bluuebunny/crossref_metadata_2025_split huggingface dataset:
Potentiation of the anti‐obesity effect of the selective β3‐adrenoceptor agonist BRL 35135 in obese Zucker rats by exercise
Authors: Santti Eriika , Huupponen Risto , Rouru Juha , Hanninen Virve , Pesonen Ullamari , Jhanwar‐Uniyal Meena , Koulu Markku 
Published: July 2012

The effects of chronic treatments with a selective β3‐adrenoceptor agonist and a selective α2‐adrenoceptor antagonist and their interactions with physical exercise training were studied in experimental obesity.
BRL 35135 (β3‐agonist, 0.5 mg kg−1 day−1 p.o.), atipamezole (α2‐antagonist, 4.0 mg kg−1 day−1 p.o.) and placebo were given to genetically obese male Zucker rats. Half of the rats were kept sedentary whereas the other half were subjected to moderate treadmill exercise training. Body weight gain, cumulative food intake, the neuropeptide Y content of the hypothalamic paraventricular nucleus, brown adipose tissue thermogenic activity (measured as GDP binding), plasma insulin and glucose levels were measured after 3 weeks' treatment and exercise.
Treatment with BRL 35135 reduced weight gain by 19%, increased brown adipose tissue thermogenic activity 45‐fold and reduced plasma insulin by 50%. Atipamezole slightly increased food intake and neuropeptide Y content in the paraventricular hypothalamic nucleus but had no effect on the other measured parameters. Exercise alone had no effect on weight gain, food intake or thermogenic activity, whereas it reduced plasma insulin and glucose levels.
The effect of BRL 35135 on weight gain and thermogenic activity was significantly potentiated by exercise; the reduction in weight gain was 56% in comparison with 19% in sedentary animals. Food intake was significantly reduced in the BRL 35135‐treated‐exercise‐trained animals, although neither β3‐agonist nor exercise alone affected it.
Based on the present results in genetically obese Zucker rats, combination of β3‐agonist treatment with a moderate physical training may offer a new feasible approach to the therapy of obesity.
Interactions of chloroethylclonidine with rauwolscine‐ and prazosin‐sensitive adrenoceptors in dog saphenous vein
Authors: Low A.M. , Bowdish D.M. , Prashad T.R. , Gaspar V. 
Published: July 2012

α1‐Adrenoceptors have been classified pharmacologically into four subtypes (α1A, α1B, â1c and α1D) on the basis of their differential affinity for novel antagonists such as chloroethylclonidine (CEC). While CEC is considered an α1B‐adrenoceptor antagonist, our earlier studies revealed that it also acted like an agonist in the dog saphenous vein (DSV). The present study characterized the contraction induced by CEC in endothelium‐denuded rings from DSV.
Concentration‐response curves for CEC were constructed in the absence (EC50 value of 11.13 ± 3.6 μm, n = 8) and presence of propranolol (β‐adrenoceptor antagonist, 30 nm), rauwolscine (α2‐adrenoceptor antagonist, 30 nm), prazosin (α1‐adrenoceptor antagonist, 30 nm) or methysergide (5HT2 antagonist, 30 nm) or both prazosin and rauwolscine. Pretreatment with methysergide (9.83 ± 5.14μm, n = 4) or propranolol (23.78 ± 12.32μm, n = 4) had no consistent effect. In the presence of rauwolscine, the concentration‐response curve for CEC was significantly shifted to the right with an EC50 value of 48.82 ± 13.2 JAM (n = 8). In the presence of prazosin, the CEC concentration‐response curve had an EC50 value of 29.12 ± 6.42 μm (n = 8). Pretreatment with both prazosin and rauwolscine shifted the concentration‐response curve for CEC to the right with an EC50 value of 72.67 ± 10.69 JAM (n = 8, P < 0.05). Maximum responses were significantly reduced only in tissues that were treated with both prazosin and rauwolscine.
CEC (100 μm) pretreatment abolished prazosin binding sites and reduced the Bmax for rauwolscine by 50% without affecting the IQ value or the Hill slope.
In Ca2+‐free Krebs solution containing 50 /IM EGTA, CEC produced a small transient contraction, suggesting that it can mobilize internally‐stored Ca2+. Pretreatment with rauwolscine abolished the CEC‐induced contraction in Ca2+‐free medium; prazosin pretreatment reduced but did not abolish CEC response in Ca2+“free medium.
Restoring Ca2+ (0.5‐2.5 μm) to the extracellular solution increased CEC contraction in a concentration‐dependent manner, reaching a plateau at around 1.5 mm Ca2+. The contraction was insensitive to nicardipine (1 μm), a voltage‐operated Ca2+channel blocker, but was blocked in a concentration‐dependent manner by the putative receptor‐operated Ca2+channel blockers, SK&F 96365 (1–10 μm) and genistein, also a tyrosine kinase inhibitor (10–100μm).
We conclude that CEC acts on rauwolscine‐ and, to a less extent, prazosin‐sensitive adrenoceptors in DSV to release internally stored Ca2+ and to open receptor‐operated Ca2+ channels. The inhibitory effect on CEC‐induced contraction that depended on external Ca2+ by genistein suggests a role for tyrosine kinase in the regulation of dihydropyridine‐insensitive Ca2+ entry.
Inhibitory 5‐hydroxytryptamine receptors involved in pressor effects obtained by stimulation of sympathetic outflow from spinal cord in pithed rats
Authors: Morán A. , Velasco C. , Salvador T. , Martín M.L. , Román L. San 
Published: July 2012

A study was made of the effects of 5‐hydroxytryptamine (5‐HT) on pressor response induced in vivo by electrical stimulation of the sympathetic outflow from the spinal cord of pithed rats. All animals had been pretreated with atropine. Intravenous infusion of 5‐hydroxytryptamine at doses of 10 and 20 μg kg−1 min−1 reduced the pressor effects obtained by electrical stimulation at intervals of 10 min over the 1 h of infusion.
This inhibitory action of 5‐HT was depressed by cyproheptadine and methiothepin but was not modified by ketanserin or MDL‐72222. By contrast, the inhibitory action of 5‐HT was lost in pithed rats that had been pretreated with exogenous noradrenaline.
The 5‐HT1 receptor agonist 5‐carboxamidotryptamine (5‐CT) caused an inhibition of the pressor response, whereas the 5‐HT3 receptor agonist, 1‐phenylbiguanide, produced a variable but significant increase in the pressor response. The 5‐HT2 receptor agonist, m‐CPP, did not modify the pressor sympathetic response.
Our results suggest that 5‐hydroxytryptamine interferes with sympathetic neurotransmission by inhibiting pressor effects as a result of stimulation of the complete sympathetic outflow, and that this inhibition is mainly through a presynaptic 5‐HT1 mechanism.
Characterization of the adenosine receptors mediating hypothermia in the conscious mouse
Authors: Anderson R. , Sheehan M.J. , Strong P. 
Published: July 2012

The effects of a range of adenosine receptor‐selective ligands on body temperature were investigated following intracerebroventricular (i.c.v.) and intraperitoneal (i.p.) injection in conscious mice. The compounds tested were the non‐selective adenosine receptor agonist 5′‐N‐ethyl‐carboxamidoadenosine (NECA), the adenosine A1 receptor‐selective agonists cyclopentyl‐adenosine (CPA), N6‐(9R‐phenyl‐isopropyl)‐adenosine (R‐PIA) and N‐(1S,trans)‐[2‐hydroxycyclopentyl]‐adenosine (GR79236), the A2a receptor selective agonist 2‐[p‐(2‐carboxyethyl)phenethylamino]‐5′‐N‐ethylcarboxamidoadenosine (CGS‐21680), the A2b receptor agonist N‐[(2‐methylphenyl)methyl]adenosine (metrifudil) and the A3 receptor agonist N6‐(4‐aminophenylethyl)adenosine (APNEA).
NECA (0.01‐1 μg, i.c.v.), all of the A1‐selective agonists (0.01‐1 μg, i.c.v.) and APNEA (0.1–3 μg i.c.v.) produced profound and dose‐related hypothermia and sedation. However, CGS‐21680 (0.1–10 μg i.c.v.) and metrifudil (0.01‐1 μg i.c.v.), produced only mild hypothermia at the highest doses tested.
The hypothermic response to the A1 receptor‐selective agonists, GR79236 and R‐PIA was dose‐dependently antagonized by peripheral administration of either the non‐selective adenosine receptor antagonist, 8‐phenyltheophylline (8‐PT, approximately 40 and 30 fold rightward shifts of the dose‐response curves respectively at 10 mg kg−1, i.p.), or the adenosine A1 receptor‐selective antagonist, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX, approximately 20 fold shift of the GR79236 dose‐response curve at 1 mg kg−1, i.p.). The hypothermic response to APNEA was similarly dose‐dependently antagonized by the A1 receptor‐selective antagonist, DPCPX (5 fold shift at 0.1 mg kg−1, i.p.).
8(p‐Sulphophenyl)theophylline (8‐SPT, 10 and 30 mg kg−1, i.p.), a non‐selective adenosine receptor antagonist that penetrates the blood brain barrier poorly, produced only modest antagonism (approximately 2 fold shift at 30 mg kg−1, i.p.) of the hypothermic response to GR79236.
These data suggest that hypothermia induced by adenosine analogues in the conscious mouse is mediated via adenosine Ai receptors, which are probably located in the CNS.
Variable potency of nitrergic‐nitrovasodilator relaxations of the mouse anococcygeus against different forms of induced tone
Authors: Gibson A. , McFadzean I. , Tucker J.F. , Wayman C. 
Published: July 2012

U46619 (thromboxane A2 receptors; 0.002‐1 μm), carbachol (muscarinic M3 receptors; 0.1–100μm), cyclopiazonic acid (CPA; Ca2+‐ATPase inhibitor; 0.1–30 μm) and K+ (5‐100mM) produced concentration‐dependent contractions of the mouse isolated anococcygeus muscle. Equi‐effective, sub‐maximal concentrations of each agent were used in further experiments (40 nm U46619; 5 μm carbachol; 5μm CPA; 70 mm K+).
Nifedipine (1 μm) totally abolished contractile responses to K+; those to U46619, carbachol and CPA were reduced by only 20–30% in the presence of nifedipine, but were greatly reduced (>90%) by a combination of nifedipine and SKF 96365 (0.1–40 μm).
In Ca2+‐free medium, contractions to K+ and CPA were abolished. Small residual responses remained to both carbachol and U46619; those to carbachol were transient, could not be repeated in the continued absence of Ca2+ and were prevented by pre‐incubation with CPA, but unaffected by SKF 96365; those to U46619 were sustained, could be repeated in the absence of Ca2+, and were resistant to CPA and SKF 96365.
Tone induced by all four agents could be relaxed by sodium nitroprusside (SNP), but with a clear order of potency. SNP (pIC40) was most effective against U46619 (7.92), less so against carbachol (6.80) and CPA (6.68), and least potent against K+ (5.94). A similar order of potency was observed with 8Br‐cyclic GMP (50 μm) and nitrergic field stimulation (1–20 Hz).
The relaxant potency of SNP was similar in normal Krebs solution and in high K+ (70 μm) Krebs containing 1 μm nifedipine.
Inclusion of SNP (0.01‐1 μm) or 8Br‐cyclic GMP (50 μm) in the Ca2+‐free medium inhibited the transient residual response to carbachol. Inclusion of similar concentrations of SNP or 8Br‐cyclic GMP, during Ca2+ re‐loading, increased the subsequent residual contraction to carbachol in Ca2+‐free medium.
At higher concentrations, SNP (0.1–10 μm) produced a partial relaxation of the sustained contraction to U46619 in Ca2+‐free medium.
Thus, the relaxant potency of the nitrergic stimuli was dependent on the agent and mechanism used to induce tone in the preparation. Examination of the contractile/relaxant interactions suggests that altered Ca2+ sequestration and inhibition of contractile protein function may underlie nitrergic relaxations of this tissue.
Nitric oxide formation from glyceryl trinitrate by rabbit aortic strip: detection by rabbit taenia coli concurrent with vasorelaxation
Authors: Hussain Aman S. , Poklewska‐Koziell Margo , Brien James F. , Marks Gerald S. , Nakatsu Kanji 
Published: July 2012

The purpose of the present study was to assay NO formation from GTN biotransformation by the rabbit aortic strip (RAS) at times concurrent with its vasorelaxation. Such an assay is an important test of the prodrug hypothesis where it is postulated that glyceryl trinitrate (GTN) is biotransformed to nitric oxide (NO), the active species that initiates vascular smooth muscle relaxation. To test such a hypothesis, we propose that a sample of smooth muscle, poorly responsive to GTN, yet sensitive to the effects of NO could be used to detect RAS production of NO from GTN.
Muscle strips of rabbit taenia coli (RTCS) and RAS in close apposition, were mounted in tissue baths, and muscle relaxation was recorded with isometric force transducers. Tissues were submaximally precontracted with 30–35 mm K+ depolarizing solution and exposed to increasing concentrations of GTN (0.1 nm‐10 μm).
EC25 for GTN‐induced relaxation of RTCS in the presence of RAS was significantly decreased to that for RTCS in the absence of RAS (5.9 ± 3.0 × 10−8 m and 5.5 ± 3.7 × 10−6 m, respectively). Mean maximal levels of GTN‐induced relaxation of similarly precontracted RTCS also differed in the presence and absence of RAS, viz., 80.8 ± 2.1% and 29.8 ± 8.3% respectively.
RTCS was found to relax upon administration of NO gas bubbled through the incubation medium. Analysis of tissue bath medium revealed that the NO concentration to which RTCS was exposed attained a maximum of 33 nm. Relaxation of RTCS by NO gas was inhibited by 1 μm reduced haemoglobin.
For GTN‐incubation with intestinal and vascular smooth muscle preparations, NO formation was greater with RAS compared to RTCS. Thus, in the two‐issue bioassay, the RAS was the predominant source of NO formation from GTN.
Reduced deoxyhaemoglobin (1 μm), a potent extracellular NO scavenger, was found to decrease the augmented GTN‐induced relaxation in the RTCS‐RAS sandwich preparation from 17.3 ± 1.8% to 8.0 ± 0.8%. The augmented RTCS response was restored upon washout and subsequent addition of GTN, in the absence of reduced Hb.
These data indicate that nitric oxide or a closely related NO‐donor is produced by vascular biotransformation of GTN as seen by the increased sensitivity of RTCS to GTN when in the presence of RAS. The results of this bioassay thus support the GTN‐NO prodrug hypothesis.
Impairment of nitrergic‐mediated relaxation of rat isolated duodenum by experimental diabetes
Authors: Martinez‐Cuesta M.A. , Massuda H. , Whittle B.J.R. , Moncada S. 
Published: July 2012

Diabetes mellitus is associated with changes in gastrointestinal motility. The effects of experimental diabetes, induced by streptozotocin administration to rats 3–4 weeks previously, on the nitric oxide (NO)‐mediated (nitrergic) relaxation of the duodenum have now been investigated.
The non‐adrenergic, non‐cholinergic (NANC) relaxation of the isolated duodenum induced by nicotine (0.3 – 10 μm) or the nicotinic agonist, 1,1‐dimethyl‐4‐phenylpiperazinium (DMPP; 10 μm) was inhibited by the NO synthase inhibitor, NG‐nitro‐l‐arginine (3–100 μm).
This nitrergic relaxation induced by nicotine or DMPP of the duodenum from diabetic rats was substantially smaller than that of the tissue from control rats.
By contrast, the relaxation of the duodenum from diabetic rats to the NO donor, nitroprusside (0.3–10 μm) was similar to that of control tissue, whereas the relaxation to ATP (0.1–3 μm) was enhanced to a small but significant degree.
Incubation of duodenal tissue from control rats at 4°C for 72 h, which leads to neuronal disruption, significantly attenuated the relaxation to nicotine or DMPP whereas the relaxation induced by nitroprusside or ATP was not affected. Comparable cold‐storage did not affect the endothelium‐dependent relaxation of rat aortic rings induced by acetylcholine (0.01–2 μm).
The calcium‐dependent NO synthase activity in duodenal tissue, determined by the conversion of radiolabelled l‐arginine to citrulline, was significantly reduced in cold‐stored tissue and in tissue obtained from diabetic rats.
These findings in the rat duodenum indicate that a reduction in intestinal NO synthase activity is associated with an impairment of the NANC relaxation. A defect in the intestinal nitrergic innervation could thus contribute to the motility dysfunction observed in diabetes.
Canine renovascular responses to sumatriptan and 5‐carboxamidotryptamine: modulation through endothelial 5‐HT1‐like receptors by endogenous nitric oxide
Authors: Whiting M.V. , Cambridge D. 
Published: July 2012

In anaesthetized dogs, intra‐left atrial (i.l.a.) administration of the 5‐HT1‐like receptor agonists, sumatriptan (1 – 10 μg kg−1) and 5‐carboxamidotryptamine (0.03 – 0.3 μg kg−1) produced dose‐related reductions in renal blood flow and vascular conductance, which were characterized by their rapid onset and recovery.
In these animals, i.v. administration of the inhibitor of nitric oxide (NO) synthase, NG‐nitro‐l‐arginine methyl ester (l‐NAME; 10 mg kg−1) significantly augmented the renal vasoconstrictor responses to i.l.a. sumatriptan and 5‐carboxamidotryptamine.
The effects of l‐NAME upon these responses to sumatriptan and 5‐carboxamidotryptamine were significantly reversed by subsequent i.v. administration of l‐arginine (1000 mg kg−1).
l‐NAME significantly attenuated the systemic hypotensive responses to i.v. acetylcholine (0.3 – 3 μg kg−1) and this effect was also reversed by l‐arginine.
l‐NAME had no effect upon the renal vasoconstrictor response to i.l.a. administration of angiotensin II, nor did it affect the renal vascular conductance recovery response to brief mechanical occlusion of the renal artery.
These data suggest that sumatriptan and 5‐carboxamidotryptamine stimulate the release of NO through the activation of a 5‐HT1‐like receptor located on the endothelial cells.
It is concluded that in canine renal vasculature, 5‐HT1‐like agonists (and presumably endogenous 5‐hydroxytryptamine) can cause simultaneous activation of a 5‐HT1‐like receptor on both vascular smooth muscle and endothelial cells. The net renal vascular response to these agonists is therefore a function of both the vascular smooth muscle vasoconstriction and the concurrent vasodilator influence of NO released from the endothelium.
Interaction of β‐carboline inverse agonists for the benzodiazepine site with another site on GABAA receptors
Authors: Im Haesook K. , Im Wha Bin , Carter Donald B. , McKinley Denise D. 
Published: July 2012

We examined the effects of methyl 6,7‐dimethoxy‐4‐ethyl‐β‐carboline‐3‐carboxylate (DMCM), a β‐carboline inverse agonist for the benzodiazepine site, on γ‐aminobutyric acid (GABA)‐induced Cl− currents in several cloned rat GABAA receptor subtypes expressed in human embryonic kidney cells. The Cl− currents were measured in the whole cell configuration of patch clamp techniques.
DMCM at low concentrations (<0.5 μm) occupying only the benzodiazepine site decreased GABA‐induced Cl currents in the α1β2γ2 and α3β2γ2 subtypes as expected from an inverse agonist, but produced no change in the α6β2γ2 subtype (perhaps a neutral antagonist). The drug at higher concentrations (> 0.5 μm) enhanced Cl− currents in all the subtypes, with a half maximal concentration of 6 to 20 μm, depending on the α isoform. In the α1β2 subtype, which is without the benzodiazepine site, DMCM monophasically increased Cl− currents with a half maximal concentration of 1.9 μm.
Ro 15–1788 (a classical benzodiazepine antagonist) had no effect on Cl− current enhancement by DMCM and, in fact, increased the current level through blocking current inhibition by DMCM via the benzodiazepine site. Also, Cl− current enhancement by pentobarbitone or by 3α, 21‐dihydroxy‐5α‐pregnan‐20‐one was additive to that by DMCM at saturating doses. It appears that the agonist site for DMCM is distinct from those for benzodiazepines, barbiturates and neurosteroids.
Among β‐carboline analogues, methyl‐β‐carboline‐3‐carboxylate and propyl‐β‐carboline‐3‐carboxylate markedly enhanced GABA‐induced Cl currents in the α1β2γ2 subtype, while N‐methyl‐β‐carboline‐3‐carboxamide and 1‐methyl‐7‐methoxy‐3,4‐dihydro‐β‐carboline did not. It appears that the 3‐carboxyl ester moiety is necessary for β‐carbolines to interact with a novel site on GABAA receptors as agonists.
Effect of the NMDA‐antagonist, MK 801, on benzodiazepine‐opioid interactions at the spinal and supraspinal level in rats
Authors: Luger Thomas J. , Lorenz Ingo H. , Grabner‐Weiss Christina , Hayashi Takahiko 
Published: July 2012

Benzodiazepines potentiate morphine antinociception at the spinal level via GABAergic mechanisms. At the supraspinal level, the inhibitory effect of midazolam on morphine antinociception cannot be easily explained by GABAA receptor activation. Since excitatory amino acids play a role in central transmission, we investigated the effect of dizocilpine (MK 801) on this interaction in spinal cord and brain.
In rats with an intrathecal or intracerebroventricular catheter, the mecahnisms of the antinociceptive effect of benzodiazepine‐morphine combinations were tested during thermal nociceptive tests.
The principal findings of this study were that at the spinal level, midazolam potentiation of morphine antinociception can be antagonized by the NMDA antagonist, MK 801 (10 μg), as assessed by hot‐plate and tail‐flick tests. When drugs were administered supraspinally, midazolam inhibited morphine antinociception only in the hot‐plate test, an effect also inhibited by MK 801. In the tail‐flick assay, midazolam failed to influence the morphine response.
The NMDA antagonist significantly affected midazolam antinociception at the spinal level, but was not effective following i.c.v. administration of the drugs. MK 801 had no effect on morphine antinociception after i.t. and i.c.v. administration of the drugs.
The paradoxical effect of midazolam on morphine antinociception and its reversal by MK 801 might be due to modulation at various levels of the neuraxis and/or modulation of different pathways mediated via both GABAA and NMDA receptor mechanisms.
Role of angiotensin converting enzyme in the vascular effects of an endopeptidase 24.15 inhibitor
Authors: Telford Sarah E. , Smith A. Ian , Lew Rebecca A. , Perich Rose B. , Madden Anna C. , Evans Roger G. 
Published: July 2012

1 We investigated the role of angiotensin converting enzyme (ACE) in the cardiovascular effects of N‐[1‐(R,S)‐carboxy‐3‐phenylpropyl]‐Ala‐Ala‐Tyr‐p‐aminobenzoate (cFP), a peptidase inhibitor selective for metalloendopeptidase (EP) E.C. 3.4.24.15.2 In conscious rabbits, cFP (5 mg kg−1, i.v.) markedly slowed the degradation of [3H]‐bradykinin, potentiated the depressor response to right atrial administration of bradykinin (10–1000 ng kg−1), and inhibited the pressor response to right atrial angiotensin I (10–100 ng kg−1). In each of these respects, the effects of cFP were indistinguishable from those of the ACE inhibitor, captopril (0.5 mg plus 10 mg kg−1h−1 i.v.). Furthermore, the effects of combined administration of cFP and captopril were indistinguishable from those of captopril alone.3 In experimentally naive anaesthetized rats, cFP administration (9.3 mg kg−1, i.v.) was followed by a moderate but sustained fall in arterial pressure of 13 mmHg. However, in rats pretreated with bradykinin (50 μg kg−1) a more pronounced fall of 30 mmHg was observed. Captopril (5 mg kg−1) had similar hypotensive effects to those of cFP, and cFP had no effect when it was administered after captopril.4 CFP displaced the binding of [125I]‐351A (the p‐hydroxybenzamidine derivative of lisinopril) from preparations of rat plasma ACE and solubilized lung membrane ACE (KD = 1.2 and 0.14 μm respectively), and inhibited rat plasma ACE activity (KI = 2.4 μm). Addition of phosphoramidon (10 μm), an inhibitor of a range of metalloendopeptidases, including neutral endopeptidase (E.C.3.4.24.11), markedly reduced the potency of cFP in these systems.5 Taken together these findings suggest that the actions of cFP in vivo are attributable to inhibition of ACE rather than EP 24.15. Given that cFP is a poor inhibitor of ACE in the presence of phosphoramidon in vitro, it is likely that cFP is cleaved by a phosphoramidon‐sensitive metallopeptidase in vivo to liberate N‐[1‐(R,S)‐carboxy‐3‐phenylpropyl]‐Ala‐Ala, a potent ACE inhibitor.