bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prostaglandin E receptor subtypes in smooth muscle: agonist activities of stable prostacyclin analogues
Authors: Dong Y.J. , Jones R.L. , Wilson N.H. 
Published: July 2012

The agonist activities of a range of prostaglandin analogues on smooth muscle preparations sensitive to prostaglandin E2 (PGE2) have been investigated. When necessary thromboxane‐like activity was eliminated using the thromboxane receptor antagonists EP 045 and EP 092.
On the bullock iris sphincter, rat stomach fundus and guinea‐pig trachea, (±) ω‐tetranor‐16‐p‐chlorophenoxy PGE2 (ICI 80205) and 16,16‐dimethyl PGE2 were more active contractile agents than PGE2, whereas for relaxant activity on the cat trachea, guinea‐pig trachea and dog hind limb arterial vessels in vivo the order of potency was reversed. 11‐Deoxy PGE, exhibited greater relaxant than contractile activity when compared to PGE2.
Iloprost and 6a‐carba‐Δ6,6aPGI1 (potent mimetics of PGI2) showed high contractile activity on the PGE‐sensitive preparations. PGI2 was less active and another potent PGI2 mimetic, ZK 96480, showed only very weak activity. When tested, the dibenzoxazepines SC 19220 and SC 25191 blocked the contractile actions of iloprost and 6a‐carba‐Δ6,6aPGI1 and those of PGE2 and 16,16‐dimethyl PGE2 to similar extents. Each of the PGI2 analogues showed weak activity on the relaxant systems.
On the proximal portion of the ascending colon of the rat, PGI2, iloprost, 6a‐carba‐Δ6,6aPGI1 and ZK 96480 always inhibited spontaneous activity at nanomolar concentrations. PGE2 and PGE1 showed weak contractile activity. The distal portion of the ascending colon was more responsive to the contractile action of PGE analogues: both iloprost and 6a‐carba‐Δ6,6aPGI1 showed evidence of contractile activity, whereas PGI2 and ZK 96480 always inhibited spontaneous activity.
Evidence was obtained that the rat stomach fundus also contains a PGF receptor; (±) ω‐tetranor‐16‐m‐trifluoromethylphenoxy PGF2α (ICI 81008) acted as a specific agonist. PGF2α and its ω‐tetranor‐16‐p‐fluorophenoxy analogue produced a higher maximum response that ICI 81008 probably due to their additional agonist action at the PGE receptor.
The data support the hypothesis that there are two subtypes of the PGE receptor. ZK 96480 has minimal activity on both receptor subtypes and appears to be a highly specific PGI2 mimetic.
A comparison of the action of the endothelium‐derived relaxant factor and the inhibitory factor from the bovine retractor penis on rabbit aortic smooth muscle
Authors: Bowman Anne , Gillespie J.S. , Soares‐da‐Silva P. 
Published: July 2012

The dependence of relaxation of rabbit aortic strips by carbachol and by the inhibitory factor from the bovine retractor penis (BRP) on the presence of endothelium has been compared. Carbachol‐induced relaxation is abolished by removing the endothelium, inhibitory factor‐induced relaxation is unimpaired. The inhibitory factor, therefore, does not act by releasing an endothelium‐derived relaxing factor (EDRF).
The effect of inhibitors of eicosanoid metabolism on relaxation was examined. Quinacrine and nordihydroguaiaretic acid abolished the relaxant effect of carbachol and flurbiprofen had no effect. The relaxation produced by the inhibitory factor was unaffected by quinacrine and flurbiprofen while nordihydroguaiaretic acid potentiated the response. No eicosanoid appears, therefore, to be involved in the relaxant effect of the inhibitory factor from the BRP.
Methylene blue, a drug reported to inhibit guanylate cyclase, in a concentration of 10 μM selectively abolished the relaxation produced by carbachol. However, at the higher concentration of 30 μM it abolished almost completely the response to inhibitory factor from the BRP and reduced inhibition by sodium nitroprusside.
It is not possible from these results to exclude the possibility that the EDRF and the inhibitory factor from the BRP are chemically related.
Prostaglandin endoperoxide analogues which are both thromboxane receptor antagonists and prostacyclin mimetics
Authors: Armstrong R.A. , Jones R.L. , MacDermot J. , Wilson N.H. 
Published: July 2012

Two prostaglandin endoperoxide analogues, EP 035 and EP 157, behave as specific thromboxane receptor antagonists on isolated smooth muscle preparations such as rabbit aorta, dog saphenous vein and guinea‐pig trachea. However, in human platelet‐rich plasma (PRP) they produce an unsurmountable block of aggregation induced by a wide range of agents (ADP, platelet‐activating factor, thrombin); this inhibitory profile is typical of that seen with either prostaglandin I2 (PGI2) or PGD2.
EP 035 and EP 157 induce large increases in cyclic AMP levels (up to 20 times basal) in human PRP. Simultaneous exposure to PGE, markedly reduces their effect on cyclic AMP; exposure to PGD2 is much less effective in this respect. The adenylate cyclase inhibitor SQ 22,536 opposes the inhibitory action of EP 035, EP 157, iloprost (a stable PGI2 analogue) and PGD2 on platelet aggregation. However, the xanthone derivative AH 6809 blocks the inhibitory action of PGD2 but does not affect EP 035, EP 157 and PGI2 and its structural analogues.
EP 035 and EP 157 displace [3H]‐iloprost binding to the PGI2 receptor on human platelet membranes. Displacing ability is ranked as follows: iloprost > 6a‐carba PGI2 > EP 157 > EP 035 > EP 164 (α‐dinor derivative of EP 157). This order of potency is the same as that found for activation of adenylate cyclase in homogenates of washed human platelets and for inhibition of aggregation in washed human platelets.
The activities of EP 035 and EP 157 were studied in two other systems containing PGI2 receptoradenylate cyclase complexes, the NCB‐20 cell line and human lung tissue. In both cases stimulation of adenylate cyclase was found but maximum rates were below that achieved with iloprost. These effects of EP 035 and EP 157 could be correlated with their abilities to displace [3H]‐iloprost binding.
These results indicate that EP 035 and EP 157 inhibit the aggregation of human platelets by acting as agonists at the PGI2 receptor linked to adenylate cyclase. They represent a class of compound with both thromboxane receptor blocking activity and prostacyclin mimetic activity.
The contribution of intrinsic activity to the action of opioids in vitro
Authors: Miller Lynne , Shaw J.S. , Whiting Elaine M. 
Published: July 2012

The effects of opioids were compared in five field‐stimulated isolated tissue models, the guinea‐pig ileum and vasa deferentia from rat, rabbit and mice of the Alderley Park and C57BL/6 strains.
Although the μ‐receptor agonist [D‐Ala2, MePhe4, Gly‐ol5] enkephalin appeared to act at similar receptors in the guinea‐pig ileum, rat vas deferens, mouse vas deferens and C57BL/6 mouse vas deferens preparations, its potency varied considerably between these preparations. Similar potency differences were also observed with the k‐agonist, ethylketocyclazocine.
It is proposed that these variations in potency reflect differences in the number of spare receptors present in each model. The finding that some drugs which have agonist activity in the more sensitive preparations behave as antagonists in the less sensitive tissues supports this proposal and highlights the importance of intrinsic activity in determining the action of opioids.
Many of the prototypic opioid agonists were found to be either partial agonists (eg. morphine and bremazocine) or to possess affinity for more than one receptor type (eg. ethylketocyclazocine, Mr 2034).
Vasopressin induced myocardial depression is neurally mediated and not due to impaired coronary blood flow
Authors: Hof Robert P. 
Published: July 2012

The mechanism of the cardiodepressant effect of vasopressin was studied by measuring simultaneously myocardial contractile force and coronary blood flow (with tracer microspheres) in anaesthetized open‐chest rabbits.
Lysine‐vasopressin administered at two dose levels (10 and 100 mu kg−1 infused in 2 min with a maintenance dose of 2 mu kg−1 min−1 between these two loading doses) to a group of 6 rabbits caused dose‐dependent myocardial depression and also severely decreased coronary blood flow in a dose‐dependent manner. Blood pressure remained almost unchanged but heart rate, cardiac output and total peripheral conductance were also decreased dose‐dependently.
In another group of 6 rabbits treated in the same way with lysine‐vasopressin, darodipine (PY 108‐068, 30 and 100 μg kg−1) was infused intravenously. It reversed the vasopressin‐induced coronary constriction and cardiodepression. The high dose of vasopressin brought back cardiac depression but did not reduce coronary blood flow below baseline values. Myocardial depression could therefore not be adequately explained by the changes in coronary blood flow.
In a further group of rabbits which had been subjected to cervical vagotomy and β‐adrenoceptor blockade (propranolol 1 mg kg−1 i.v.) before the experiment, vasopressin still caused coronary constriction which was reversed by darodipine, but had no effect on myocardial contractile force and heart rate.
The cardiodepressant effect of vasopressin can thus be explained fully by effects on the autonomic nervous system which are reversed by lowering blood pressure, whereas the severe reduction of coronary flow did not contribute to the vasopressin‐induced myocardial depression.
BW A256C, a chemically novel class 1 antiarrhythmic agent. A comparison of in vitro and in vivo activity with other class 1 antiarrhythmic agents
Authors: Allan G. , Donoghue S. , Follenfant M.J. , Sawyer D.A. 
Published: July 2012

BW A256C (5(3)‐amino‐6‐(2,3‐dichlorophenyl)‐2,3(2,5)‐dihydro‐3(5)‐imino‐2‐isopropyl‐1,2,4‐triazine) is a novel class 1 antiarrhythmic agent designed to combine the features of potency with reduced central nervous system penetration.
BW A256C reduced the maximum rate of depolarization of guinea‐pig ventricle and dog Purkinje fibres in vitro (EC50, 2.2 × 10−6 M and 1.8 × 10−6 M, respectively), being significantly more potent than quinidine, lidocaine, disopyramide and flecainide. BW A256C was also more potent than these agents at inhibiting aconitine‐induced arrhythmias in anaesthetized rats; however, unlike these agents, BW A256C was devoid of hypotensive activity at antiarrhythmic doses.
In anaesthetized dogs, intravenous administration of BW A256C (0.25‐1 mg kg−1) caused a dose‐dependent suppression of ventricular arrhythmias that occurred on reperfusion of an occluded coronary artery.
In conscious dogs, intravenous infusion (total dose, 1.5 mg kg−1) or oral administration of BW A256C (1.25‐5 mg kg−1) caused dose‐dependent suppression of the ventricular ectopic activity that occurred following 20–24 h of permanent coronary artery ligation.
In the conscious dog, BW A256C was approximately 7 times more potent and was also longer acting than flecainide.
Administration of BW A256C was not associated with any evidence of peripheral or CNS toxicity. However, plasma levels 3–4 times greater than the antiarrhythmic levels were associated with a pro‐arrhythmic activity.
Studies on the stereoisomers of β‐adrenoceptor antagonists in conscious A‐V blocked dogs
Authors: Boucher Michel , Duchêne‐Marullaz Pierre , Moundanga Joseph Loufoua 
Published: July 2012

Atrial and ventricular chronotropic effects of the individual stereoisomers of propranolol, pindolol, metoprolol and penbutolol were studied in conscious dogs with chronic atrio‐ventricular (A‐ V) block. Ventricular β‐adrenoceptor blocking activity was assessed for all drugs against isoprenaline under the same experimental conditions.
At low doses, the stereoisomers of propranolol and penbutolol decreased atrial rate, whereas those of pindolol and metoprolol produced an increase. At higher doses, all drugs increased atrial rate. All drugs decreased ventricular rate dose‐dependently except (+)‐pindolol.
Relative ventricular β‐blocking potencies of the (‐)‐isomers of propranolol, pindolol, metoprolol and penbutolol were respectively 38, 21, >43 and 31 times higher than those of their corresponding (+)‐isomers. In addition, β‐blocking potencies of (‐)‐ and (+)‐pindolol were respectively 60 and 120 times higher, those of (‐)‐ and (+)‐penbutolol 7 and 8 times higher and those of (‐)‐ and (+)‐metoprolol 4 and >4 times weaker than those of (‐)‐ and (+)‐propranolol.
At comparable levels of ventricular β‐adrenoceptor blockade, (‐)‐pindolol and (‐)‐metoprolol were more potent in producing ventricular bradycardia than their respective (+)‐isomers, whereas (‐)‐ and (+)‐propranolol and (‐)‐ and (+)‐penbutolol were equiactive. In addition, regardless of which isomer was being studied, the order of ventricular bradycardiac potencies, at comparable levels of β‐adrenoceptor blockade, was metoprolol > propranolol > penbutolol > pindolol.
These results show that antagonism of β‐adrenoceptors in the ventricle is at least partly responsible for the ventricular bradycardiac effect produced by these drugs, but also that some other factor, apparently distinct from the membrane stabilizing activity, is involved, suggesting the existence of some other as yet unknown pharmacological property of the β‐adrenoceptor blocking drugs, especially evident in metoprolol. Finally, these results demonstrate that the intrinsic sympathomimetic activity exhibited by some of these drugs attenuate their bradycardiac effect.
The protective action of allopurinol in an experimental model of haemorrhagic shock and reperfusion
Authors: Allan G. , Cambridge D. , Lee‐Tsang‐Tan L. , Van Way C.W. , Whiting M.V. 
Published: July 2012

Haemorrhagic shock was induced in anaesthetized, open‐chest dogs by controlled arterial bleeding, sufficient to reduce and maintain mean arterial blood pressure at 40 mmHg for 30 min. The blood volume was then restored to the pre‐shock level by rapid, intravenous reinfusion of the blood shed during the shock period.
Haemorrhagic shock produced significant haemodynamic changes, characterized by a marked depression of myocardial function. Cardiac output (1226 ± 57 ml min−1), peak aortic blood flow (6030 ± 383 ml min−1) and maximum rate of rise of left ventricular pressure (2708 ± 264 mmHg s−1) were all reduced by more than 50%. The haemodynamic profile was markedly improved by reinfusion of shed blood but this improvement was not sustained. There was a gradual decline such that 50% of the untreated animals suffered complete circulatory collapse and death between 60 and 120 min following reinfusion.
Neither haemorrhagic shock, nor reinfusion of shed blood produced any consistent or significant changes in the myocardial adenine nucleotide pool. The ATP, ADP and AMP levels were, respectively, 25.9 ± 4.2; 15.6 ± 1.0; 4.3 ± 1.9 nmol g−1 protein, before haemorrhagic shock; 21.6 ± 3.4; 21.5 ± 2.5; 10.2 ± 2.7 nmolg−1 protein, after 30min haemorrhagic shock; and 29.9 ± 3.9; 16.5 ±1.2; 4.2 ± 1.1 nmolg−1 protein, 60 min following reinfusion of shed blood.
Pretreatment with allopurinol (50.0 mg kg−1 i.v.), 60 min before inducing haemorrhagic shock, had no significant effect upon the haemodynamic response to shock, but did prevent the gradual decline seen following reinfusion in the untreated animals. All of the allopurinol‐treated animals displayed significantly better haemodynamic profiles than the untreated animals, furthermore, there was a 100% survival rate in this group.
Allopurinol had no significant effect upon the myocardial adenine nucleotide pool either during haemorrhagic shock or following reinfusion of shed blood.
Effects of an increase in haemoglobin O2 affinity produced by BW12C on myocardial function in the erythrocyte‐perfused rabbit heart in vitro and myocardial infarct size in the dog
Authors: Allan G. , Chapple D. J. , Hughes B. 
Published: July 2012

The effects of BW12C on myocardial function in the erythrocyte‐perfused rabbit heart and on myocardial infarct size in the anaesthetized dog have been evaluated.
Perfusion of rabbit hearts with erythrocytes pretreated with BW12C (10−3 M‐4× 10−3 M) produced concentration‐dependent decreases in left ventricular pressure (LVP), LVP dP/dt and coronary perfusion pressure. A concomitant decrease in PO2 and an increase in lactate production by the myocardium was also observed.
Perfusion of rabbit hearts with Krebs Henseleit buffer containing BW12C (10−5 − 10−4 M) caused no change in measured variables. Although BW12C (10−3 M) caused a small decrease in LVP, coronary perfusion pressure and heart rate, these changes were not significant.
In anaesthetized dogs, an infusion of BW12C (total dose 50 mg kg−1, i.v.) caused small, but significant, changes in haemodynamic status. The oxygen saturation curve was shifted to the left and relative % oxygenation (P20) was shifted to the left throughout the course of the experiment. (P20, control 16.3 ± 0.4 mmHg; after BW12C 7.9 ± 1.4 mmHg).
Pretreatment with BW12C (total dose 50 mg kg−1) caused no change in area at risk but significantly increased the myocardial infarct size by 410%.
These studies with BW12C demonstrate that alteration in haemoglobin‐oxygen affinity can induce adaptive physiological changes in tissue function and metabolism and can assume a critical role when oxygen supply may be impaired due to a flow‐limiting stenosis.
Actions of α, β‐methylene ATP and 6‐hydroxydopamine on sympathetic neurotransmission in the vas deferens of the guinea‐pig, rat and mouse: support for co‐transmission
Authors: Allcorn R.J , Cunnane T.C. , Kirkpatrick K. 
Published: July 2012

α‐Adrenoceptor antagonists (prazosin or phentolamine) reduced the contractile response to field stimulation of the isolated vasa deferentia of guinea‐pig, rat and mouse. α, β‐Methylene ATP (α, β‐MeATP) reduced that portion of the contraction which was resistant to α‐adrenoceptor blockade.
α, β‐MeATP (1–800 μM) did not affect action potential conduction in the guinea‐pig vas deferens nerves, and (up to 10 μM) did not reduce the stimulation‐evoked overflow of [3H]‐noradrenaline from this tissue.
Spontaneous excitatory junction potentials (s.e. j.ps) in the majority of cells of guinea‐pig, rat, and mouse vasa were abolished by α, β‐MeATP (0.1–10 μM). In a small number of cells s.e.j.ps were resistant to the actions of α, β‐MeATP (10 μM).
Excitatory junction potentials (e.j.ps) in the majority of cells in vasa of all species studied were abolished by α, β‐MeATP (1–10 μM). E.j.ps elicited in some ‘resistant’ cells demonstrated marked facilitation characteristics.
It is concluded that α, β‐MeATP inhibits s.e.j.ps and e.j.ps by a postjunctional action.
In all species pretreatment of animals with 6‐hydroxydopamine produced a marked reduction in noradrenaline (NA) content (as determined by fluorescence histochemistry) and abolished e.j.ps, findings which suggest that e.j.ps originated from sympathetic nerves.
The results support the hypothesis that NA and ATP are co‐transmitters in the sympathetic nerves of rodent vasa.
Effects of γ‐aminobutyric acid and (‐)‐baclofen on calcium and potassium currents in cat dorsal root ganglion neurones in vitro
Authors: Robertson Brian , Taylor W. Rowland 
Published: July 2012

Calcium and potassium currents were examined in dialysed, isolated dorsal root ganglion neurones of the cat by use of a single electrode voltage clamp.
Two calcium currents were identified, a low threshold inactivating (transient) current and a higher threshold slowly inactivating (sustained) current. Both currents were blocked by 1 mM cadmium and replacement of calcium with manganese, which revealed an underlying nonspecific outward current. The sustained current disappeared with internal dialysis over a period of 20 to 30 min.
(‐)‐Baclofen (100 μM) and γ‐aminobutyric acid (GABA, 100 μM) were found to reduce the peak amplitude of the sustained calcium current, an effect which became more pronounced with increasing concentrations of external magnesium (1–5 mM). In 5 mM external magnesium, 100 μM baclofen reduced the calcium current by 28%.
The voltage‐activated delayed rectifier appeared to be the most prominent potassium current in these cells. We were unable to find any evidence for a significant contribution from calcium‐activated potassium conductance or a transient potassium conductance under our recording conditions.
Baclofen and GABA at 100 μM had no consistent effect on the voltage‐activated potassium current. Baclofen did not change the resting potassium conductance.
Electrophysiological effects of acetyl glyceryl ether phosphorylcholine on cardiac tissues: comparison with lysophosphatidylcholine and long chain acyl carnitine
Authors: Nakaya Haruaki , Tohse Noritsugu 
Published: July 2012

Electrophysiological effects of synthetic platelet activating factor, acetyl glyceryl ether phosphorylcholine (AGEPC), were examined and compared with those of lysophosphatidylcholine (LPC) and long chain acyl carnitine (AC) in canine Purkinje fibres and guinea‐pig papillary muscles, by use of standard microelectrode techniques.
In canine Purkinje fibres, AGEPC at concentrations higher than 3 × 10−5 M, decreased maximum diastolic potential, action potential amplitude and the maximum upstroke velocity of phase 0. AGEPC also induced abnormal automaticity arising from depolarized membrane potentials.
LPC and AC in concentrations higher than 3 × 10−5 M also produced virtually identical electrophysiological alterations in Purkinje fibres.
Although twitch tension was slightly decreased by low concentrations (10−6 − 10−5 M) of these amphiphilic lipids, a transient positive inotropic response appeared at the beginning of a progressive depolarization after exposure to higher concentrations of the amphiphiles.
In guinea‐pig papillary muscles, AGEPC in concentrations higher than 3 × 10−5 M produced slight decreases in resting membrane potential, action potential amplitude and action potential durations, concomitantly with a positive inotropic response. These electrophysiological and mechanical changes were also induced by LPC and AC at comparable concentrations.
In guinea‐pig papillary muscles depolarized with 25 mM [K+]o, AGEPC, LPC and AC all evoked slow action potentials at a concentration of 10−4 M.
It is concluded that in isolated cardiac tissues AGEPC exerts electrophysiological effects similar to those of LPC and AC only at high concentrations, and that the non‐specific interaction of amphiphiles with sarcolemmal membrane may be responsible for the electrophysiological and mechanical effects.