bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of idazoxan and other α2‐adrenoceptor antagonists on urine output in the rat
Authors: Jackson Helen C. , Griffin Ian J. , Birkett Sonia D. , Nutt David J. 
Published: July 2012

In normally‐hydrated Wistar rats the α2‐adrenoceptor antagonist, idazoxan (1, 3, 10 mg kg−1 i.p.), increased urine output during the 6 h following injection.
The more selective and specific α2‐adrenoceptor antagonist, RX811059 (0.3, 1, 3 mg kg−1 i.p.), and the peripherally‐acting α2‐adrenoceptor antagonist, L‐659,066 (1, 3, 10 mg kg−1 i.p.), had no effect on urine output in normally‐hydrated animals.
In rats given a 25 ml kg−1 water‐load orally, idazoxan (10 mg kg−1, i.p.) produced an initial antidiuretic response which was followed by an increase in urine output which was apparent 4 and 6 h after drug administration.
RX811059 (1, 3 mg kg−1 i.p.) and L‐659,066 (3, 10 mg kg−1 i.p.) significantly decreased urine output in water‐loaded rats in the 2 h after injection.
The antidiuretic effects of L‐659,066 were attenuated in Brattleboro rats which are deficient in vasopressin; only the highest dose (10 mg kg−1 i.p.) decreased urine output, and this was only a small response in comparison with its virtual abolition of urine output in water‐loaded Wistar rats.
The results with the selective α2‐adrenoceptor antagonists in Wistar and Brattleboro rats suggest that α2‐adrenoceptors in the periphery may play a physiological role in the control of water balance through a mechanism which involves vasopressin.
The paradoxical diuretic effects of idazoxan contrast with the effects of the other α2‐adrenoceptor antagonists and therefore may be attributed to a property of this compound unrelated to α2‐adrenoceptor blockade.
Peripheral analgesic activities of peptides related to α‐melanocyte stimulating hormone and interleukin‐1β193–195
Authors: Poole S. , Bristow A.F. , Lorenzetti B.B. , Das R.E. Gaines , Smith T.W. , Ferreira S.H. 
Published: July 2012

The hyperalgesic effects of interleukin‐1β (IL‐1β) and prostaglandin E2 (PGE2) were measured in rats.
Hyperalgesic responses to IL‐1β were inhibited in a dose‐dependent manner by α‐melanocyte stimulating hormone (α‐MSH)‐related peptides with the following order of potency: [N14,d‐Phe7]α‐MSH > α‐MSH > Lys‐d‐Pro‐Val > Lys‐Pro‐Val > Lys‐d‐Pro‐Thr > d‐Lys‐Pro‐Thr.
Hyperalgesic responses to PGE2 were not inhibited by Lys‐d‐Pro‐Thr and d‐Lys‐Pro‐Thr but were inhibited in a dose‐dependent manner by the other peptides with the same order of potency as against IL‐1β.
The potencies of [N14, d‐Phe7]α‐MSH and α‐MSH were greatly diminished by deletion of their C‐terminal tripeptide, Lys11‐Pro‐Val13.
Nor‐binaltorphimine (Nor‐BNI) largely reversed the analgesic effects of α‐MSH, [N14, d‐Phe7]α‐MSH, Lys‐Pro‐Val and Lys‐d‐Pro‐Val indicating that κ‐opioid receptors mediated the analgesic activity of these peptides.
Nor‐BNI did not antagonize the inhibition by Lys‐d‐Pro‐Thr and d‐Lys‐Pro‐Thr of IL‐1β evoked hyperalgesia indicating that these peptides were not acting via κ‐opioid receptors.
Pituitary adenylate cyclase activating polypeptides, PACAP‐27 and PACAP‐38: stimulators of electrogenic ion secretion in the rat small intestine
Authors: Cox Helen M. 
Published: July 2012

The effects of pituitary adenylate cyclase activating polypeptide (PACAP)‐27 and PACAP‐38 were investigated and compared with vasoactive intestinal polypeptide (VIP) responses in voltage clamped preparations of rat jejunum. Under these conditions electrogenic ion secretion was continuously recorded.
PACAP‐27 is the most potent secretagogue described thus far, exhibiting a concentration‐dependent dual secretory action. At low concentrations it stimulated rapid, transient secretory responses (not seen with either PACAP‐38 or VIP) and these were inhibited by tetrodotoxin (TTX). At higher nm concentrations of PACAP‐27 more prolonged secretory responses predominated which were insensitive to TTX.
In the presence of TTX, the concentration‐response curve to PACAP‐27 gave an EC50 value of 29.4 ± 5.4 nm (n = 4) compared with 0.8 ± 0.1 nm (n = 9) for PACAP‐27 alone and 30.6 ± 5.6 nm (n = 5) for PACAP‐38. C‐terminal fragments of PACAP‐38 were not significantly effective.
Blockade of muscarinic and nicotinic receptors partially inhibited the low concentration effects of PACAP‐27. Substance P densensitization and capsaicin pretreatment were effective at inhibiting the transient secretory PACAP‐27 responses. Evidence is presented for selective, high affinity PACAP‐27 receptors on submucous neurones innervating the mucosal region of the rat jejunum.
Enteral absorption of octreotide: absorption enhancement by polyoxyethylene‐24‐cholesterol ether
Authors: Drewe Jürgen , Fricker Gert , Vonderscher Jacky , Beglinger Christoph 
Published: July 2012

The somatostatin octapeptide‐analogue octreotide was absorbed as an intact peptide from the gastro‐intestinal tract with an absolute bioavailability of about 0.3% in rats. Administration of octreotide in the presence of polyoxyethylene (24)‐cholesterol‐ether (POECE) resulted in an about 23 fold increase of bioavailability.
In vitro studies with Caco‐2 cells showed a dose‐dependent increase in octreotide permeation with increasing doses of coadministered POECE. The use of [3H]‐polyethyleneglycol (PEG) 4000 as an extracellular marker also indicated that higher doses of POECE may partly enhance paracellular transport of macromolecules.
By means of fluorescence microscopy it was shown that transepithelial transport of the fluorescent octreotide analogue (4‐nitrobenzo‐2‐oxa‐1,3‐diazol [NBD] labelled octreotide) was enhanced by the addition of POECE. Besides an increased enterocyte uptake, there was evidence of enhanced partition of NBD‐octreotide into the intercellular space between enterocytes after co‐administration of POECE. In addition, there appeared to be changes in the hepatic topographic disposition of NBD‐octreotide when it was given together with POECE compared with its administration alone.
In a study in healthy volunteers, 16 mg POECE significantly enhanced by 8 fold the absorption of octreotide after oral administration.
Protective effects of bradykinin on the ischaemic heart: implication of the B1 receptor
Authors: Chahine R. , Adam A. , Yamaguchi N. , Gaspo R. , Regoli D. , Nadeau R. 
Published: July 2012

We studied the role of bradykinin (BK) and its active metabolite Des‐Arg9‐BK on noradrenaline release in association with the incidence of ventricular arrhythmias at reperfusion of the ischaemic myocardium.
Experiments were performed in Langendorff perfused isolated hearts of rats subjected to 30 min no flow followed by 5 min reperfusion. The electrocardiogram was monitored continuously and noradrenaline was measured in the effluent as well as in the myocardial tissue.
In untreated hearts, cumulative noradrenaline overflow following global ischaemia reached 226 ± 35 pmol g−1 of heart (n = 8, P < 0.05) during the 5 min of reperfusion along with ventricular tachycardia and/or fibrillation. A decrease in myocardial noradrenaline (–31%) was also observed.
Bradykinin perfused at concentrations between 0.01 and 1 μm, 10 min before flow was stopped and at reperfusion, inhibited noradrenaline overflow in a concentration‐dependent manner. At a concentration of 1 μm, bradykinin completely abolished noradrenaline overflow. For the same concentration of bradykinin, myocardial noradrenaline contents were significantly higher (n = 5–8, P < 0.05). Ventricular fibrillation but not ventricular tachycardia was also prevented.
Des‐Arg9‐BK (0.1 μm) in the same experimental conditions had similar effects. While Hoe 140, a selective antagonist at B2 receptors, did not abolish the effects of bradykinin, Lys [Leu8] Des‐Arg9‐BK, an antagonist at B1 receptors, abolished the effects of both Des‐Arg9‐BK and bradykinin.
These results suggest that the cardioprotective action of bradykinin in the preparation may be mediated partially by an inhibitory effect on noradrenaline liberation which could be mediated by the activation of B1 receptors.
Allopurinol and amlodipine improve coronary vasodilatation after myocardial ischaemia and reperfusion in anaesthetized dogs
Authors: Sobey Christopher G. , Dalipram Romina A. , Woodman Owen L. 
Published: July 2012

We have assessed the effect of allopurinol, amlodipine and propranolol pretreatment on both endothelium‐dependent and endothelium‐independent coronary vasodilatation in vivo, by comparing pre‐ischaemic responses with those measured after 60 min of coronary artery occlusion and 30 min of reperfusion in anaesthetized dogs.
In 15 untreated dogs ischaemia and reperfusion attenuated the increases in coronary blood flow produced by either acetylcholine (0.01–0.05 μg kg−1, i.a.) or glyceryl trinitrate (0.05–0.2 μg kg−1, i.a.), to an average of 39 ± 4% and 42 ± 5% of the pre‐ischaemic control response, respectively (both P < 0.05).
In 5 dogs treated with allopurinol (25 mg kg−1, orally, 24 h previously, plus 50 mg kg−1, i.v., 5 min before occlusion), the increases in coronary blood flow after ischaemia and reperfusion (acetylcholine: 78 ± 12%, glyceryl trinitrate: 60 ± 3% of pre‐ischaemic response) were significantly larger than post‐ischaemic responses in untreated dogs (both P < 0.05).
Similarly, amlodipine treatment (3 μg kg−1 min−1, i.v., starting 90 min before occlusion) in 5 dogs improved post‐ischaemic increases in blood flow (acetylcholine: 58.5%, glyceryl trinitrate: 66 ± 6% of pre‐ischaemic response, significantly greater than post‐ischaemic responses in untreated dogs, P < 0.05).
In contrast, in a further 6 dogs pretreated with propranolol (1 mg kg−1, i.v., 30 min before occlusion, plus 0.5 mg kg−1 h−1, i.v.), blood flow responses after ischaemia and reperfusion were not different from post‐ischaemic responses in untreated dogs (acetylcholine: 46 ± 6%, glyceryl trinitrate: 46 ± 6% of pre‐ischaemic response).
These results suggest that allopurinol and amlodipine protect against the post‐ischaemic impairment of endothelium‐dependent and endothelium‐independent coronary vasodilatation in vivo by mechanisms additional to endothelial protection.
Mediators of nonadrenergic, noncholinergic inhibition in the proximal, middle and distal regions of rat colon
Authors: Suthamnatpong Naowarat , Hata Fumiaki , Kanada Atsunori , Takeuchi Tadayoshi , Yagasaki Osamu 
Published: July 2012

The mediators of non‐adrenergic non‐cholinergic (NANC) relaxation of the longitudinal muscle of rat proximal, middle and distal colon were examined in vitro.
Electrical transmural stimulation (TMS) of proximal, middle and distal segments of rat colon induced NANC relaxations which were inhibited by tetrodotoxin (1 μm), but not by atropine (1 μm) or guanethidine (4 μm).
In the proximal colon, l‐nitro‐arginine (N5‐nitroamidino‐l‐2,5‐diaminopentanoic acid) inhibited the TMS‐induced NANC relaxation and l‐arginine (1 mm) reversed this inhibition. Nitric oxide (0.3–10 μm) induced relaxation of the proximal segment.
NANC relaxation of the proximal segments was still evident after desensitization to vasoactive intestinal peptide (VIP). A VIP antagonist (VIP 10–28, 10 μm) had no effect on the TMS‐induced NANC relaxation, which was also resistant to α‐chymotrypsin (2 units ml−1) and a substance P antagonist ([d‐Pro2, d‐Trp7,9]substance P, 1 μm).
In the middle colon, l‐nitro‐arginine did not inhibit the TMS‐induced NANC relaxation in 6 of 9 preparations tested and partially inhibited the relaxation in the other 3 preparations. l‐Arginine did not reverse the partial inhibition.
Complete desensitization to VIP was not achieved in the middle colon. The VIP antagonist had no effect on the TMS‐induced NANC relaxation. After α‐chymotrypsin treatment of the segment, desensitization of the segments to substance P, or in the presence of the substance P antagonist, the TMS‐induced NANC relaxation was augmented.
In the distal colon, l‐nitro‐arginine did not have any significant effect on the TMS‐induced relaxation and nitric oxide did not induce relaxation. The VIP antagonist significantly inhibited TMS‐induced NANC relaxation. α‐Chymotrypsin‐treatment of the distal segments resulted in significant inhibition of NANC relaxation. No desensitization to substance P was achieved. Treatment with the substance P antagonist had no effect.
These results suggest that nitric oxide is the mediator of the NANC inhibitory response in the proximal region of rat colon; in the middle colon, substance P acts as an excitatory neurotransmitter, antagonizing the NANC relaxation caused by the mediator of the response, which is still uncertain. Our results also suggest that VIP is the most likely candidate as a NANC transmitter in the distal colon.
Central α2‐autoreceptors: agonist dissociation constants and recovery after irreversible inactivation
Authors: Agneter E. , Drobny H. , Singer E.A. 
Published: July 2012

Rats received an intraperitoneal injection of 1.6 mg kg−1 N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ) to achieve an irreversible inactivation of presynaptic release‐modulating α2‐autoreceptors. Cerebral cortex slices were prepared at different times after the injection (24, 48, 96, 192, 336, 774 h), incubated with [3H]‐noradrenaline ([3H]‐NA), superfused and stimulated electrically with 4 pulses at 100 Hz (= autoinhibition‐free condition). Overflow of radioactivity was used to measure release. Furchgott analysis was used to estimate agonist dissociation constants (KA) and pool size of resynthesized receptors (q).
The KA values of the three α2‐autoreceptor agonists, bromoxidine (UK‐14304), clonidine and noradrenaline (NA) were 187 nm, 72 nm, and 1202 nm, respectively.
The release‐inhibiting effects of the agonists returned considerably faster than the receptor pool. The calculated half‐lives for the recovery of the maximal release‐inhibiting effects of bromoxidine, clonidine and NA were 30.7, 63.6 and 20.8 h, respectively, whereas the half‐life for the recovery of the receptor pool was 445 h.
The data indicate a large receptor reserve at presynaptic α2‐autoreceptors for the agonists used and validate the use of EEDQ as a tool for the determination of agonist dissociation constants.
The action of SDZ 205,557 at 5‐hydroxytryptamine (5‐HT3 and 5‐HT4) receptors
Authors: Eglen R.M. , Alvarez R. , Johnson L.G. , Leung E. , Wong E.H.F. 
Published: July 2012

The interaction of the novel antagonist, SDZ 205,557 (2‐methoxy‐4‐amino‐5‐chloro benzoic acid 2‐(diethylamino) ethyl ester), at 5‐HT3 and 5‐HT4 receptors has been assessed in vitro and in vivo.
In guinea‐pig hippocampus and in the presence of 0.4 μm 5‐carboxamidotryptamine, 5‐HT4‐mediated stimulation of adenylyl cyclase was competitively antagonized by SDZ 205,557, with a pA2 value of 7.5, and a Schild slope of 0.81. In rat carbachol‐contracted oesophagus, 5‐HT4‐receptor mediated relaxations were surmountably antagonized by SDZ 205,557 with a similar pA2 value (7.3). This value was agonist‐independent with the exception of (R)‐zacopride, against which a significantly lower value (6.4) was observed.
In functional studies of 5‐HT3 receptors, SDZ 205,557 exhibited an affinity of 6.2 in guinea‐pig ileum compared with 6.9 at binding sites labelled by [3H]‐quipazine in NG108‐15 cells. In the anaesthetized, vagotomized micropig, SDZ 205,557 produced only a transient blockade of 5‐HT4‐mediated tachycardia. This contrasted with tropisetron, which was active for over 60 min after administration. The half‐lives for the inhibitory responses of SDZ 205,557 and tropisetron were 23 and 116 min, respectively.
In conclusion, SDZ 205,557 has similar affinity for 5‐HT3 and 5‐HT4 receptors. The apparent selectivity observed in guinea‐pig is due to the atypical nature of the 5‐HT3 receptor in this species. The short duration of action of this novel antagonist may complicate its use in vivo. SDZ 205,557 should, therefore, be used with appropriate caution in studies defining the 5‐HT4 receptor.
Effect of opioid receptor subtype‐selective agonists on purinergic and adrenergic components of neurogenic contractions of mouse vas deferens
Authors: Driessen Bernd , Bültmann Ralph , von Kügelgen Ivar , Starke Klaus 
Published: July 2012

Effects of opioid agonists on the purinergic and adrenergic components of neurogenic contractions and in some experiments on transmitter overflow were studied in the mouse isolated vas deferens.
When the vas deferens was stimulated every 2 min by pairs of pulses 2 s apart in the presence of prazosin 0.3 μm (to isolate the purinergic component) or α,β‐methylene‐ATP 3 μm (to isolate the adrenergic component), each pulse elicited a separate twitch. The opioid agonists [d‐Ala2,N‐Me‐Phe4,Gly5‐ol]enkephalin (DAMGO, μ‐receptor‐selective), [d‐Pen2,d‐Pen5]enkephalin (DPDPE, δ‐selective) and trans‐(±)‐3,4‐dichloro‐N‐methyl‐N‐[2‐(1‐pyrrolidinyl)‐cyclohexyl]‐benzeneacetamide (U‐50488, κ‐selective) concentration‐dependently reduced both purinergic and adrenergic contractions. For each agonist, maximal effects and concentrations causing half‐maximal effects were very similar for inhibition of the purinergic component on the one hand and for inhibition of the adrenergic component on the other hand, although the adrenergic component was inhibited with a slight preference. Moreover, effects on contractions elicited by the first and the second pulse of the pairs were very similar.
When vasa deferentia preincubated with [3H]‐noradrenaline were stimulated with trains of 100 pulses delivered at 20 Hz, morphine 10 μm reduced significantly both evoked tritium overflow and evoked contractions. Its effect was antagonized by naloxone.
It is concluded that, in contrast to drugs acting at some other presynaptic receptors, opioid μ‐, δ‐and κ‐agonists inhibit purinergic and adrenergic neurogenic contractions of the mouse vas deferens in a similar manner. In contrast to a previous report, no enhancement by morphine of the release of noradrenaline elicited by high frequency pulse trains was observed.
A novel ETA‐receptor antagonist, FR 139317, inhibits endothelin‐induced contractions of guinea‐pig pulmonary arteries, but not trachea
Authors: Cardell Lars Olaf , Uddman Rolf , Edvinsson Lars 
Published: July 2012

The effects of a proposed endothelin‐receptor antagonist, FR 139317, on the contraction induced by endothelin‐1, endothelin‐2 and endothelin‐3, were analysed on isolated circular segments of pulmonary arteries and rings of trachea from the guinea‐pig.
The pharmacological profiles of endothelin‐1 and endothelin‐2 were almost identical in the guinea‐pig pulmonary artery, whereas endothelin‐3 demonstrated a weaker and less potent contractile effect. The contractions induced by endothelin‐1 and endothelin‐2 were competitively antagonized by FR 139317. Schild plot analysis revealed a straight line with a slope that did not differ from unity. The pA2 value was 6.65. In contrast, the endothelin‐3 induced contractile response was unaffected by FR 139317.
In tracheal segments endothelin‐1, endothelin‐2 and endothelin‐3 evoked contractions of similar magnitude and sensitivity. FR 139317 had no effect on the endothelin‐induced contractions in tracheal segments.
In ring segments of pulmonary artery and trachea, potassium, noradrenaline and histamine caused concentration‐dependent contractile effects. These contractions were not modified by FR 139317 in the concentration range 10−7 to 3 × 10−6 m.
FR 139317 seems to be a selective ETA‐receptor antagonist which competitively antagonizes the endothelin‐1‐ and endothelin‐2‐induced contractions of guinea‐pig isolated pulmonary arteries. Thus, the guinea‐pig pulmonary artery appears to be endowed with one receptor type (ETA) which is antagonized by FR 139317 and with another endothelin‐receptor subtype which responds to endothelin‐3, but is not antagonized by FR 139317. In the trachea, all three peptides act on a homogeneous population of receptors which is unaffected by FR 139317. This suggests an ETA‐receptor in the guinea‐pig pulmonary artery and another receptor, probably of ETB‐type, in the guinea‐pig trachea.
The affinity of betaxolol, a β1‐adrenoceptor‐selective blocking agent, for β‐adrenoceptors in the bovine trachea and heart
Authors: Satoh Eisaku , Narimatsu Akihiro , Hosohata Yoshiaki , Tsuchihashi Hiroshi , Nagatomo Takafumi 
Published: July 2012

The specificity of betaxolol, a β‐adrenoceptor antagonist, for β1 and β2‐adrenoceptors was compared with that of other β‐antagonists, atenolol, ICI‐118551, butoxamine and (±)‐propranolol, in the bovine trachea and heart by competitive interaction with [3H]‐CGP12177 as a radioligand.
The radioligand Kd values were 0.75 ±0.12 and 1.60 ± 0.11 nm in the trachea and heart, respectively, and the Bmax values were 34.00 ± 4.41 and 21.54 ± 2.94 fmol mg−1 protein, respectively.
Using ICI‐118551, we determined the ratio of β1:β2‐adrenoceptors in the trachea and heart to be approximately 29:71 and 56:44, respectively.
In the trachea, a β2‐predominant tissue, betaxolol and atenolol were more selective for β1‐adrenoceptor binding sites than β2‐adrenoceptor binding sites, whereas ICI‐118551 and butoxamine were more selective for β2‐adrenoceptor binding sites.
The β1‐selectivity of betaxolol was 2.2 and 2.7 fold higher than that of atenolol in the bovine trachea and heart. These findings suggest that betaxolol may be useful in the treatment of hypertension, cardiac arrhythmia and angina pectoris.
Quantitative analysis of the agonist and antagonist actions of some ATP analogues at P2X‐purinoceptors in the rabbit ear artery
Authors: Leff P. , Wood B.E. , O'Connor S.E. , McKechnie K. 
Published: July 2012

The agonist and antagonist effects of a series of β,γ‐methylene dihalo‐ and 2‐methylthio‐substituted analogues of ATP at P2x‐purinoceptors have been analysed on the rabbit isolated ear artery preparation. Cumulative and sequential dosing experimental protocols were employed in the construction of agonist concentration‐effect curves in order to address the possible influence of acute receptor desensitization on subsequent analyses.
Using the cumulative curve design the following results were obtained: d‐AMP‐PCBr2P, 2‐methylthio‐d‐AMP‐PCCl2P, l‐AMP‐PCF2P, l‐AMP‐PCCl2P and LAMP‐PCBr2P each behaved as partial agonists. d‐AMP‐CPP was used as a reference full agonist and these analogues were analysed by the comparative method of Barlow et al. (1967), to provide estimates of affinity and efficacy. 2‐Methylthio‐l‐AMP‐PCBr2P was virtually silent as an agonist and was analysed as a competitive antagonist by Schild analysis.
Two agonists, l‐AMP‐PCCl2P and l‐AMP‐PCBr2P, were analysed by the sequential curve design, and the antagonist effects of one of the agonists, l‐AMP‐PCBr2P were also analysed using this protocol. The resulting estimates of affinity and efficacy, while similar to those obtained with the cumulative design, indicated that acute desensitization may affect curve definition and estimation of these quantities.
The following structure‐activity trends emerged: d‐analogues tended to have higher efficacy but lower affinity than l‐analogues; efficacy varied markedly and inversely with the atomic weight of the halogen while affinity was only minimally affected; 2‐methylthio‐ substitution also reduced efficacy with minimal effect on affinity.
The results of this analysis are discussed in terms of the utility of affinity and efficacy information in the classification of purinoceptors and the design of chemical probes for them.