bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of angiotensin AT1 and AT2 receptors in mediating the renal effects of angiotensin II in the anaesthetized dog
Authors: Clark Kenneth L. , Robertson Mark J. , Drew G. Michael 
Published: July 2012

Experiments were performed using the selective AT1 receptor antagonist, GR117289, and the selective AT2 receptor antagonist, PD123177, to assess the relative importance of AT1 versus AT2 receptors in mediating the renal effects of angiotensin II (AII) in vivo, in salt‐replete pentobarbitone‐anaesthetized dogs.
The AT1 receptor antagonist, GR117289 (0.5 mg kg−1 + 1 μg kg−1 min−1, i.v.), caused renal vasodilatation, characterized by a mean increase of 21 ± 5% in renal blood flow, 45 min post‐dose. GR117289 also caused a fall in mean blood pressure (12 ± 4%), but despite this, sodium and urine excretion were not reduced. Indeed, there was a tendency for urine output and sodium excretion to increase, although the changes were not statistically significant. GR117289 caused a reduction in plasma aldosterone levels (−35 ± 16%) 45 min post‐dose, despite increasing plasma renin activity (+ 173 ± 42%). In contrast to GR117289, the AT2 receptor antagonist, PD123177 (20 μg kg−1 min−1 intra‐renal artery; i.r.a.) caused no significant change in blood pressure, renal blood flow, or sodium and urine excretion, indicating that the renal effects of endogenous AII in these salt‐replete animals are mediated predominantly by AT1 receptors.
Intra‐renal artery infusion of AII (1–300 ng kg−1 min−1) caused dose‐related renal vasoconstriction, and decreases in urine output, sodium excretion, fractional excretion of sodium, and glomerular filtration rate (GFR). The AT1 receptor antagonist, GR117289 (0.5 mg kg−1 + 1 μg kg−1 min−1, i.v.) antagonized these renal effects of AII, causing 15–38 fold rightward displacements of mean dose‐response curves for these parameters. In contrast, PD123177 (20 μg kg−1 min−1, i.r.a.) failed to antagonize the renal haemodynamic and excretory effects of lower doses of AII (1–10 ng kg−1 min−1, i.r.a.). However, at higher doses of AII (30–300 ng kg−1 min−1, i.r.a.), while PD123177 still failed to antagonize the effects of the peptide on urine output, sodium excretion and GFR, it did cause a small, but significant, degree of inhibition of AII‐induced renal vasoconstriction. In addition, at a higher dose (50 μg kg−1 min−1, i.r.a.), PD123177 caused a greater degree of antagonism of AII‐induced renal vasoconstriction, while renal excretory responses to AII remained unaffected.
This study shows that the renal haemodynamic and excretory effects of AII in salt‐replete anaesthetized dogs are mainly mediated by angiotensin AT1 receptors. However, the inhibitory effect of PD123177 on renal vasoconstrictor responses to high doses of AII, raises the possibility that functionally important AT2 receptors are present in the canine renal vasculature.
A comparison of rat brain amino acid and monoamine content in diazepam withdrawal and after exposure to a phobic stimulus
Authors: Andrews Nick , Barnes Nicholas M. , Steward Luanda J. , West Katie E. , Cunningham Jo , Wu Pei‐Ying , Zangrossi Helio , File Sandra E. 
Published: July 2012

The content of amino acids (taurine, glycine, glutamic acid, γ‐aminobutyric acid (GABA) and aspartic acid) and monoamines (5‐hydroxytryptamine (5‐HT), 5‐hydroxyindoleacetic acid (5‐HIAA) and noradrenaline) in homogenates of rat cortical and hippocampal tissue were measured by high performance liquid chromatography (h.p.l.c.) with fluorescent and electrochemical detection respectively, after two anxiogenic treatments: exposure to a phobic stimulus (cat odour) and withdrawal from chronic diazepam treatment.
In neither of the two anxiogenic situations was there a significant change in any amino acid content, in either brain area.
In the group withdrawn from chronic diazepam, cortical 5‐HT and 5‐HIAA levels and hippocampal 5‐HT levels were significantly increased. Noradrenaline content was significantly decreased in the hippocampus.
The changes in 5‐HT and 5‐HIAA levels following cat odour exposure were area‐specific in that they decreased in the hippocampus, but increased in the cortex.
Following cat odour exposure, noradrenaline levels appeared not to change in either area studied. However during exposure to cat odour, it was found that half the animals avoided the odour source and half were indifferent. The animals showing marked avoidance had significantly higher cortical noradenaline content and this was significantly different from control, whereas hippocampal noradrenaline levels were not dependent upon the differences in avoidance of the odour source.
The results show clearly different neurochemical changes in the rat following exposure to a phobic stimulus and withdrawal from diazepam. It is hoped comparative studies such as this will enable better understanding of anxiety states in the rat which could parallel the different classes of anxiety recognised in the clinic
Support of renal blood flow after ischaemic‐reperfusion injury by endogenous formation of nitric oxide and of cyclo‐oxygenase vasodilator metabolites
Authors: Cristol J.P. , Thiemermann C. , Mitchell J.A. , Walder C. , Vane J.R. 
Published: July 2012

Ischaemia‐reperfusion injury in the kidney is associated with a loss of autoregulation, an increase in renal vascular resistance (RVR), a decrease of renal blood flow (RBF) and ultimately acute renal failure. The aim of this study was to investigate the role of the release of endogenous nitric oxide (NO) in the recovery of RBF after ischaemic injury of the renal vascular bed.
Anaesthetized rats (thiopentone sodium; 120 mg kg−1, i.p.) were submitted to acute renal ischaemia followed by 2 or 6 h of reperfusion (I/R). Reperfusion was associated with a significant reduction in RBF, an increase in RVR, and an impairment of the vasodilator effect of acetylcholine (ACh).
NG‐nitro‐l‐arginine methyl ester (l‐NAME, 30 μg kg−1 min−1, i.v., n = 5) significantly prevented the recovery of RBF after I/R injury. Similarly, inhibition of prostanoid formation with indomethacin (5 mg kg−1, i.v., n = 4) significantly enhanced the rise in RVR associated with I/R injury.
Infusion of l‐arginine (l‐Arg; 1 or 3 mg kg−1 min−1, i.v., n = 5 and 4, respectively) or d‐Arg (1 mg kg−1 min−1, i.v., n = 6), starting 30 min after occlusion, did not improve the recovery of RBF. Furthermore, infusion of l‐Arg (20 mg kg−1 min−1 for 15 min; n = 4) had no effect on the I/R‐induced impairment of the vasodilator responses to ACh.
To elucidate the relative importance of the constitutive and inducible NO synthase isoforms for the formation of NO after I/R, calcium‐dependent (constitutive) and calcium‐independent (inducible) NO synthase activities were measured in kidney homogenates obtained from ischaemic or non‐ischaemic kidneys. A calcium‐independent NO synthase activity was not detectable in kidney homogenates obtained from either sham‐operated control rats or from animals subjected to I/R. Moreover, dexamethasone (3 mg kg−1, i.v., 60 min prior to I/R, n = 6), an inhibitor of the induction of NO synthase, had no effect on either RBF or RVR in rats subjected to I/R. In contrast to I/R, lipopolysaccaride (LPS, endotoxin; 5 mg kg−1, i.p., n = 3) caused a significant induction of a calcium‐independent NO synthase activity in the kidney.
These results confirm the importance of the release of vasodilator cyclo‐oxygenase metabolites in the compromised renal circulation and indicate that the formation of NO derived from the constitutive, but not the inducible NO synthase, is also important for the maintenance of RBF after I/R injury of the renal vascular bed.
Effects of vasoactive intestinal polypeptide on antigen‐induced bronchoconstriction and thromboxane release in guinea‐pig lung
Authors: Ciabattoni Giovanni , Montuschi Paolo , Currò Diego , Togna Giuseppina , Preziosi Paolo 
Published: July 2012

Exogenous vasoactive intestinal polypeptide (VIP) infused into the pulmonary artery of isolated and ventilated lungs of guinea‐pigs decreased, in a dose‐dependent fashion (1.0–10.0 nmol), airway resistance and thromboxane B2 (TXB2, the stable hydrolysis product of TXA2) release in the perfusion medium. Prostacyclin (PGI2) synthesis, as reflected by the release of its stable hydrolysis product 6‐oxo‐PGF1α, was unaffected. Pretreatment with the 5‐lipoxygenase inhibitor BWA4c (3.5 × 10−5 m) did not modify the bronchodilatory effect of VIP or its inhibitory action on TXB2 release.
Basal release of immunoreactive VIP from perfused lungs decreased from an initial value of 0.96 ± 0.10 ng min−1 (mean ± s.e.mean) in the first 2 min to an average of 0.58 ± 0.10 ng min−1 in the following 15–20 min.
Antigen challenge with ovalbumin (0.1%) in sensitized lungs caused an anaphylactic reaction in 45% of tested lungs, concomitant with a 5 fold increase in both VIP and TXB2 release. Tetrodotoxin pretreatment (10−6 m) reduced basal VIP release by > 80% and abolished the VIP increase observed during anaphylaxis, without modifying TXB2 release or the bronchoconstrictor response.
Indomethacin (10−6 m) inhibited TXB2 synthesis and release by > 90%, delayed the bronchoconstrictor response and blunted the increased VIP release during lung anaphylaxis, without influencing basal VIP release.
The 5‐lipoxygenase inhibitor BWA4c (3.5 × 10−5 m) blunted the increase of TXB2 and VIP release from guinea‐pig lung and attenuated the bronchoconstrictor response following ovalbumin challenge.
The administration of exogenous VIP as a continuous infusion (10−8 m) attenuated the bronchoconstriction and the release of cyclo‐oxygenase metabolites following antigen challenge.
Acetylcholine (10−6‐10−5 m) infused into the pulmonary artery induced a dose‐dependent bronchoconstriction not associated with enhanced VIP or TXB2 release.
The TXA2 mimetic U‐46619 (0.1–1.0 nmol) caused dose‐dependent increases in airway resistance, concomitant with an up to 10 fold increase in VIP release. VIP inhibited arachidonate‐induced in vitro aggregation of washed rabbit platelets in a dose‐dependent manner over a dose range 10−8‐10−6 M. Despite the antiaggregatory effect of VIP, TXB2 and PGE2 synthesis was reduced only to a minor extent, and there was no redirection of arachidonate metabolism from TXA2 to PGE2, indicating that VIP does not act as a TX synthase inhibitor in vitro.
We conclude that VIP may play a role in regulating bronchial smooth muscle reactivity in lung anaphylaxis by inhibiting the synthesis and release of TXA2, a potent vasoactive and bronchoconstrictor agent. TXA2, on the other hand, strongly enhances neuronal VIP release.
Effects of the κ‐opioid agonist U50,488 on parturition in rats
Authors: Douglas A.J. , Clarke G. , MacMillan S.J.A. , Bull P.M. , Neumann I. , Way S.A. , Wright D.M. , McGrory B.G. , Russell J.A. 
Published: July 2012

The effects of the K‐opioid agonist U50,488 on parturition were studied in the rat.
Given directly after the birth of the second pup U50,488 (5 mg or 10 mg kg−1, i.p.) delayed the birth of the subsequent 4 pups by ca. 100 min, acting like morphine (10 mg kg−1, i.p.). In controls given the vehicle i.p., the birth of the 4 pups after treatment took 45.4 ± 4.6 min. The effects of U50,488 could be prevented by simultaneous naloxone injection (10 mg kg−1). Injection of either U50,488 or morphine at 1 mg kg−1, i.v. also significantly delayed parturition. The effects of U50,488 but not of morphine were fully prevented by preinjection with nor‐binaltorphimine (0.5 mg kg−1, i.v.) showing selective κ‐opioid receptor‐mediated inhibition by U50,488 of established parturition.
In rats with an indwelling jugular venous cannula, i.v. injection of U50,488 (5 mg kg−1) after the birth of the second pup slowed parturition in a similar way to i.p. injection and significantly reduced blood plasma oxytocin concentration measured by radioimmunoassay compared with vehicle‐injected controls.
Bolus i.v. injections of oxytocin (4 mu once per 5 min) significantly reduced the delay in parturition caused by i.v. U50,488, but continuous i.v. infusion of oxytocin (4 mu 5 min−1) was less effective.
Since i.v. oxytocin did not immediately reverse the effects of U50,488 on parturition, direct effects of U50,488 on isometric uterine contractions in vitro were sought. U50,488 inhibited spontaneous or oxytocin‐stimulated contractions of uteri from rats within 24 h after parturition in a dose‐related manner; the inhibitory effect was not naloxone‐reversible.
Thus U50,488 inhibited established parturition in the rat in a κ‐opioid selective manner by reducing oxytocin secretion. The inhibitory effect may well have been potentiated by a direct non‐opioid depressant action on contractile activity of the uterus.
Effect of tienoxolol, a new diuretic β‐blocking agent, on urinary prostaglandin excretion in the rat
Authors: Caussade François , Cloarec Alix 
Published: July 2012

The effects of tienoxolol, (ethyl 2‐[3‐[(1,1‐dimethylethyl)amino]‐2‐hydroxypropoxy]‐5‐[(2‐thienylcarbonyl) amino] benzoate, hydrochloride), a novel drug exhibiting both diuretic and β‐adrenoceptor blocking properties, were investigated on urinary 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) and PGE2 excretion in the rat and compared to those of reference diuretic (furosemide) and β‐adrenoceptor antagonists (acebutolol, propranolol). Since tienoxolol was shown to bind to A1 and A2 adenosine receptors, the action of theophylline was also evaluated.
Tienoxolol (8–128 mg kg−1, p.o.) induced a dose‐related increase of 6‐keto‐PGF1α excretion from 32 mg kg−1 but a significant elevation of urinary PGE2 levels was only reached after administration of 128 mg kg−1. However, renal prostaglandin concentrations were not modified by tienoxolol.
Furosemide (32 mg kg−1) displayed a strong diuretic activity but did not enhance 6‐keto‐PGF1α excretion. Likewise, the latter was unaffected by acebutolol and propranolol (128 mg kg−1) and no significant diuresis was observed following administration of these two β‐blocking agents. Theophylline (64 mg kg−1), like tienoxolol, was able to induce both diuresis and urinary prostaglandin excretion. Furthermore, they bound with similar affinities to A1 and A2 adenosine receptors. This led to the suggestion that a relationship between P1‐purinoceptors, prostaglandin release, diuresis and natriuresis could exist.
Oral co‐administration of NECA (0.2 mg kg−1) with tienoxolol markedly reduced the urinary 6‐keto‐PGF1α excretion observed when tienoxolol was administered alone. However, neither diuresis nor natriuresis were modified, demonstrating that the proposed relationship was untenable.
In conclusion, PGI2 probably does not participate in the diuretic and natriuretic activity of tienoxolol. The increase of urinary 6‐keto‐PGF1α excretion may result not only from the haemodynamic properties of the drug but also from the rise of the urinary flow induced by tienoxolol.
Inhibition by the adenosine analogue, (R‐)‐N6‐phenylisopropyl‐adenosine, of kainic acid neurotoxicity in rat hippocampus after systemic administration
Authors: MacGregor D.G. , Stone T.W. 
Published: July 2012

Binding of the peripheral benzodiazepine receptor ligand, [3H]‐PK 11195, to rat hippocampal membranes has been used to quantify the reactive gliosis resulting from neuronal death induced by intraperitoneally administered kainic acid.
Intraperitoneal administration of kainic acid (10 mg kg−1) caused a 350–500% increase in [3H]‐PK 11195 binding measured in rat hippocampal P2 membranes 7 days later. Co‐treatment with the adenosine derivative R‐phenylisopropyladenosine (R‐PIA) (100, 25 or 10 μg kg−1, i.p.) abolished this elevation. The protective action of R‐PIA could itself be abolished by co‐treatment with 8‐phenyltheophylline (1 mg kg−1).
Body temperatures were recorded in the antagonist experiments and no significant changes were recorded, suggesting that the protective action of R‐PIA was not mediated by hypothermia.
Since systemic kainic acid‐induced neurotoxicity has been claimed as a good model of neuronal death in temporal lobe epilepsy, the results suggest that the systemic administration of purines in low doses may provide protection against certain neurodegenerative insults.
Mechanisms of vasodilatation in pregnancy: studies of the role of prostaglandins and nitric‐oxide in changes of vascular reactivity in the in situ blood perfused mesentery of pregnant rats
Authors: Chu Z.M. , Beilin L.J. 
Published: July 2012

To examine the possible mechanisms of the vasodilatation and blunted pressor responses in late pregnancy, we have studied vascular reactivity of the in situ blood perfused mesenteric resistance vessels of 18–20 day pregnant Wistar‐Kyoto rats (WKY).
Intra‐arterial mean blood pressure (MBP) was lower in pregnant rats than in nonpregnant controls. There was no significant difference in basal mesenteric perfusion pressure (BPP) between groups.
Vascular reactivity to electrical stimulation (ES) or intra‐arterial noradrenaline (NA), angiotensin II (AII) and arginine vasopressin (AVP) was decreased in the preparations from pregnant rats compared to that from nonpregnant controls. Noradrenaline spillover into mesenteric venous blood following ES was similar in pregnant and nonpregnant animals.
Indomethacin (5 mg kg−1, i.v.), an inhibitor of cyclo‐oxygenase, induced significant increases in reactivity to ES in both pregnant and nonpregnant groups while potentiating the responses to NA and AII in nonpregnant animals only and having no effect on AVP‐induced contractions in the preparations from either pregnant or nonpregnant animals.
NG‐nitro‐l‐arginine (l‐NOARG) (5 mg kg−1, i.v.), an inhibitor of nitric‐oxide synthase, increased MBP and BPP in both pregnant and nonpregnant animals, but the difference in MBP between groups was still evident.
l‐NOARG enhanced mesenteric vascular responses to ES, NA and AII in both pregnant and nonpregnant groups. Only the difference in NA responses between groups was abolished after pretreatment with l‐NOARG.
These data show that vasoconstrictor responses to a variety of agonists are decreased in the in situ blood‐perfused mesenteric resistance vessels of pregnant rats. Increase in endothelial‐dependent nitric‐oxide generation could contribute to the vasodilatation seen in pregnancy but other mechanisms might also be involved. Cyclo‐oxygenase products are not responsible for any decreased contractile responses in this preparation.
Interactions between responses mediated by activation of adenosine A2 receptors and α1‐adrenoceptors in the rabbit isolated aorta
Authors: Wiener Harvey L. , Thalody George P. , Maayani Saul 
Published: July 2012

This paper describes aspects of the functional antagonism between the responses mediated by activated α1‐adrenoceptors and adenosine A2 receptors in the adventitia‐ and endothelium‐denuded aorta of the rabbit.
Adenosine A2 receptor agonists relaxed aortic rings pre‐contracted with phenylephrine. The relaxation response was agonist concentration‐dependent and saturable. The respective contractile and relaxation responses were stable, reproducible, and reversible.
Increasing the phenylephrine concentration caused a progressive attenuation of the action of adenosine A2 receptor agonists, consisting of a decreased maximal response and a dextral shift of the adenosine agonist concentration‐response curve. This functional antagonism could be completely reversed upon removal of adenosine by either the addition of adenosine deaminase or by wash‐out of the adenosine agonist from the tissue. The relaxation response to the adenosine A2 receptor partial agonists, N6‐cyclohexyladenosine and R‐(−)‐N6‐(2‐phenylisopropyl)adenosine, was abolished at higher phenylephrine concentrations (e.g. 30 EC50).
A 1000 fold increase in the adenosine concentration was required to shift the value of the EC50 of phenylephrine six fold, while a similar increase in the value of the EC50 of adenosine could be elicited by only a 32 fold increase in the phenylephrine concentration. A 30 fold increase in the phenylephrine concentration shifted the value of the EC50 of 5′‐N‐ethylcarboxamidoadenosine four fold.
Analysis of the functional antagonism between the responses mediated by these receptors using the Black & Leff (1983) operational model of agonism allowed for the estimation of the agonist dissociation constant, KA, and the apparent efficacy, τ, for both phenylephrine and adenosine A2 receptor agonists. Increasing the concentration of phenylephrine reduced the value of τ for adenosine agonists in a concentration‐dependent and saturable manner. Similarly, increasing the concentration of adenosine reduced the value of τ for phenylephrine in a concentration‐dependent and saturable manner. The phenylephrine KA value obtained by the method of functional antagonism (1.9 μm) was similar to that obtained by the receptor inactivation method (2.1 μm).
Partial occlusion of the α1‐adrenoceptor by the alkylating agent, dibenamine, demonstrated that the magnitude of the adenosine A2 receptor‐mediated relaxation was inversely proportional to the number of functional α1‐adrenoceptors.
It is concluded that the magnitude of functional antagonism is proportional to the stimulus elicited through either receptor. We propose that this tissue preparation and pair of receptors is a good model to study quantitative aspects of functional antagonism between activated receptors.
Interaction between the effects of 5‐hydroxytryptamine and adrenaline on the growth of platelet thrombi in the coronary artery of the anaesthetized dog
Authors: McAuliffe S.J.G. , Snow H.M. , Cox B. , Smith C.C.T. , Noble M.I.M. 
Published: July 2012

The interaction between adrenaline and 5‐hydroxytryptamine (5‐HT) has been quantitated on the rate of thrombus formation, in the stenosed coronary artery with damaged endothelium of the anaesthetized dog.
Changes in the plasma concentration of adrenaline were produced by varying the rate of an intravenous infusion of adrenaline and in the effects of 5‐HT, by intravenous injections of the selective 5‐HT2 receptor antagonist, ICI 170809.
Increases in the plasma concentration of adrenaline, which did not cause significant changes in blood pressure and heart rate, increased the rate of thrombus formation.
Antagonism of the 5‐HT2 receptor by ICI 170809, in the absence of an infusion of adrenaline, abolished thrombus formation (mean ED50 0.41 μg kg−1, i.v.).
The effects of adrenaline were non‐competively antagonized by ICI 170809; maximum effects were obtained in the dose‐range 50–200 μg kg−1, i.v., when the mean dose‐ratio increase in adrenaline required to restore equivalent rates of thrombus formation was 39 fold.
These results are consistent with a synergism between adrenaline and 5‐HT and emphasize the importance of both on thrombus formation.