bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclic GMP release and vasodilatation induced by EDRF and atrial natriuretic factor in the isolated perfused kidney of the rat
Authors: Burton G.A. , MacNeil S. , DE Jonge A. , Haylor J. 
Published: July 2012

Guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) release and vascular tone was measured in the isolated kidney of the rat perfused at constant flow with Krebs‐Henseleit solution. The effects of 3 vasodilators, acetylcholine (ACh), atrial natriuretic factor (ANF) and sodium nitroprusside (SNP) on the renal release of cyclic GMP and vascular tone were examined. The ability of the endothelial‐derived relaxing factor (EDRF) inhibitors, haemoglobin and gossypol, to modify vasodilatation and vasodilator‐induced changes in cyclic GMP releases from the kidney was also investigated.
Renal cyclic GMP release was elevated 8 fold by ANF (0.01 μm), 5 fold by SNP (1 μm) and 3 fold by ACh (0.3 μm).
For ACh, both the increase in renal cyclic GMP release and the vasodilatation were reduced by the EDRF inhibitors, haemoglobin (1 μm) and gossypol (15 μm). For SNP, neither the increase in renal cyclic GMP release nor vasodilatation were inhibited by gossypol (15 μm).
For ANF, neither the increase in cyclic GMP release from the kidney nor its vasodilator activity were affected by haemoglobin (1 μm).
EDRF inhibitors reduced the basal release of cyclic GMP from 0.32 ± 0.06 pmol min−1 to 0.18 ± 0.03 pmol min−1, gossypol being more effective than haemoglobin.
The results are consistent with the ability of ACh to induce EDRF‐mediated vasodilatation in the isolated perfused kidney of the rat. Basal EDRF release appears to contribute approximately 50% to the basal release of cyclic GMP from this preparation. The renal vasodilator action of ANF however, is independent of EDRF, although the renal vascular endothelium cannot be discounted as a site at which ANF stimulates cyclic GMP production.
Inhibition of elevated arginine vasopressin secretion in response to osmotic stimulation and acute haemorrhage by U‐62066E, a κ‐opioid receptor agonist
Authors: Yamada K. , Nakano M. , Yoshida S. 
Published: July 2012

The effect of kappa (κ) opioid receptor activation on the increase in arginine vasopressin (AVP) secretion evoked by two acute and quite different stimuli (i.e., haemorrhage and osmotic stimulus due to hypertonic saline infusion) were evaluated in conscious Long‐Evans rats, by use of U‐62066E, a highly selective κ‐opioid receptor agonist, and MR2266, an opioid receptor antagonist with some selectivity for κ‐receptors.
An acute haemorrhage, which reduced the mean blood pressure by approximately 50%, resulted in a large increase in the plasma AVP (pAVP) levels of control rats. However, the administration of U‐62066E (0.2 mg kg−1 or 2.0 mg kg−1) reduced the increase due to haemorrhage in a dose‐dependent manner. In contrast, concomitant administration of 2.0 mg kg−1 of MR2266 with U‐62066E significantly attenuated the inhibition of pAVP levels produced by U‐62066E 2.0 mg kg−1.
Hypertonic saline infusion (5% hypertonic saline solution at a rate of 0.24 ml kg−1 min−1 for 10 min) caused the elevation of plasma osmolality (pOsm) from 294.0 ± 1.6 mosmol kg−1 to 304.4 ± 1.9 mosmol kg−1, simultaneously resulting in a significant increase in pAVP levels from 2.34 ± 0.28 pg ml−1 to 4.54 ± 0.51 pg ml−1. However, the administration of U‐62066E (0.05 mg kg−1 or 0.2 mg kg−1) reduced the osmotically induced increase in pAVP in a dose‐dependent manner although pOsm showed the same degree of increase as in controls. In contrast, concomitant administration of 0.2 mg kg−1 of MR2266 with U‐62066E significantly attenuated the inhibition of pAVP levels produced by U‐62066E 0.2 mg kg−1, whereas pOsm showed the same degree of increase as in controls. No significant changes in the mean blood pressure of the respective groups were observed during this experiment.
It is suggested that the κ‐opioid receptor activation reduces the increase in AVP secretion evoked by these two different stimuli and that the inhibitory involvement occurs in the neural lobe in the process of AVP secretion.
Prevention of non‐specific airway hyperreactivity after allergen challenge in guinea‐pigs by the PAF receptor antagonist SDZ 64–412
Authors: Havill Andrew M. , van Valen Ronald G. , Handley Dean A. 
Published: July 2012

Allergen challenge by aerosol in sensitized guinea‐pigs elicited non‐specific airway hyperreactivity assessed by reactivity to i.v. histamine or acetylcholine. Airway hyperreactivity to histamine persisted for at least 48 h and was accompanied by pulmonary eosinophilia as determined by bronchoalveolar lavage cell analysis.
Airway hyperreactivity was independent of vagal reflex mechanisms since it was not abrogated by bilateral vagotomy.
The novel platelet‐activating factor (PAF) receptor antagonist SDZ 64–412 inhibited the development of airway hyperreactivity, as measured 24 h after aerosol allergen challenge, when given as a single treatment orally 2 h before allergen challenge. The PAF receptor antagonist WEB 2086 as well as methylprednisolone and ketotifen also showed efficacy in preventing development of airway hyperreactivity.
Neither the two PAF antagonists nor ketotifen had any effect on bronchoalveolar lavage (BAL) eosinophil numbers. Methylprednisolone was the only substance which readily prevented eosinophil recruitment in addition to airway hyperreactivity.
We conclude that allergen‐induced airway hyperreactivity in guinea‐pigs is inhibited by prophylactic anti‐asthma drugs and specific PAF receptor antagonists, thus demonstrating a pivotal role of PAF in this response. There was a lack of correlation between airway hyperreactivity and the presence of BAL eosinophils.
Muscarinic receptor stimulation and cyclic AMP‐dependent effects in guinea‐pig ventricular myocardium
Authors: Schmied Robert , Korth Michael 
Published: July 2012

The effect of carbachol on force of contraction, contraction duration, intracellular Na+ activity and cyclic AMP content was studied in papillary muscles of the guinea‐pig exposed to isoprenaline or the phosphodiesterase inhibitor 3‐isobutyl, 1‐methyl xanthine (IBMX). The preparations were obtained from reserpine‐pretreated animals and were electrically driven at a frequency of 0.2 Hz.
Isoprenaline (10 nm) and IBMX (100 μm) produced comparable positive inotropic effects of 9.8 and 9.7 mN, respectively. Carbachol (3 μm) attenuated the inotropic effects by 82% (isoprenaline) and by 79% (IBMX). The shortening of contraction duration which accompanied the positive inotropic effect of isoprenaline (by 14.9%) and of IBMX (by 22.4%) was not significantly affected by 3 μm carbachol.
The positive inotropic effect of 10 nm isoprenaline and of 100 μm IBMX was accompanied by an increase in cellular cyclic AMP content of 58 and 114%, respectively. Carbachol (3 μm) failed to reduce significantly the elevated cyclic AMP content of muscles exposed to either isoprenaline or IBMX.
In the quiescent papillary muscle, isoprenaline (10 nm) and IBMX (100 μm) reduced the intracellular Na+ activity by 28 and 17%, respectively. This decline was not influenced by the additional application of 3 μm carbachol.
The results demonstrate that muscarinic antagonism in guinea‐pig ventricular myocardium exposed to cyclic AMP‐elevating drugs is restricted to force of contraction. The underlying mechanism does not apparently involve the cytosolic signal molecule cyclic AMP.
Antagonism of GABAB‐receptor‐mediated responses in the guinea‐pig isolated ileum and vas deferens by phosphono‐analogues of GABA
Authors: Kerr David I.B. , Ong Jennifer , Prager Rolf H. 
Published: July 2012

The phosphono‐analogues of γ‐aminobutyric acid (GABA), 4‐amino‐butylphosphonic acid (4‐ABPA), 3‐amino‐2‐(4‐chlorophenyl)‐propylphosphonic acid (phaclofen) and 3‐amino‐2‐cyclohexylpropylphosphonic acid, each antagonized the GABA‐ and baclofen‐induced GABAB‐receptor‐mediated depression of twitch responses to transmural stimulation in the guinea‐pig isolated ileum, in a concentration‐dependent, reversible and surmountable manner (apparent pA2 = 4.0 ± 0.1, 4 ± 0.2 and 3.7 ± 0.2 respectively, compared with 3.9 ±0.1 for δ‐aminovaleric acid). No such activity was found in a variety of related analogues.
By contrast, 3‐amino‐propylphosphonic acid (3‐APPA) behaved as a partial agonist, itself partly depressing ileal twitch contractions in a manner sensitive to 4‐ABPA and phaclofen, as well as antagonizing the depression of the ileal twitch by GABA and baclofen (apparent pA2 = 4.0 ± 0.2).
Both 4‐ABPA and phaclofen also antagonized the baclofen‐induced depression of the twitch in the guinea‐pig isolated vas deferens (apparent pA2 = 4.0 ± 0.1 for each), whilst 3‐APPA behaved as a partial agonist, slightly depressing the vas twitch, and antagonised the baclofen‐induced depression of the twitch (apparent pA2 = 3.9 ±0.1).
None of these phosphono‐analogues exhibited any action at ileal GABAA‐receptors, nor influenced the ileal twitch depression with morphine, adenosine or noradrenaline, suggesting their selectivity as antagonists at GABAB‐receptors.
Simultaneous perfusion of rat isolated superior mesenteric arterial and venous beds: comparison of their vasoconstrictor and vasodilator responses to agonists
Authors: Warner Timothy D. 
Published: July 2012

A new isolated perfused preparation is described that allows a direct comparison to be made of the responses of the perfused arterial and retrogradely perfused venous circulations of the rat superior mesenteric vascular bed.
In experiments comparing the responses of the intact arterially perfused mesentery and small intestine to those of the same preparation following removal of the intestine and division of the circulations, the increases in perfusion pressure produced by arginine‐vasopressin (30 pmol) and noradrenaline (1 nmol) were retained by the arterial circulation and those induced by angiotensin II (30pmol) by the venous circulation. Endothelin‐1 (30pmol) constricted both portions of the vasculature but the prolonged nature of its response was associated with only the venous vessels.
In the simultaneously perfused arterial and venous preparation arginine vasopressin (3–100 pmol) was a selective constrictor of the arterial circulation and angiotensin II (3–100 pmol) of the venous circulation. In addition, noradrenaline (0.3–10 nmol), 5‐hydroxytryptamine (0.3–10 nmol) and KCl (1–60 μmol) were more active as constrictors of the arterial than the venous vessels, and U46619 (10–300 pmol) a more active constrictor of the venous than the arterial vessels. Endothelin‐1 (3–100 pmol) constricted both the arterial and venous portions of the vasculature but was significantly longer acting as a venoconstrictor than an arterioconstrictor.
Angiotensin I (300 pmol) caused constrictions of the venous circulation which were dependent upon the presence of angiotensin converting enzyme for captopril (10 μm) abolished constrictions caused by angiotensin I but not by angiotensin II.
In preparations preconstricted by U46619 (0.3–3 μm), acetylcholine (0.01–100 nmol), bradykinin (0.001–1 nmol), sodium nitroprusside (0.01–10 nmol) or isoprenaline (1–100 pmol) produced dose‐related dilatations of both the arterial and the venous vasculatures, whereas adenosine diphosphate (ADP, 0.01–100 nmol) caused dose‐dependent dilatations of the arterial circulation but principally constrictions of the venous circulation. The dilatations caused by acetylcholine and bradykinin in both portions of the circulation, and by ADP in the arterial circulation, were endothelium‐dependent as they were inhibited by gossypol (3 μm), whereas dilatations to sodium nitroprusside were not.
This preparation allows the responses of the arteries and veins of a single perfused mesenteric bed to be compared. In addition, with this preparation it is possible to demonstrate that veins, as well as arteries, show significant endothelium‐dependent relaxations. It is concluded that the venous portion of the vasculature is significantly involved in the responses of the intact circulation.
Continuous fluorimetric assessment of the changes in cytoplasmic calcium concentration during exposure of rat isolated myocardium to conditions of simulated ischaemia
Authors: Northover B.J. 
Published: July 2012

The cytoplasmic calcium concentration ([Ca]c) of rat isolated atrial myocardium was assessed with the dye indo‐1. Dye‐loaded atria were superfused with physiological salt solution and excited with radiation at 360 nm, while epifluorescence emissions were collected simultaneously at 400 nm and 500 nm. The ratio of these emissions was used as a measure of [Ca]c.
Dye‐loaded atria showed a phasic rise and fall in [Ca]c with each applied electrical pacing stimulus. The amplitudes of systolic increments in tension and [Ca]c were augmented by the presence of isoprenaline.
Atria superfused with a solution the composition of which resembled that found extracellularly in regions of ischaemia rapidly lost systolic increments in tension and [Ca]c, while end‐diastolic [Ca]c and tension gradually rose.
The presence of lactate (20 μm) or flufenamate (5 μm) in the superfusate during simulated ischaemia aggravated the rises in both end‐diastolic tension and end‐diastolic [Ca]c. Inclusion in the superfusate of sulphinpyrazone (50 μm) or glucose (20 mm) protected against some of the deleterious effects of lactate seen during simulated ischaemia.
Characterization of the adenosine receptor in porcine coronary arteries
Authors: King A.D. , Milavec‐Krizman M. , Müller‐Schweinitzer E. 
Published: July 2012

Relaxant responses of ring preparations from porcine ventricular coronary arteries to adenosine and various stable adenosine analogues were investigated in vitro.
The adenosine analogues did not produce contraction but elicited almost complete relaxation of coronary arteries preconstricted with 3 μm prostaglandin F2α (PGF2α), even after removal of the endothelium.
The order of potency, was 5′‐N‐ethylcarboxamide‐adenosine (NECA) > 2‐(2‐phenylethylamino)5′‐N‐ethylcarboxamide‐adenosine (2‐PEA‐NECA) > 2‐phenylamino‐adenosine (CV‐1808) > N6‐[S(−)−1‐phenyl‐2‐propyl]adenosine (S‐PIA) > N6‐[S(+)‐1‐phenyl‐2‐propyl]adenosine (S‐PIA) > N6‐cyclopentyl‐adenosine (CPA) > adenosine > ATP = ADP which suggested the presence of adenosine A2‐receptor subtypes.
There was an excellent correlation between the calculated pD2 values on coronary arteries and the pKD values at adenosine A2 binding sites, whereas no correlation was obtained when the pD2 values were compared to the pKD values at adenosine A1‐binding sites on membranes from porcine striata.
The relaxant effects of adenosine and its analogues were competitively antagonized by 8‐(P‐sulphophenyl)‐theophylline (8‐SPT), producing pA2 values similar to the respective pKD value of the antagonist at adenosine A2 binding sites.
It is suggested that the porcine coronary artery possesses adenosine A2 receptors which seem to be similar to the adenosine A2 binding site in pig striatum, whereas no evidence was obtained for the presence of adenosine A1 receptors.
Influence of capsaicin‐sensitive afferent neurones on the acid secretory responses of the rat stomach in vivo
Authors: Esplugues J.V. , Ramos E.G. , Gil L. , Esplugues J. 
Published: July 2012

The influence of capsaicin‐sensitive afferent neurones in modulating acid‐secretory responses has been investigated in the continuously perfused stomach of the anaesthetized rat.
Ablation of primary afferent neurones, after systemic neonatal pretreatment with high doses of capsaicin, did not modify acid responses to direct stimuli of the oxyntic cell with histamine (5 mg kg_1), pentagastrin (20 μg kg−1) or carbachol (4 μg kg−1).
Acid responses to hypoglycaemia induced by insulin (0.3 iu kg−1) were not influenced by systemic capsaicin pretreatment or by acute coeliac ganglionectomy. Vagotomy abolished this secretory response.
The increase in acid output induced by gastric distension (20 cmH2O) was abolished by systemic neonatal capsaicin pretreatment. Likewise, vagotomy and acute coeliac ganglionectomy eliminated this secretory response.
Acute intragastric infusion with high doses of capsaicin inhibited the acid responses to distension but failed to modify the increase in acid output induced by insulin.
Local application (7–14 days before) of capsaicin to the coeliac ganglion abolished the acid response to gastric distension. This lack of secretory response was not the result of a nonspecific destruction of the ganglion, since changes in intragastric pressure after electrical stimulation of the coeliac ganglion were unaffected by such treatment.
These observations indicate that peripheral capsaicin‐sensitive sensory neurones, located both in the gastric mucosa and in the coeliac ganglion, play a physiological role in the acid secretory responses to gastric distension.
A study of the pyrogenic actions of interleukin‐1α and interleukin‐1β: interactions with a steroidal and a non‐steroidal anti‐inflammatory agent
Authors: Davidson J. , Milton A.S. , Rotondo D. 
Published: July 2012

The pyrogenic effects of intravenously administered human recombinant interleukin‐1α (IL‐1α) and IL‐1β were studied in the rabbit.
Both cytokines produced dose‐related increases in body temperature. At all doses studied (100–5000 u kg−1) both cytokines elicited a monophasic increase in body temperature, beginning 15 min and reaching a maximum 45 min after administration.
A comparison of thermal response index (TRI2, the magnitude of febrile responses over 2 h obtained by integrating the change in temperature in °C against time in hours) values indicated that IL‐1β (500 u kg−1, TRI2 = 0.69 ± 0.04, n = 4) was approximately 5 fold more potent than IL‐1α (2500 u kg−1, TRI2 = 0.73 ± 0.07, n = 4, all values are means ± s.e.means) in elevating body temperature. ΔTmax values for the above doses of IL‐1β and IL‐1α were 0.60 ± 0.06 and 0.61 ± 0.03 respectively. When IL‐1α and IL‐1β were heated for 30 min at 60°C prior to administration no biological activity was observed.
A cyclo‐oxygenase inhibitor, ketoprofen (3 mg kg−1) administered 15 min before either cytokine completely abolished the fever induced by both IL‐1α (2500 u kg−1) and IL‐1β (500 u kg−1).
Intravenous administration of the steroidal anti‐inflammatory agent dexamethasone (3 mg kg−1) 1 h before either cytokine attenuated the fever induced by IL‐1α (2500 u kg−1) and IL‐1β (500 u kg−1).
The effects of ketoprofen and dexamethasone on IL‐1 pyrogenicity indicate that prostanoids are almost certainly involved in the responses. The different potencies of IL‐1α and IL‐1β may be related to their relative ability to stimulate prostanoid biosynthesis.
Action of noradrenaline on isolated proximal and distal coronary arteries of rat: selective release of endothelium‐derived relaxing factor in proximal arteries
Authors: Nyborg Niels C. Berg 
Published: July 2012

The effect of noradrenaline (NA) on the vascular smooth muscle and endothelial cells in isolated ring segments from the proximal and distal part of the left coronary artery (LCA) in rats was examined.
NA had a weak concentration‐dependent contractile effect on proximal but relaxed distal segments of the LCA. The maximal NA‐induced contraction of the proximal segments was doubled while the relaxation of the distal LCA segments was converted to a contraction after blockade of β‐adrenoceptors with propranolol 3 × 10−6m, thus indicating the presence of both α‐ and β‐adrenoceptors in the arteries, with dominance of α‐adrenoceptors and of β‐adrenoceptors in the proximal and distal segments of the LCA, respectively.
The contractile effect of NA (β‐adrenoceptors blocked) was doubled in the proximal LCA segments after the endothelium was removed. Endothelial denudation had, in contrast, no potentiating effect on the contractile response of the distal arteries to NA. Both proximal and distal segments became more sensitive to the contractile action of NA after removal of the endothelium.
The spontaneous myogenic tone increased in both proximal and distal LCAs after endothelial removal, indicating spontaneous release of a relaxing endothelial factor in the vessels.
Following contraction with prostaglandin F2α (PGF2α), and in the presence of propranolol, 3 × 10−6 m, and prazosin, 10−6 m, NA induced an endothelium‐dependent relaxation of only proximal but not distal segments of the precontracted LCA. The NA‐induced relaxation of the proximal segments of the LCA was not altered by indomethacin 10−5 m but was completely abolished after incubation with methylene blue, 3 × 10−6 m, or following endothelium removal. These results are compatible with NA‐induced release of EDRF in these arteries.
The selective α2‐adrenoceptor agonist, B‐HT 933, only induced a weak relaxation of PGF2α‐precontracted proximal (endothelium intact) LCA segments at a concentration of 10−4m. The NA‐induced relaxation of these vessels was unaffected by incubating the vessels with 10−5 m B‐HT 933. The NA relaxation response curve was shifted ca 1.1 log unit to the right by rauwolscine, 10−6m, giving an estimated pA2‐value of 7.12. The receptor through which NA activates the endothelium appears to be of an atypical α2‐subtype.
Evidence for the involvement of cyclic GMP in adenosine‐induced, age‐dependent vasodilatation
Authors: Moritoki Hideki , Matsugi Takeshi , Takase Hideshi , Ueda Haruyasu , Tanioka Asao 
Published: July 2012

Adenosine‐induced dilatation of rat aorta was present in aorta taken from 4 week‐old rats, attenuated with increase in age of rats to 8 weeks, and was virtually absent in the aorta from 12 week‐old rats.
Removal of the endothelium by mechanical rubbing attenuated adenosine‐induced dilatation.
Haemoglobin and methylene blue partly reversed the adenosine‐induced endothelium‐dependent dilatation.
The order of potency of adenosine derivatives was 5′‐(N‐ethylcarboxamido)adenosine (NECA) > 2‐phenylaminoadenosine (CV‐1808) > 2‐chloroadenosine > N6‐([R]‐[‐]‐phenylisopropyl)adenosine (R‐PIA) > adenosine > N6‐cyclohexyladenosine (CHA) > N6‐([S]‐[+]‐phenylisopropyl)adenosine (S‐PIA), indicating that adenosine receptors mediating the dilatation are of the A2 subtype.
[3H]‐NECA bound to preparations of membranes from rats of 4 weeks old; it was displaced more effectively by NECA and the A2 ligand CV‐1808 than by the A1 ligands CHA and S‐PIA. ligands CHA and S‐PIA.
The number but not affinity of specific binding sites for NECA decreased considerably with increase in age of rats to 8 weeks, and binding sites for [3H]‐NECA were hardly detected in membrane preparations from rats of 20 weeks old.
Adenosine caused a marked increase in cyclic GMP production, but did not induce an increase in the cyclic AMP level.
This increase in cyclic GMP production induced by adenosine was abolished by methylene blue or 8‐phenyltheophylline, or by removal of the endothelium.
The age‐associated decrease in adenosine‐induced dilatation was found to be associated with a reduction in the formation of cyclic GMP, but not of cyclic AMP.
These results suggest that adenosine causes dilatation via A2 receptors by inducing production of an endothelium‐derived relaxing factor (EDRF), which in turn stimulates soluble guanylate cyclase, and so increases production of cyclic GMP. It is also suggested that the main reason for the age‐associated decrease in adenosine‐induced dilatation is a decrease in the number of A2‐receptors or the ability of the endothelium to produce EDRF, leading to decreased production of cyclic GMP.