pKB 8.80±0.20), while the selective β2‐antagonist, ICI 118551 (0.1 μm) failed to inhibit isoprenaline relaxation consistently.
(–)‐Isoprenaline caused relaxation of taenia coli with a pEC50 of 6.70±0.17. Propranolol (0.1 μm), CGP 20712A (0.1 μm) and ICI 118551 (0.1 μm) inhibited the isoprenaline response with similar low affinities (pKB values 7.93, 7.71 and 7.54, respectively). Carbachol pre‐contracted circular smooth muscle preparations failed to relax consistently to isoprenaline and these responses were not characterized.
β1‐ and β2‐Adrenoceptor mRNAs were present in circular/longitudinal muscle samples and taenia coli samples, and lower levels were detected in mucosa. β3‐mRNA was also present in both muscle preparations but was not detected in human colonic mucosa.
In summary, β1‐adrenoceptors are the predominant subtype mediating isoprenaline‐induced relaxation of the thin longitudinal smooth muscle of human colon, while β3‐receptors do not appear to be involved in these responses. However, β3‐adrenoceptors may play a role in relaxation of the taenia coli as conventional antagonist affinities are low. β3‐Adrenoceptor mRNA was present in taenia coli and circular/longitudinal smooth muscle but absent from human colonic mucosa.

British Journal of Pharmacology (1997) 120, 1527–1535; doi:10.1038/sj.bjp.0701056
Depression of A and C fibre‐evoked segmental reflexes by morphine and clonidine in the in vitro spinal cord of the neonatal rat
Authors: Faber E. S. L. , Chambers J. P. , Brugger F. , Evans R. H. 
Published: August 2006

Population synaptic responses of motoneurones were recorded from a ventral root following electrical stimulation of the corresponding lumbar dorsal root in neonatal rat hemisected spinal cord preparations in vitro. Two levels of electrical stimulation were used to elicit dorsal root compound action potentials that contained either an A fibre component alone or both A and C fibre components. The effects of centrally acting analgesics and an N‐methyl‐d‐aspartate (NMDA) receptor antagonist were tested on synaptic responses produced by these two levels of stimulation.
At stimulus intensities below four times threshold (T) there was no C fibre component in the dorsal root compound action potential. Responses to a single pulse at 3T (the low intensity excitatory postsynaptic potential (e.p.s.p.)), a train of five pulses at 2T (the train e.p.s.p.) and a single supramaximal pulse (the high intensity e.p.s.p.) were used to compare the depressant actions of morphine, clonidine and the competitive NMDA antagonist CGP40116 (d‐(E)‐2‐amino‐4‐methyl‐5‐phosphono‐pentenoic acid). The train e.p.s.p. (mean half‐time to decay 5±0.6 s, n=6) had a similar profile to the high intensity e.p.s.p. (mean half‐time to decay 6.8±0.7, n=8).
The monosynaptic compound action potential of motoneurones (MSR) was resistant to all three drugs irrespective of the intensity of dorsal root stimulation. The low intensity e.p.s.p., the train e.p.s.p. and the high intensity e.p.s.p. were depressed by all three drugs. The EC50 values for depression by morphine were 79±1 nm (n=8) for the high intensity e.p.s.p. and 99±1 nm (n=4) for the low intensity e.p.s.p. The corresponding values for clonidine were 25±1 nm (n=8) and 9±1 nm (n=4) and those for CGP40116 were 860±1.3 nm (n=4) and 76±1.1 nm (n=4).
The depressant profile of the NMDA antagonist, having the least depressant activity on the C fibre‐mediated response, was different from that of the two analgesics. CGP40116 (3 μm) depressed the high intensity e.p.s.p. to 62±8%, the low intensity e.p.s.p. to 22±4% and the train e.p.s.p. to 16±2% of control values.
The depressant actions of morphine were fully reversed by naloxone (1 μm) and those of clonidine were fully reversed by atipamezole (1 μm).
These results show that, in contrast to previous findings, activation of primary afferent C fibres in dorsal roots is not required for generation of morphine‐ or clonidine‐sensitive synaptic responses in ventral roots of this in vitro preparation.

British Journal of Pharmacology (1997) 120, 1390–1396; doi:10.1038/sj.bjp.0701064