bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of endothelin‐1 and NG‐nitro‐l‐arginine methyl ester on regional haemodynamics in conscious rats with streptozotocin‐induced diabetes mellitus
Authors: Kiff RJ. , Gardiner S.M. , Compton A.M. , Bennett T. 
Published: July 2012

Resting haemodynamic status and responses to endothelin‐1 (0.004, 0.04, 0.4 nmol kg−1) and NG‐nitro‐l‐arginine methyl ester (l‐NAME, 10 mg kg−1) were assessed in conscious, Wistar rats treated with streptozotocin (STZ) to induce diabetes mellitus, and in control animals treated with saline.
In the resting state, STZ‐treated rats had a bradycardia relative to control animals (291 ± 13 and 337 ± 10 beats min−1, respectively), but mean arterial blood pressures were the same in the two groups (STZ‐treated 109 ± 3; control 114 ± 4 mmHg). However, the STZ‐treated rats had raised renal (105 ± 9 units) and mesenteric (114 ± 16 units) vascular conductances and reduced hindquarters vascular conductance (26 ± 4 units) relative to control rats (renal, 80 ± 6; mesenteric, 75 ± 7; hindquarters, 37 ± 3 units).
Increasing doses of endothelin‐1 caused similar, early falls and subsequent rises in mean arterial blood pressures in both groups of rats. Although there were initial hindquarters vasodilatations with endothelin‐1 that were not different in STZ‐treated and control rats, there were subsequent renal and mesenteric vasoconstrictions that were greater in the former. Hence, the similar rises in mean arterial blood pressures must have been accompanied by a greater reduction in cardiac output in the STZ‐treated rats.
l‐NAME caused similar renal and mesenteric vasoconstrictions in control and STZ‐treated rats, but there was a smaller pressor effect and an attenuated hindquarters vasoconstrictor response to l‐NAME in STZ‐treated rats.
Collectively, the results indicate that the resting renal and mesenteric vasodilatations in STZ‐treated rats relative to control were probably not due to diminished vascular sensitivity to endogenous endothelin‐1 or to enhanced sensitivity to, or production of, nitric oxide in these vascular beds. However, the relative hindquarters vasoconstriction in the resting state and the diminished hindquarters vasoconstrictor response to l‐NAME in STZ‐treated rats is consistent with diminished nitric oxide production in that vascular bed.
Characterization of catecholamine‐mediated relaxations in rat isolated gastric fundus: evidence for an atypical β‐adrenoceptor
Authors: McLaughlin Daniel P. , MacDonald Allan 
Published: July 2012

Experiments were carried out in order to characterize the receptors mediating relaxant responses to catecholamines in the rat gastric fundus. The effects of noradrenaline, isoprenaline and the ‘atypical’ or β3‐adrenoceptor agonist, BRL 37344, on methacholine‐induced tone were measured. Prazosin, propranolol and cyanopindolol were used as antagonists.
Relaxant responses to noradrenaline, in the presence of propranolol (1 μm) were antagonized in a concentration‐dependent manner by prazosin (0.01 to 1 μm), although this antagonism was weak and non‐competitive in nature. Relaxant responses to isoprenaline, in the presence of prazosin (0.1 μm), were antagonized only by the highest concentration of propranolol (1 μm) giving a pKB of 6.3. BRL 37344 also relaxed the rat gastric fundus in the presence of prazosin (0.1 μm), and the responses to BRL 37344 were unaffected by propranolol (1 μm).
Tachyphylaxis to BRL 37344 was observed, a second concentration‐response curve being significantly shifted to the right. Exposure of tissues to BRL 37344 (1 μm) between concentration‐response curves also caused an 11 fold rightward shift in the response to isoprenaline.
In the presence of prazosin (0.1 μm) and propranolol (1 μm), the rank order of potency of the agonists was: (–)‐isoprenaline (1.0) > (–)‐noradrenaline (0.39) > BRL 37344 (0.10).
Responses to BRL 37344 in the presence of prazosin (0.1 μm) and propranolol (1 μm) were antagonized by (±)‐cyanopindolol (1 μm), with a pKB of 6.56. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (±)‐cyanopindolol (0.1–1 μm), with the slope of a Schild plot close to unity and a pA2 value of 7.44.
The resistance to blockade by prazosin and propranolol and the antagonism by cyanopindolol of the responses mediated by isoprenaline and BRL 37344 suggest that atypical β‐adrenoceptors similar to ‘atypical’ β‐adrenoceptors in rat adipocytes and other tissues are present in the rat gastric fundus.
Selective impairment of hindquarters vasodilator responses to bradykinin in conscious Wistar rats with streptozotocin‐induced diabetes mellitus
Authors: Kiff R.J. , Gardiner S.M. , Compton A.M. , Bennett T. 
Published: July 2012

Male, Wistar rats were treated with streptozotocin (STZ, 70 mgkg−1, i.p.) or saline and chronically instrumented with pulsed Doppler probes and intravascular catheters (implanted under sodium methohexitone anaesthesia) to allow assessment of haemodynamics in the conscious state 28 days later.
Control and STZ‐treated rats received bolus doses of glyceryl trinitrate (10–80 nmol kg−1), acetylcholine (0.1–5 nmol kg−1) and bradykinin (0.3–30 nmol kg−1).
Although, as reported previously, STZ‐treated rats had normal mean arterial blood pressure together with renal and mesenteric vasodilatations and hindquarters vasoconstriction relative to control rats, both groups showed similar hypotensive and regional haemodynamic responses to glyceryl trinitrate and acetylcholine. However, while the depressor effects of bradykinin were similar in control and STZ‐treated rats, the former showed a hindquarters vasodilator response to bradykinin that was absent in the STZ‐treated rats.
A loss of bradykinin‐mediated vasodilatation in the hindquarters vascular bed in STZ‐treated rats in the presence of normal, hindquarters vasodilator responses to other agents and normal bradykinin‐mediated vasodilator responses in other vascular beds is consistent with existing evidence that the vasodilatation elicited by bradykinin in the hindquarters vascular bed is particularly dependent on nitric oxide synthesis and that this is impaired selectively in STZ‐treated rats.
Interference of anti‐inflammatory and anti‐asthmatic drugs with neutrophil‐mediated platelet activation: singularity of azelastine
Authors: Renesto Patricia , Balloy Viviane , Vargaftig B. Boris , Chignard Michel 
Published: July 2012

The capacity of various drugs (acetylsalicylic acid (ASA), ketoprofen, diclofenac, piroxicam, BW 755C, BW A4C, nedocromil sodium and azelastine) to inhibit human polymorphonuclear neutrophil (PMN)‐mediated platelet activation was investigated. In this model, stimulated PMN release cathepsin G (Cat G), a serine proteinase which, in turn, induces platelet activation.
Among the different tested drugs, azelastine (100 μm for 1 min) was the only one able to prevent platelet aggregation. The cyclo‐oxygenase inhibitors were all inactive, although used at effective concentrations as judged by inhibition of thromboxane B2 (TxB2) formation. Inhibition of platelet aggregation by azelastine was concentration‐dependent, the range of active concentrations being of 20–70 μm. Release from platelets of 5‐hydroxytryptamine was also inhibited at 30 μm and above, but never reached 100%.
The inhibition by azelastine is due to an effect on both cells. Indeed, β‐glucuronidase release from activated PMN and platelet activation by purified Cat G were both affected.
However, used at high concentrations (>100 μm) azelastine was toxic since it released significant amounts of lactate dehydrogenase (LDH) from PMN and platelets.
These results show the capacity of azelastine, an anti‐allergic and anti‐asthmatic compound, to inhibit the cell‐to‐cell communication between PMN and platelets, an effect which may be relevant for its therapeutic efficacy or for a new application in diseases in which PMN and platelets are involved.
Tachykinin antagonists and capsaicin‐induced contraction of the rat isolated urinary bladder: evidence for tachykinin‐mediated cotransmission
Authors: Maggi Carlo Alberto , Patacchini Riccardo , Santicioli Paolo , Giuliani Sandro 
Published: July 2012

The possible involvement of tachykinins (TKs) in the contraction produced by capsaicin in the rat isolated urinary bladder was addressed on the hypothesis that co‐release of substance P (SP) and neurokinin A (NKA) occurs from sensory nerve terminals.
A low concentration of SP (30 nm) produced a rapid contraction which faded to baseline within 10 min. A low concentration of NKA (10 nm) produced a slowly developing contraction which was still evident at 10 min. Capsaicin (1 μm) produced a rapid phasic response and a tonic response (late response to capsaicin). Co‐administration of SP and NKA mimicked the response to capsaicin more than each TK alone.
Fading of the response to SP was not caused by receptor desensitization and was partially prevented by peptidase inhibitors.
Spantide (3 μm) selectively antagonized the SP‐induced contraction while L‐659,877 (3–10 μm) or MEN 10,376 (10–30 μm) which are NK2 receptor selective antagonists selectively blocked the response to NKA. Co‐administration of spantide and L‐659,877 inhibited the response to both SP and NKA by an amount not greater than that produced by each antagonist alone.
Spantide selectively reduced the peak response to capsaicin, while leaving the late response unaffected. L‐659,877 (3 μm) and MEN 10,376 (10 μm) selectively inhibited the late response to capsaicin while, at higher concentrations, also reduced the peak response to capsaicin. Co‐administration of spantide and L‐659,877 reduced the peak response to capsaicin more than that produced by each antagonist alone.
Bombesin (10 nm) produced a tonic contraction similar to that induced by NKA. The response to bombesin was not affected by spantide, L‐659,877 or MEN 10,376.
P2x purinoceptor desensitization by repeated administration of α,β‐methylene ATP depressed the twitch response to electrical stimulation of postganglionic nerves but did not affect the peak or the late response to capsaicin.
We conclude that multiple TKs are coreleased by capsaicin in the rat bladder and mediate the capsaicin‐induced contraction by activating both NK1 and NK2 receptors. Endogenous TK with preferential affinity for the NK1 receptor (putatively SP) are selectively involved in the peak response to capsaicin while endogenous TK with preferential affinity for the NK2 receptor (putatively NKA) are selectively involved in the late response to capsaicin and partly contribute to the peak response. These findings provide pharmacological evidence for tachykinin‐mediated cotransmission in the rat urinary bladder. ATP is unlikely to be involved in the efferent function of capsaicin‐sensitive sensory nerves in the rat bladder.
Characterization of the 5‐HT receptor subtypes involved in the motor behaviours produced by intrathecal administration of 5‐HT agonists in rats
Authors: Fone K.C.F. , Robinson A.J. , Marsden C.A. 
Published: July 2012

The motor behavioural effects of intrathecal injections of 5‐hydroxytryptamine (5‐HT) and a variety of 5‐HT receptor agonists were examined in adult Wistar rats to establish; (a) which 5‐HT receptor subtype/s elicit each behaviour and (b) whether these receptors are located within the spinal cord.
Intrathecal injection of 5‐methoxy‐N,N′‐dimethyltryptamine (5‐MeODMT), (+)‐1‐(2,5‐dimethoxy‐4‐iodophenyl)‐2‐aminopropane hydrochloride (DOI) or 2,5‐dimethoxy‐α,4‐dimethylbenzene ethamine hydrochloride (DOM) produced dose‐related back muscle contractions (BMC) and wet dog shakes (WDS) which were both markedly attenuated by intraperitoneal pretreatment with either ritanserin (1 mg kg−1), ketanserin (0.16 mg kg−1) or mianserin (0.6 mg kg−1) indicating the involvement of 5‐HT2 receptors in both these motor behaviours. Both fluoxetine (1–20 mg kg−1, i.p.) and high doses of 5‐HT (50 μg) following fluoxetine (5 mg kg−1, i.p.) also elicited BMC, further confirming the involvement of 5‐HT in this behaviour.
Intrathecal 5‐carboxamidotryptamine (5‐CT) evoked a marked wet‐dog shake response without producing any BMC. Intrathecal pretreatment with 8‐hydroxy‐2‐(di‐n‐propylamino)tetraline (8‐OH‐DPAT) enhanced, while in contrast 2‐methyl‐5‐HT pretreatment attenuated, 5‐HT agonist‐induced BMC without affecting WDS. These data suggest that the spinal 5‐HT2 receptors mediating BMC are positively modulated by 5‐HT1A but negatively influenced by 5‐HT3 receptor activation and may be of a different subtype to the supra‐spinal 5‐HT2 receptors which elicit WDS.
A contrast, reciprocal forepaw treading, lateral head weaving, flat body posture and Straub‐tail were evoked by 5‐MeODMT, 8‐OH‐DPAT or 5‐CT but not by DOI or DOM indicating that these behaviours were not produced by 5‐HT2 receptor activation alone. Ritanserin (1 mg kg−1, i.p.) or ketanserin (0.16 mg kg−1, i.p.) pretreatment reduced the reciprocal forepaw treading induced by high intrathecal doses of either 5‐MeODMT (25 μg) or 5‐CT (50 μg) suggesting that this behaviour may be facilitated by 5‐HT2 receptor activation.
Intrathecal injection of 5‐HT (0.05–50 μg, after systemic fluoxetine, 5 mg kg−1, i.p.), or 1‐(3‐chlorophenyl)piperazine (mCPP) produced dose‐related forepaw‐licking and grooming, neither of which were attenuated by ketanserin (0.16 mg kg−1, i.p.) pretreatment suggesting these behaviours may be mediated by 5‐HT1C receptors. In contrast, 2‐methyl‐5‐HT (50 and 100 μg) produced sideward tail‐flicks, not evoked by any other 5‐HT agonist and could therefore be mediated by spinal 5‐HT3 receptor activation.
These data provide behavioural evidence for the existence of spinal 5‐HT2 receptors which produce a novel motor behaviour, BMC. Ligand binding studies and dose‐response studies with a range of selective 5‐HT antagonists are required to establish whether BMC and WDS are mediated by different subtypes of 5‐HT2 receptors.
Rate and concentration‐dependent effects of UK‐68,798, a potent new class III antiarrhythmic, on canine Purkinje fibre action potential duration and Vmax
Authors: Knilans Timothy K. , Lathrop David A. , Nánási Péter P. , Schwartz Arnold , Varró András 
Published: July 2012

The frequency‐dependent electrophysiological effects of UK‐68,798 in concentrations of 1, 3, 10 and 30 nm were examined in isolated cardiac Purkinje fibres of the dog at both a number of constant rates of stimulation and following abrupt changes in pacing cycle length.
In all concentrations evaluated, UK‐68,798 lengthened action potential duration in a concentration‐and rate‐dependent manner (e.g., at a cycle length = 500 ms, control APD90 = 234.0 ± 3.3 ms, while after 10 nm UK‐68,798, APD90 = 315.0 ± 5.9 ms).
The duration of action potentials evoked following abrupt changes in pacing rate were also increased in a concentration‐dependent manner at all diastolic intervals tested.
The fast and slow time constants for restitution of APD were not altered by UK‐68,798. However, the amplitude terms for this relation were increased.
In addition, the maximum upstroke velocity (V̇max) was not significantly affected by exposure to UK‐68,798 at any concentration or diastolic interval. The kinetics for recovery of V̇max were thus unaffected.
These findings are similar to those previously reported for recognized class III antiarrhythmic agents (e.g., bretylium, clofilium, and sotalol); however, UK‐68,798 was 1,000 to 10,000 times more potent.
The combined potency and selectivity of this agent seem to make it an ideal tool for the investigation of cardiac potassium channels believed responsible for controlling the duration of the action potential.
This potent and highly selective compound may prove extremely useful in the control of cardiac arrhythmias.
Inhibitory and excitatory effects of adenosine receptor agonists on evoked transmitter release from phrenic nerve endings of the rat
Authors: Correia‐de‐Sá P. , Sebastião A.M. , Ribeiro J.A. 
Published: July 2012

The effects of the adenosine analogues, 5′‐N‐ethyl‐carboxamide adenosine (NECA), R‐N6‐phenylisopropyladenosine (R‐PIA), 2‐chloroadenosine (CADO), and CGS 21680C on electrically evoked tritium outflow from preparations loaded with [3H]‐choline and on evoked endplate potentials (e.p.ps), as well as the ability of the xanthines, 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX) and PD 115,199 to antagonize the effects of the adenosine analogues, were investigated in phrenic nerve‐diaphragm preparations.
NECA, R‐PIA and CADO decreased, in a concentration‐dependent manner, the evoked tritium outflow from preparations loaded with [3H]‐choline. NECA and R‐PIA were about equipotent and more potent than CADO.
DPCPX shifted to the right in a near parallel fashion the concentration‐response curve for the inhibitory effect of R‐PIA on evoked tritium outflow.
In the presence of DPCPX, NECA increased, rather than decreased, evoked tritium outflow. PD 115,199 antagonized, in a concentration‐dependent manner, this excitatory effect of NECA.
CGS 21680C, in low nanomolar concentrations, increased evoked tritium outflow, an effect also antagonized by PD 115,199.
CGS 21680C increased, and R‐PIA decreased, the amplitude of e.p.ps recorded from preparations paralysed with tubocurarine. Both effects could be observed in the same endplate.
It is concluded that both inhibitory (probably A1) and excitatory (probably A2) adenosine receptors coexist at the rat neuromuscular junction, modulating the evoked release of acetylcholine.
Role of 5‐HT1‐like receptors in the reduction of porcine cranial arteriovenous anastomotic shunting by sumatriptan
Authors: den Boer Marinus O. , Villalón Carlos M. , Heiligers Jan P.C. , Humphrey Patrick P.A. , Saxena Pramod R. 
Published: July 2012

The new tryptamine derivative sumatriptan (GR43175) is effective in the treatment of migraine. Since several antimigraine agents reduce cranial arteriovenous anastomotic blood flow in the anaesthetized pig, we have investigated the carotid haemodynamic effects of sumatriptan.
Sumatriptan (10, 30, 100 and 300 μg kg−1, i.v.) reduced total common carotid blood flow, exclusively by affecting its arteriovenous anastomotic fraction; the capillary fraction even increased with the highest doses.
These reductions in the carotid arteriovenous anastomotic (‘shunt’) blood flow were mediated by a 5‐HT1‐like receptor, as methiothepin, but not ketanserin, antagonized the responses to sumatriptan.
Sumatriptan increased the difference in oxygen saturation between arterial and jugular venous blood, which is likely to be a consequence of the reduction of the carotid shunt blood flow.
The selective reduction in arteriovenous anastomotic blood flow produced by sumatriptan may reflect its antimigraine action, thought to involve vasoconstriction of those cranial vessels, be they ‘shunt’ vessels or not, which are distended and inflamed during a migraine attack.
Characterization and actions of human umbilical endothelium derived relaxing factor
Authors: Chaudhuri G. , Buga Georgette M. , Gold Michele E. , Wood Keith S. , Ignarro Louis J. 
Published: July 2012

A bioassay cascade superfusion technique was utilized to study the properties of endothelium derived relaxing factor (EDRF) from human umbilical vein (HUV) and compare its actions on umbilical, chorionic plate and bovine pulmonary arterial strips.
Histamine (1 μm), bradykinin (1 μm) and A‐23187 (0.3 μm, 1 μm) but not acetylcholine (1 μm) released EDRF.
The non‐innervated human foetoplacental vessels, i.e., umbilical and chorionic plate arteries, do relax to EDRF by a guanosine 3′: 5′‐cyclic monophosphate (cyclic GMP)‐mediated mechanism.
The sensitivity of the human umbilical arterial strips to EDRF was less than that of the chorionic plate arterial strips. Bovine pulmonary arterial strips were the most sensitive to the relaxant actions of human umbilical EDRF.
Yohimbine increases submaxillary kallikrein release into the saliva in dogs: evidence for α2‐adrenoceptor‐mediated inhibition of cholinergic pathways
Authors: Girolami Jean‐Pierre , Bascands Jean‐Loup , Pécher Christiane , Berlan Michel , Montastruc Jean‐Louis , Montastruc Paul 
Published: July 2012

The effects of the α2‐adrenoceptor antagonist, yohimbine (0.5 mg kg−1, i.v.) on basal, sympathetic and parasympathetic stimulation‐induced submaxillary kallikrein release were investigated in the anaesthetized dog. Kallikrein was measured by its kininogenase activity before and after trypsin activation which also allowed a study of the proportion of active to total enzyme.
Yohimbine induced a rapid, three fold increase in basal kallikrein release correlated with an increase in salivary flow rate which lasted for 60 min following injection.
Sectioning the chorda tympani did not affect basal kallikrein release but abolished yohimbine‐induced rise in salivary kallikrein secretion.
Parasympathetic stimulation alone induced a 3 to 4 fold increase in basal kallikrein release correlated with an increase in salivary flow rate. Yohimbine induced a significant additional increase in parasympathetic‐stimulated kallikrein release.
When the cervical sympathetic nerve was sectioned the basal kallikrein release decreased by 30 to 40%.
Sympathetic stimulation alone also induced a 3 to 4 fold increase in basal kallikrein. This was not correlated with the salivary flow and unaffected by yohimbine.
The results indicate that yohimbine increases submaxillary kallikrein release into the saliva by inhibition of presynaptic α2‐adrenoceptors located on the chorda tympani nerve endings.
5‐HT1‐like receptors mediate 5‐hydroxytryptamine‐induced contraction of guinea‐pig isolated iliac artery
Authors: Sahin‐Erdemli I. , Hoyer D. , Stoll A. , Seiler M.P. , Schoeffter P. 
Published: July 2012

The effects of 5‐hydroxytryptamine (5‐HT) and of the 5‐HT1‐like receptor agonists, 5‐carboxamidotryptamine (5‐CT) and sumatriptan (GR43175) were investigated in isolated ring preparations of guinea‐pig common iliac artery.
The three agonists induced very weak, if any, contractions of unstimulated preparations, whereas they elicited concentration‐dependent contractions in preparations given a moderate tone by a threshold concentration of prostaglandin F2α (PGF2α).
Under the latter conditions, Emax values for 5‐HT and 5‐CT reached about 45% of PGF2α maximal effect, whereas the Emax value of sumatriptan was significantly lower (about 35%). The rank order of potency (mean EC50 value, nm) was 5‐CT (6.6) > 5‐HT (22.9) > sumatriptan (155). Pargyline, cocaine or deoxycorticosterone were without significant effect on the contractions induced by 5‐HT.
The 5‐HT3 receptor antagonist, (1αH,3α,5αH‐tropan‐3‐yl) 1‐H‐indole‐3‐carboxylic acid ester (ICS 205–930; 1 μm), had no effect on 5‐HT‐, 5‐CT‐ and sumatriptan‐induced contractions.
The 5‐HT2 receptor antagonist, ketanserin (1 μm) caused only small rightward shifts (concentration‐ratios, about 2) in the concentration‐response curves to 5‐HT, 5‐CT and sumatriptan without significantly depressing the maximum effects.
In the presence of ketanserin (1 μm), the non‐selective 5‐HT receptor antagonist, methiothepin (0.1 μm), shifted the concentration‐response curves to 5‐HT and 5‐CT to the right in a parallel manner and to a similar extent for both agonists (respective mean pKB values, 8.07 and 8.27). The effect of sumatriptan was also antagonized by methiothepin, but solvent effects precluded quantitative analysis of this antagonism.
It is concluded that 5‐HT1‐like receptors mediate the contractions induced by 5‐HT, 5‐CT and sumatriptan in guinea‐pig isolated iliac artery. For reasons not yet understood, these receptors are detected only when the tissues are moderately pre‐contracted by PGF2α.