bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of α1‐adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries
Authors: Smith K. M. , Macmillan J. B. , McGrath J. C. 
Published: January 2005

Cutaneous resistance arteries (c.r.a.) (internal diameter=240.94±5.42 μm, n=67/25 (number arteries/number animals)) from New Zealand white rabbits were mounted in wire myographs and a normalization procedure followed.
Cumulative concentration‐response curves (CCRCs) were constructed for the α‐adrenoceptor agonists noradrenaline (NA), (R)A61603 and phenylephrine (PE) in the presence of cocaine (3 μM), propranolol (1 μM) and corticosterone (10 μM). The effects of competitive α1‐adrenoceptor antagonists, prazosin, WB4101, 5‐methyl‐urapidil, HV723, BMY7378 and the irreversible α1B selective compound chloroethylclonidine (CEC) were examined versus the potency and maximum response of the c.r.a.s to noradrenaline.
The high potency of A‐61603 relative to PE has been shown to differentiate both functional and binding site α1A‐ or α1B‐adrenoceptors from α1D‐adrenoceptors: A‐61603 was 944 times more potent than phenylephrine (at EC50) suggesting the presence of a functional α1A or α1B as opposed to an α1D‐subtype.
Exposure to chloroethylclonidine (CEC; 100 μM) decreased the maximum response to noradrenaline but did not significantly change noradrenaline sensitivity indicating that a substantial part of noradrenaline‐induced vasoconstriction in rabbit cutaneous arteries is CEC‐insensitive.
The potencies of prazosin (pA2=9.14) and WB4101 (pA2=9.30) indicate the involvement of prazosin‐sensitive functional α1‐adrenoceptors. The slopes of corresponding Schild plots for prazosin and WB4101 did not include negative unity which implies the possible involvement of more than one functional α1‐adrenoceptor subtype in noradrenaline‐induced vasoconstriction in rabbit cutaneous resistance arteries. In contrast to this, in the case of 5‐methyl‐urapidil and HV723, the Schild plot slope parameters were not significantly different from negative unity over the range of concentrations used; the low pA2 value for 5‐methylurapidil (7.27) suggests the non‐involvement of an α1A‐ or an α1D‐adrenoceptor; the low pA2 value for HV723 (8.47) was similar to that against responses postulated as α1L.
We conclude that rabbit cutaneous resistance arteries express a prazosin‐sensitive functional α1‐adrenoceptor resembling the α1B and another low affinity site for prazosin which on the basis of the functional antagonism produced by HV723 most closely resembles the α1L‐adrenoceptor; the low pA2 value for HV723 (8.47) is similar to that against responses postulated as α1L.

British Journal of Pharmacology (1997) 122, 825–832; doi:10.1038/sj.bjp.0701451
Multiple effects of nordihydroguaiaretic acid on ionic currents in rat isolated type I carotid body cells
Authors: Hatton C. J. , Peers C. 
Published: January 2005

The effects of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) on the ionic currents of rat carotid body type I cells were investigated by use of whole‐cell and outside‐out patch clamp techniques.
NDGA (5–50 μM) produced a concentration‐dependent inhibition of whole‐cell K+ currents at all activating test potentials (holding potential −70 mV). The time‐course of the inhibition was also concentration‐dependent and the effects of NDGA were only reversible following brief periods of exposure (<2 min). Another lipoxygenase inhibitor, phenidone (5 μM), was without effect on whole‐cell K+ currents in carotid body type I cells.
NDGA (5–50 μM) also inhibited whole‐cell Ca2+ channel currents (recorded with Ba2+ as charge carrier) in a concentration‐dependent manner.
Isolation of voltage‐gated K+ channels by use of high [Mg2+] (6 mM), low [Ca2+] (0.1 mM) solutions revealed a direct inhibition of the voltage‐sensitive component of the whole‐cell K+ current by NDGA (50 μM).
In excised, outside‐out patches NDGA (20–50 μM) increased large conductance, Ca2+ activated K+ channel activity approximately 10 fold, an effect which could be reversed by either tetraethylammonium (10 mM) or charybdotoxin (30 nM).
It is concluded that NDGA activates maxi‐K+ channels in carotid body type I cells and over the same concentration range inhibits voltage‐sensitive K+ and Ca2+ channels. The inhibition of whole cell K+ currents seen is most likely due to a combination of direct inhibition of the voltage‐sensitive K+ current and indirect inhibition of maxi‐K+ channel activity through blockade of Ca2+ channels.

British Journal of Pharmacology (1997) 122, 923–929; doi:10.1038/sj.bjp.0701452
Enhancement by exogenous and locally generated angiotensin II of purinergic neurotransmission via angiotensin type 1 receptor in the guinea‐pig isolated mesenteric artery
Authors: Onaka Uran , Fujii Koji , Abe Isao , Fujishima Masatoshi 
Published: January 2005

Angiotensin II is known to enhance sympathetic neurotransmission in the vasculature by increasing the release of noradrenaline, but little is known about the effect on the co‐released transmitter, adenosine 5′‐triphosphate (ATP). In the present study we have examined the effect of angiotensin II on the excitatory junction potential (e.j.p.) elicited by repetitive field stimulation in the guinea‐pig isolated mesenteric artery, to establish the angiotensin II receptor subtype involved in modulating the release of ATP and the role of the endothelium in converting angiotensin I to angiotensin II.
Suramin (300 μM), a P2 purinoceptor antagonist, abolished both the e.j.ps and depolarizing response to α,β‐methylene‐ATP, a stable analogue of ATP, without affecting the resting membrane potential and noradrenaline‐induced depolarization.
Angiotensin II (0.1 μM) affected neither the resting membrane potential nor the amplitude of the first e.j.p., but increased the amplitudes of the subsequent e.j.ps. This enhancing effect of angiotensin II was abolished by CV‐11974 (0.1 μM), an angiotensin II type 1 (AT1) receptor antagonist, but unaffected by PD 123319 (1 μM), an angiotensin II type 2 (AT2) receptor antagonist, or CGP 42112A (1 μM), AT2 receptor ligand.
Angiotensin I (0.1 μM) exerted a similar effect on e.j.ps to that of angiotensin II. CV‐11974 (0.1 μM) or temocaprilat (10 μM), an angiotensin converting enzyme (ACE) inhibitor, abolished the effect of angiotensin I. Removal of the endothelium did not alter the action of angiotensin I.
The results of the present study indicate that the release of ATP from sympathetic nerves innervating the guinea‐pig isolated mesenteric artery, as determined from the magnitude of the e.j.p., can be enhanced by angiotensin II via activation of prejunctional AT1 receptors. Qualitatively similar effects were observed with angiotensin I, which appears to be converted into angiotensin II by a subendothelial process.

British Journal of Pharmacology (1997) 122, 942–948; doi:10.1038/sj.bjp.0701458
Dilatation by angiotensin II of the rat femoral arterial bed in vivo via pressure/flow‐induced release of nitric oxide and prostaglandins
Authors: Heinemann Akos , Wachter Christof H. , Peskar Bernhard A. , Holzer Peter 
Published: January 2005

The haemodynamic effects of angiotensin II (AII) and, for comparison, arginine vasopressin (AVP) in the femoral and superior mesenteric artery of urethane‐anaesthetized rats were analysed with the ultrasonic transit time shift technique.
I.v. bolus injection of AII (0.1–3 nmol kg−1) and AVP (0.03–1 nmol kg−1) increased blood pressure which was accompanied by a decrease in blood flow through the superior mesenteric artery and an increase in femoral blood flow. The femoral hyperaemia was in part due to vasodilatation as indicated by a rise of femoral vascular conductance up to 200% relative to baseline. The femoral vasodilatation caused by AVP, but not AII, was followed by vasoconstriction.
Blockade of angiotensin AT1 receptors by telmisartan (0.2–20 μmol kg−1) prevented all haemodynamic responses to AII.
The femoral dilator responses to AII and AVP depended on the increase in vascular perfusion pressure since vasodilatation was reversed to vasoconstriction when blood pressure was maintained constant by means of a gravity reservoir. However, the AII‐evoked femoral vasodilatation was not due to an autonomic or neuroendocrine reflex because it was not depressed by hexamethonium (75 μmol kg−1), prazosin (0.25 μmol kg−1) or propranolol (3 μmol kg−1).
The AII‐induced femoral vasodilatation was suppressed by blockade of nitric oxide (NO) synthesis with NG‐nitro‐L‐arginine methyl ester (L‐NAME, 40 μmol kg−1) and reversed to vasoconstriction when L‐NAME was combined with indomethacin (30 μmol kg−1), but was left unaltered by antagonism of endothelin ETA/B receptors with bosentan (37 μmol kg−1).
These results demonstrate that the effect of AII to increase systemic blood pressure and the resulting rise of perfusion pressure in the femoral artery stimulates the formation of NO and prostaglandins and thereby dilates the femoral arterial bed. This local vasodilator mechanism is sufficient to mask the direct vasoconstrictor response to AII.

British Journal of Pharmacology (1997) 122, 975–984; doi:10.1038/sj.bjp.0701460
Characterization of α1‐adrenoceptor subtypes mediating contractions to phenylephrine in rat thoracic aorta, mesenteric artery and pulmonary artery
Authors: Hussain Monira B. , Marshall Ian 
Published: January 2005

The subtype of α1‐adrenoceptor mediating contractions to phenylephrine of the rat thoracic aorta, mesenteric artery and pulmonary artery were investigated by use of antagonists which show selectivity between the cloned α1‐adrenoceptor subtypes in binding studies.
Cumulative concentration‐contraction curves for phenylephrine were competitively antagonized in the rat thoracic aorta by prazosin (pA2 9.9), WB4101 (pA2 9.6), 5‐methylurapidil (pA2 8.1), benoxathian (pA2 9.2) and indoramin (pA2 7.4). These compounds were also competitive antagonists in the mesenteric and pulmonary arteries (except for 5‐methylurapidil in the pulmonary artery), (prazosin pA2 9.9 and 9.7; WB4101 pA2 9.8 and 9.6; 5‐methylurapidil pA2 7.9 and pKB estimate 8.0; benoxathian pA2 8.8 and 9.3; indoramin pA2 7.2 and 7.5, respectively).
RS 17053 was not a competitive antagonist in any blood vessel as Schild plot slopes were greater than unity. The pKB estimates for RS 17053 were 7.1 in aorta, 7.0 in the mesenteric artery and 7.7 in the pulmonary artery.
The α1D‐subtype selective antagonist BMY 7378 appeared to be non‐competitive with shallow Schild plot slopes. The data were better fitted with two lines in all tissues, with Schild plot slopes that were no longer different from unity, except in the pulmonary artery. The higher affinity site for BMY 7378 in the aorta had a pA2 of 9.0, while it was 8.8 and 8.9 in the mesenteric and pulmonary arteries, respectively.
MDL73005EF acted in a non‐competitive manner in all three blood vessels, with shallow Schild plot slopes. The pKB estimates for MDL73005EF were 8.4 in aorta, 7.5 in the mesenteric artery and 8.0 in the pulmonary artery.
In all three blood vessels the functionally determined antagonist affinity estimates correlated best with published pKi values for their displacement of [3H]‐prazosin binding on membranes expressing cloned α1d‐adrenoceptors compared with α1a‐ or α1b‐adrenoceptors. The antagonist affinity estimates in the aorta, mesenteric and pulmonary arteries correlated highly with their previously published pA2 values in rat aorta (α1D) and less well with those for α1A‐ and α1B‐adrenoceptors mediating contraction of the rat epididymal vas deferens and rat spleen, respectively.
The results of this study suggest that the contraction to phenylephrine of the rat thoracic aorta, mesenteric artery and pulmonary artery are mediated in part via the α1D‐subtype of adrenoceptor. The data for both BMY 7378 and MDL73005EF in all three blood vessels are consistent with receptor heterogeneity. However, the identity of the second site is unclear.

British Journal of Pharmacology (1997) 122, 849–858; doi:10.1038/sj.bjp.0701461
Modulation of nicotinic ACh‐, GABAA‐ and 5‐HT3‐receptor functions by external H‐7, a protein kinase inhibitor, in rat sensory neurones
Authors: Hu Hong‐Zhen , Li Zhi‐Wang 
Published: January 2005

The effects of external H‐7, a potent protein kinase inhibitor, on the responses mediated by γ‐aminobutyric acid A type (GABAA)‐, nicotinic acetylcholine (nicotinic ACh)‐, ionotropic 5‐hydroxytryptamine (5‐HT3)‐, adenosine 5′‐triphosphate (ATP)‐, N‐methyl‐D‐aspartate (NMDA)‐ and kainate (KA)‐receptors were studied in freshly dissociated rat dorsal root ganglion neurone by use of whole cell patch‐clamp technique.
External H‐7 (1–1000 μM) produced a reversible, dose‐dependent inhibition of whole cell currents activated by GABA, ACh and 5‐HT.
Whole‐cell currents evoked by ATP, 2‐methylthio‐ATP, NMDA and KA were insensitive to external H‐7.
External H‐7 shifted the dose‐response curve of GABA‐activated currents downward without changing the EC50 significantly (from 15.0±4.0 μM to 18.0±5.0 μM). The maximum response to GABA was depressed by 34.0±5.3%. This inhibitory action of H‐7 was voltage‐independent.
Intracellular application of H‐7 (20 μM), cyclic AMP (1 mM) and BAPTA (10 mM) could not reverse the H‐7 inhibition of GABA‐activated currents.
The results suggest that external H‐7 selectively and allosterically modulates the functions of GABAA‐, nicotine ACh‐ and 5‐HT3 receptors via a common conserved site in the external domain of these receptors.

British Journal of Pharmacology (1997) 122, 1195–1201; doi:10.1038/sj.bjp.0701462
Effect of chronic ethanol treatment in vivo on excitability in mouse cortical neurones in vitro
Authors: Ibbotson T. , Field M. J. , Boden P. R. 
Published: January 2005

The effects of cessation of chronic ethanol ingestion on seizure activity in vivo and on the characteristics of the evoked synaptic potentials in cortical neurones in vitro have been investigated in mice. Withdrawal from chronic ethanol treatment increased handling seizure ratings in mice between 4 and 16 h post‐withdrawal. This ethanol‐induced increase in seizure rating was unaffected by carbamazepine (30 mg kg−1) but significantly reduced at a higher concentration (130 mg kg−1).
Intracellular recordings were made from cortical layer II neurones in vitro from control mice and from mice following chronic ethanol ingestion. Evoked synaptic potentials were generated in these neurones through intralaminar stimulation.
Neurones from control mice displayed an evoked potential consisting of a fast excitatory postsynaptic potential (e.p.s.p.) mediated by AMPA‐type glutamate receptors and an inhibitory postsynaptic potential (i.p.s.p.) mediated via GABAA receptors. Application of pentylenetetrazole (PTZ) or bicuculline onto these neurones inhibited the i.p.s.p., caused a large increase in both the amplitude and duration of the e.p.s.p. and initiated spontaneous excitatory activity. The resulting large evoked e.p.s.p. was mediated via both NMDA‐ and AMPA‐type glutamate receptors.
Most neurones (77%) from ethanol treated mice displayed an evoked potential which comprised a large e.p.s.p. and no i.p.s.p. The e.p.s.p. consisted of several distinct components and in addition these neurones displayed spontaneous paroxysmal depolarizing shifts. This multi‐component e.p.s.p. was mediated through both NMDA‐ and AMPA‐type glutamate receptors. A population (23%) of neurones from ethanol treated mice exhibited evoked potentials which possessed both inhibitory and excitatory components and these neurones were effectively identical to those obtained from control mice.
Carbamazepine reduced the duration of the e.p.s.p. in neurones from ethanol treated mice and in PTZ‐treated control neurones.
Prolonged ethanol ingestion is known to create a neurochemical imbalance in cortical neurones resulting in abnormal neurotransmission. The present study highlights the functional consequences that arise as a result of these neurochemical changes leading to over‐excitation of neurones and pronounced epileptiform activity.

British Journal of Pharmacology (1997) 122, 956–962; doi:10.1038/sj.bjp.0701471
Subtypes of endothelin receptors that mediate venous effects of endothelin‐1 in anaesthetized rats
Authors: Palacios Beatriz , Lin Lim Su , Pang Catherine C. Y. 
Published: January 2005

The subtypes of endothelin receptors that mediate the effects of endothelin‐1 (ET‐1) on mean arterial pressure (MAP), heart rate (HR), mean circulatory filling pressure (MCFP), arterial resistance (RA), cardiac output (CO) and venous resistance (RV) were characterized in 9 groups of pentobarbitone‐anaesthetized rats via the injection of ET‐1 in the absence and presence of bosentan (Ro 47‐0203, ETA‐ and ETB‐receptor antagonist), PD 142893 (ETA‐ and ETB‐receptor antagonist) or FR 139317 (ETA‐receptor antagonist), as well as injection of the ETB‐receptor agonist, IRL 1620.
Cumulative i.v. bolus injections of ET‐1 or IRL 1620 (0.5, 1 and 2 nmol kg−1) dose‐dependently increased MAP (ET: by 22, 34 and 44; IRL: 8, 17 and 28 mmHg), RA (ET: 62, 108 and 162; IRL: 51, 63 and 86% over baseline), RV (ET: 70, 132 and 179; IRL: 81, 89 and 98% over baseline) and MCFP (ET: 1.1, 1.8 and 1.9; IRL: 0.9, 1.0 and 1.2 mmHg) and reduced CO (ET: −18, −35 and −44; IRL: −24; −26; −25% below baseline). Equimolar doses of ET‐1 and IRL 1620 caused similar initial transient depressor responses. Saline did not modify any haemodynamic variables in the time‐control group.
Bosentan (10 mg kg−1, i.v.) inhibited ET‐induced increases in MAP, RV, RA and MCFP and decrease in CO. PD 142893 (22 mg kg−1, i.v.) abolished ET‐induced changes on MAP, RV, RA and CO, but did not alter effects on MCFP. Bosentan alone did not cause haemodynamic changes, but PD 142893 alone elevated MCFP (0.9±0.3 mmHg at 1 h after injection) and did not alter other variables. Both antagonists abolished the initial depressor effects of ET‐1.
FR 139317 (1 mg kg−1, i.v.) partially inhibited the increases in MAP, RV, RA and MCFP and decreases in CO elicited by ET‐1, but did not alter the transient depressor response of ET‐1.
The results show that both ETA‐ and ETB‐receptors mediate the arterial and venous constrictor effects of ET‐1. Bosentan is more efficacious than PD 142893 in inhibiting the venous effects of ET‐1.

British Journal of Pharmacology (1997) 122, 993–998; doi:10.1038/sj.bjp.0701474
Inhibition by levetiracetam of a non‐GABAA receptor‐associated epileptiform effect of bicuculline in rat hippocampus
Authors: Margineanu Doru Georg , Wülfert Ernst 
Published: January 2005

Extracellular recording of field potentials, evoked by commissural stimulation in hippocampal area CA3 of anaesthetized rats, was performed in order to study the mode of action of the novel antiepileptic drug levetiracetam (ucb LO59).
The amplitude of orthodromic field population spike (PS2) markedly increased and repetitive population spikes appeared when the recording micropipette contained either bicuculline methiodide (BMI), or the specific GABAA antagonist gabazine (SR‐95531).
BMI‐induced increases in PS2 were reduced in a dose‐dependent manner by 1 to 320 μmol kg−1 levetiracetam i.v., with a U‐shape dose‐response relationship. However, levetiracetam did not reduce the increases in PS2 produced by gabazine.
Clonazepam (1 mg kg−1, i.p.), carbamazepine (20 mg kg−1, i.p.) and valproate (200 mg kg−1, i.v.) were ineffective in preventing BMI‐induced increases in PS2, while the calcium channel antagonist flunarizine, 50 μmol kg−1, i.p., reduced PS2 increments caused by BMI. The L‐type calcium channel blocker nifedipine, 100 μmol kg−1, i.p., was without effect. Similar to levetiracetam, flunarizine did not reduce the increases in PS2 induced by gabazine.
These data suggest that the increased excitability of CA3 neurones, caused by BMI administered in situ, involves calcium‐dependent processes not associated with blockade of GABAA receptors. The inhibition by levetiracetam of this calcium‐dependent effect of BMI might contribute to the antiepileptic effects of the drug.

British Journal of Pharmacology (1997) 122, 1146–1150; doi:10.1038/sj.bjp.0701476
Effect of thromboxane A2 antagonists on bronchial hyperresponsiveness induced immediately after interleukin‐8 inhalation in guinea‐pigs
Authors: Fujimura Masaki , Myou Shigeharu , Nomura Masaharu , Matsuda Tamotsu , Harada Akihisa , Mukaida Naofumi , Matsushima Kouji , Nonomura Akitaka 
Published: January 2005

Although repeated intranasal administration of interleukin‐8 (IL‐8) causes bronchial hyperresponsiveness (BHR) mediated via thromboxane A2 (TXA2) and airway neutrophil accumulation in guinea‐pigs, the acute effect of inhaled IL‐8 is unclear. We performed this study to clarify the acute effect of IL‐8 on bronchial responsiveness and the role of TXA2.
The effects of inhaled IL‐8 on bronchial responsiveness and of the TXA2 antagonists, S‐1452 (0.01 and 0.1 mg kg−1) and ONO‐NT‐126 (1.0 or 10 μg kg−1), on IL‐8‐induced BHR were examined by use of a modified Konzett‐Rössler method in guinea‐pigs.
Inhaled IL‐8 at 100 ng ml−1, which failed to induce significant changes in Pao (pressure at the airway opening), enhanced an increase in Pao induced by subsequent inhalations of ascending doses (50–200 μg ml−1) of methacholine and histamine, suggesting the potentiating effect of IL‐8 on bronchial responsiveness. No significant leukocyte infiltration was observed histologically sixteen minutes after the IL‐8 inhalation. Both S‐1452 and ONO‐NT‐126 reduced the IL‐8‐induced BHR.
In conclusion, IL‐8 rapidly causes BHR via TXA2 release in guinea‐pigs.

British Journal of Pharmacology (1997) 122, 1015–1020; doi:10.1038/sj.bjp.0701478
Hexamethonium‐ and methyllycaconitine‐induced changes in acetylcholine release from rat motor nerve terminals
Authors: Tian Lijun , Prior Chris , Dempster John , Marshall Ian G. 
Published: January 2005

The neuronal nicotinic receptor antagonists hexamethonium and methyllycaconitine (MLA) have been used to study the putative prejunctional nicotinic ACh receptors (AChRs) mediating a negative‐feedback control of ACh release from motor nerve terminals in voltage‐clamped rat phrenic nerve/hemidiaphragm preparations.
Hexamethonium (200 μM), but not MLA (0.4–2.0 μM), decreased the time constant of decay of both endplate currents (e.p.cs) and miniature endplate currents (m.e.p.cs), indicating endplate ion channel block with hexamethonium. However, driving function analysis and reconvolution of e.p.cs and m.e.p.cs indicated that this ion channel block did not compromise the analysis of e.p.c. quantal content.
At low frequencies of stimulation (0.5–2 Hz), hexamethonium (200 μM) and MLA (2.0 μM) increased e.p.c. quantal content by 30–40%. At high frequencies (50–150 Hz) neither compound affected e.p.c. quantal content. All effects on quantal content were paralleled by changes in the size of the pool of quanta available for release.
The low frequency augmentation of e.p.c. quantal content by hexamethonium was absent when extracellular [Ca2+] was lowered from 2.0 to 0.5 mM.
At the concentrations studied, MLA and hexamethonium produced a small (10–20%) decrease in the peak amplitude of m.e.p.cs.
Neither apamin (100 nM) nor charybdotoxin (80 nM) had effects on spontaneous or nerve evoked current amplitudes at any frequency of stimulation. Thus the ability of nicotinic antagonists to augment e.p.c. quantal content is not due to inhibition of Ca2+‐activated K+‐channels.
We suggest that hexamethonium and MLA increase evoked ACh release by blocking prejunctional nicotinic AChRs. These receptors exert a negative feedback control over evoked ACh release and are probably of the α‐bungarotoxin‐insensitive neuronal type.

British Journal of Pharmacology (1997) 122, 1025–1034; doi:10.1038/sj.bjp.0701481