bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of some monoamine oxidase inhibitors on the thiamin status of rabbits
Authors: Ali B.H.
Published: July 2012

The monamine oxidase (MAO) inhibitors harmaline, tranylcypromine, deprenyl, clorgyline and iproniazid were injected intraperitoneally for five days to rabbits at doses that produced significant MAO inhibition. The first three inhibitors raised the concentrations of pyruvate and lactate in blood, decreased the activity of erythrocyte transketolase (TK) and increased the thiamin pyrophosphate (TPP) effect. The drugs also produced anorexia and loss of body weight. The changes were suggestive of an adverse effect on the thiamin status. Clorgyline and iproniazid, however, raised the blood concentrations of pyruvate and lactate but did not affect significantly erythrocyte TK activity or TPP effect.

Treatment of rabbits for 14 days with the thiamin antagonists pyrithiamin (20 μg kg−1) or oxythiamin (0.8 mg kg−1) produced a significant drop in TK activity and increase in the lactate and pyruvate concentrations as well as an increase in TPP effect. Pyrithiamin (5, 10 or 20 μg kg−1, 14 days) lowered significantly the activity of MAO in the liver and brain of rabbits. Treatment with the other antagonist, oxythiamin, at doses of 0.2 or 0.4 mg kg−1 for 14 days had no significant effect on MAO activity. At a dose of 0.8 mg kg−1 a significant drop in MAO activity occurred.

A pair‐feeding trial indicated that the biochemical changes produced in animals treated with MAO inhibitors were attributable to the drugs per se, and not to the ensuing anorexia.

Thiamin (100 μg kg−1, subcutaneously) when given concomitantly with pyrithiamin, oxythiamin, harmaline, deprenyl and tranylcypromine was effective in preventing the development of thiamin deficiency.
[14C]‐β‐phenethylamine, its distribution after administration by various routes to cats, and the effects of monoamine oxidase inhibitors
Authors: Garcha G. , Imrie P.R. , Marley E. , Thomas D.V.
Published: July 2012

[14C]‐β‐phenethylamine ([14C]‐PEA) was instilled intragastrically, intraduodenally (i.d.) or infused into the portal vein or femoral artery of cats, anaesthetized with chloralose, to investigate its distribution in the body.

[14C]‐PEA and phenylacetic acid (PAA) accounted for approximately 85% of radioactivity recovered in blood from control cats or those pretreated with deprenyl or mebanazine. Progressively greater portal venous (PV), cranial mesenteric arterial (CMA) and PV‐CMA concentrations of PEA and PAA were observed with increase in amount of PEA instilled intraduodenally (i.d.); PAA predominated over PEA, more so in CMA than PV blood. Radioactivity was not recovered from blood following intragastric instillation of PEA.

When histamine 1.7 μmol kg−1, i.d., was combined with PEA 1.7 μmol kg−1, i.d., or tyramine 8.5 μmol kg−1, i.d., was combined with PEA 8.5 μmol kg−1, i.d., PV‐CMA values for PEA were significantly augmented.

Arterial concentrations of PEA were increased 3.5 to 5 fold compared to controls by pretreatment with mebanazine or deprenyl plus clorgyline; arterial concentrations of PAA were reduced. PEA blood concentrations were not significantly altered by clorgyline or deprenyl pretreatment.

Infusion of PEA 680, 1020 or 1360 nmol kg−1 min−1 for 20 min into the portal vein raised blood pressure 60 to 100 mmHg (at a PEA concentration of ca, 2 nmol ml−1) but lacked effect on the nictitating membrane despite peak arterial PEA concentrations of 20 nmol ml−1; in cats pretreated with mebanazine or clorgyline plus deprenyl, half‐maximum contraction of the nictitating membrane occurred with arterial PEA concentrations of 4.8 to 9 nmol ml−1. In cats pretreated with mebanazine or deprenyl plus clorgyline, half maximum contraction of the nictitating membrane was elicited also by intraduodenal PEA 8.5 μmol kg−1 at arterial PEA concentrations of ca. 2 nmol ml−1, despite lack of effect of PEA 17 μmol kg−1, i.d., in control cats with a peak arterial PEA concentration of 1.8 nmol ml−1.

[14C]‐PEA and PAA were recovered from liver, kidney, distal small intestine, lung, arterial vessel walls, skeletal muscle, brain, foetus and amniotic liquor, after PEA instilled i.d., overall concentration of PEA exceeding that of PAA except in the kidney. The combined amount of PEA and PAA in kidney was 7 to 20 fold that in other tissues. PEA content of tissues was significantly elevated and that of PAA diminished by pretreatment with deprenyl plus clorgyline, and to a lesser extent after mebanazine.
Involvement of enteric neurones in the response of guinea‐pig ileum preparations to metoclopramide
Authors: Bou J. , Fernández A.G. , Jauregui J.M. , Massingham R.
Published: July 2012

The role of myenteric neurones in mediating the stimulant effects of metoclopramide in vitro in the guinea‐pig ileum has been investigated using the non‐ionic surfactant Triton X‐100.

Histological examination of the ileum 30 days after application of Triton X‐100 to the serosal surface demonstrated a marked reduction in the number of ganglion cells and nerve elements in the myenteric plexus.

Longitudinal muscle‐myenteric plexus (LM‐MP) preparations from Triton X‐100‐treated animals were unresponsive to dimethylphenylpiperazinium and responded poorly or not at all to electrical field stimulation.

Metoclopramide (30 μM) elicited small contractions in LM‐MP preparations from control and sham‐operated animals but failed to contract Triton X‐100‐treated tissues. However, tissues responded in a similar manner to exogenous acetylcholine (ACh).

These results demonstrate the importance of a prejunctional site of action for metoclopramide in this tissue and suggest that contractile responses to the drug are mediated indirectly, probably by increased release of ACh from myenteric neurones.
Effect of apamin on responses to BRL 34915, nicorandil and other relaxants in the guinea‐pig taenia caeci
Authors: Weir Sheila W. , Weston A.H.
Published: July 2012

BRL 34915 (4–64 × 10−7 M), isoprenaline (0.5–32 × 10−8 M) and nicorandil (4–64 × 10−6 M) produced a slowly‐developing relaxation of spontaneous tone of the guinea‐pig taenia caeci; with no after‐contraction on washout. These inhibitory responses were unaffected by apamin (10−7 M).

Adenosine triphosphate (0.06‐2 × 10−3 M) and noradrenaline (1–16 × 10−7 M) produced a rapid inhibition of spontaneous tone with a prominent after‐contraction, especially on washout. Both the inhibitory effect and the rebound contraction were abolished by apamin (10−7 M).

Exposure to both BRL 34915 (64 × 10−7 M) and to nicorandil (64 × 10−6 M) produced an increase in the 86Rb efflux rate coefficient which was unaffected by apamin (10−7 M).

Exposure to isoprenaline (32 × 10−8 M) had no effect on the 86Rb efflux rate coefficient.

Exposure to noradrenaline (16 × 10−7 M) produced an increase in the 86Rb efflux rate coefficient which was abolished by apamin (10−7 M).

The results confirm that both BRL 34915 and nicorandil are capable of opening potassium channels in smooth muscle but show that the channel is not apamin‐sensitive.
A protective effect of sulphinpyrazone against coronary occlusion‐induced shortening of myocardial refractory periods in the rat
Authors: Northover B.J.
Published: July 2012

The hearts of anaesthetized, artificially ventilated rats were exposed, and the left coronary artery occluded. The diastolic threshold voltage for stimulation (DTV), the duration of the bipolar electrogram (DBE) and the functional refractory period (FRP) of the ischaemic area were measured at minute intervals for an hour after occlusion.

Coronary occlusion caused a rise in DTV, a prolongation of the DBE and a biphasic change in the FRP, with an initial prolongation phase (1–4 min) followed by a decline to below pre‐occlusion values (5–15 min).

Episodes of ventricular tachyarrhythmia (VT) were most frequent during the period 5–15 min after the onset of occlusion of the coronary artery. This coincided with the period when FRP was minimal and the difference between DBE and FRP was maximal.

Pretreatment of rats with sulphinpyrazone (2.5–40 mg kg−1) or indomethacin (5–20 mg kg−1) protected against the episodes of coronary occlusion‐induced VT and against the associated decline in FRP of the ischaemic muscle. Sulphinpyrazone was more effective than indomethacin in this respect and a combination of the two drugs was approximately as effective as sulphinpyrazone alone.

It was concluded that sulphinpyrazone protects rats against coronary occlusion‐induced episodes of VT by reducing the risk of ventricular action potential re‐entry. This effect is probably due to protection against the ischaemia‐induced shortening of the myocardial FRP.
An oxytocin receptor in anococcygeus muscles isolated from male mice
Authors: Gibson A.
Published: July 2012

The nature of the neurohypophyseal peptide receptor in the anococcygeus muscles from male mice was investigated.

The rank order of potency of naturally occurring peptides was oxytocin > Arg‐vasotocin > Arg‐vasopressin>Lys‐vasopressin, which is similar to that found in the uterus and mammary gland.

Selective agonists on the oxytocin (OT) receptors of the uterus and mammary gland (Thr4‐OT; Gly7‐OT; Thr4‐Gly7‐OT) were also potent agonists in the mouse anococcygeus.

Competitive antagonists of uterine responses to oxytocin (dP‐TyrMe‐Thr4‐OT; dP‐TyrMe‐OT; dP‐Thr4‐OT; dp‐Orn8‐OT) were also competitive antagonists of oxytocin‐induced contractions of the mouse anococcygeus.

It is concluded that the neurohypophyseal peptide receptor of the male mouse anococcygeus is of the oxytocin type; antagonist pA2 values suggest that this receptor resembles, but may not be identical to, the uterine oxytocin receptor. Possible physiological and pharmacological implications of these observations are discussed.
Inhibition of calcium currents in cultured rat dorsal root ganglion neurones by (−)‐baclofen
Authors: Dolphin A.C. , Scott R.H.
Published: July 2012

Voltage‐dependent inward calcium currents (ICa) activated in cultured rat dorsal root ganglion neurones were reversibly reduced in a dose‐dependent manner by (−)‐baclofen (10 μM to 100 μM).

Baclofen (100 μM) reduced the calcium‐dependent slow outward potassium current (IK(Ca)). This current was abolished in calcium‐free medium and by 300 μM cadmium chloride. The action of baclofen on IK(Ca) was reduced when the calcium concentration in the medium was increased from 5 mM to 30 mM.

The calcium independent fast transient voltage‐dependent outward current (IK(Vt)) was also reduced by baclofen; this effect remained present when Ca2+‐free medium was used to prevent contamination by IK(Ca).

4‐Aminopyridine (500 μM) reduced IK(Vt) and induced a small increase in ICa. The action of baclofen on ICa was partially antagonized by 4‐aminopyridine.

GABAB receptor‐mediated inhibition of ICa in cultured rat dorsal root ganglion neurones involves a direct mechanism rather than resulting indirectly from an increase in the residual outward potassium currents activated by depolarization. The reduction in ICa by baclofen was variable and dependent on the amplitude of control ICa, larger currents being more resistant to the baclofen‐induced inhibition.
Iloprost (ZK 36374) enhances recovery of regional myocardial function during reperfusion after coronary artery occlusion in the pig
Authors: van der Giessen W.J. , Schoutsen B. , Tijssen J.G.P. , Verdouw P.D.
Published: July 2012

Ligation of the left anterior descending coronary artery in open‐chest pigs for 20 min caused a complete loss of regional myocardial function, which did not recover during the first two hours of reperfusion.

Infusion of the stable prostacyclin analogue Iloprost (100 ng kg−1 min−1) did not prevent the loss of systolic wall function during ischaemia.

Recovery of regional myocardial function during the first two hours of reperfusion was enhanced to 40% of baseline by Iloprost.

This effect of Iloprost cannot be explained by a decreased O2‐demand during ischaemia or an enhanced recovery of myocardial ATP content.
A study of the H2‐receptor for histamine stimulating adenylate cyclase in homogenates of guinea‐pig lung parenchyma
Authors: Foreman J.C. , Norris D.B. , Rising T.J. , Webber S.E.
Published: July 2012

The effect of forskolin and several H2‐agonists was investigated on the activity of adenylate cyclase in homogenates of guinea‐pig lung parenchyma.

Histamine, 0.1 μM to 1 mM, dimaprit, 1 μM to 10 mM, 4‐methyl histamine, 0.1 μM to 10 mM, impromidine, 10 nM to 10μM and forskolin, 1 nM to 100 μM, all produced a dose‐dependent stimulation of adenylate cyclase activity above the basal level.

The histamine H1‐receptor antagonist mepyramine, 10 μM, and β‐adrenoceptor antagonist propranolol, 10 μM, had no effect on the stimulation by histamine of adenylate cyclase.

The dose‐response curve for stimulation by histamine of adenylate cyclase was shifted to the right in a dose‐dependent manner by increasing concentrations of several H2‐antagonists. Schild plots constructed for each H2‐antagonist produced straight lines with slopes not significantly different from unity. The equilibrium dissociation constants obtained for the H2‐antagonists in this study were similar to those previously reported for inhibition of dimaprit‐induced relaxation of the pre‐contracted lung strip, inhibition of [3H]‐tiotidine binding to homogenates of guinea‐pig lung parenchyma and inhibition of histamine‐stimulated adenylate cyclase in guinea‐pig gastric mucosa.
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.
Gastrointestinal neurotensin receptors: contribution of the aromatic hydroxyl group in position 11 to peptide potency
Authors: Donoso M. Verónica , Huidobro‐Toro J. Pablo , St Pierre Serge
Published: July 2012

Neurotensin structural analogues on tyrosine11 were tested in vitro to determine their ability to contract the fundus or relax the intestine. The rank order of potency was: neurotensin > [Phe11]‐neurotensin > [D‐Tyr11]‐neurotensin > [D‐Phe11]‐neurotensin. All peptides behaved as full agonists. It is concluded that tyrosine11 is part of the neurotensin pharmacophore; the hydroxyl group increases the affinity not the intrinsic activity of the peptide at the receptor.
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.
The effects of N‐(cyclopropylmethyl)‐19‐isopentyl‐nororvinol (M320), a potent agonist at k‐ and μ‐ opiate receptors, on urine excretion of rats
Authors: Abrahams J.M. , Boura A.L.A. , Evans R.G. , Johnston C.I. , Olley J.E.
Published: July 2012

The effects of N‐(cyclopropylmethyl)‐19‐isopentylnororvinol hydrochloride (M320) on urine excretion by rats were investigated. Further studies, using rabbit isolated vas deferens, investigated its interactions with k‐opiate receptors.

The output of urine for a 2 h period after M320, administered subcutaneously to normally hydrated Long Evans rats, showed a bell‐shaped dose‐response relationship, the maximum effect occurring after 10 μg kg−1. Urinary retention contributed to but did not fully account for the weaker diuresis after high doses. Attenuation of the ascending portion of the dose‐response curve to M320 occurred after 1 and 10 mg kg−1 but not 0.1 mg kg−1 of naltrexone intraperitoneally.

M320 in low doses (3–10 μg kg−1) caused a small but significant increase in sodium excretion. M320 (30 μg kg−1) reduced both sodium and potassium excretion.

M320 (10 μg kg−1 s.c.) did not increase the volume of urine voided in 2 h by Brattleboro rats showing diabetes insipidus, even when urine excretion was reduced to normal by 1 week of vasopressin replacement.

The volume of urine voided in 4 h by Brattleboro rats was progressively reduced to zero by M320 (10–100 μg kg−1 s.c). Urinary retention contributed to but did not account for this reduction.

Plasma levels of immunoreactive arginine vasopressin (ir‐AVP) were reduced in both normal and dehydrated Long Evans rats after doses greater than 1 μg kg−1 M320 s.c.

In vitro, M320 caused persistent inhibition of twitches of the electrically stimulated rabbit vas deferens (IC50 1.7 nM).

These data suggest that M320 has potent opioid agonist activity at k‐receptors and at higher concentrations stimulates μ‐ receptors. In the rat, its activity on k‐receptors is associated with diuresis and suppression of plasma vasopressin levels. The antidiuresis seen after high doses may be due to its activity on μ‐receptors, possibly at a central site.
Influence of the vascular endothelium on agonist‐induced contractions and relaxations in rat aorta
Authors: Bullock Gillian R. , Taylor S.G. , Weston A.H.
Published: July 2012

The influence of the vascular endothelium on agonist‐induced contractions and relaxations has been measured using intact segments of rat aorta. Contiguous rubbed segments were used as controls.

Angiotensin II, histamine, noradrenaline, U46619 and UK 14304 contracted both rubbed and intact tissues. The threshold spasmogenic concentrations of these agonists were lower in rubbed tissues than in intact preparations.

The sensitivity and responsiveness of tissues to angiotensin II, histamine, noradrenaline and UK 14304 were greater in rubbed than in intact tissues.

Acetylcholine and histamine relaxed the established spasms of intact tissues but not those of rubbed preparations, These relaxant effects of acetylcholine were abolished by pre‐incubation with haemoglobin.

In the presence of prazosin, noradrenaline or UK 14304 relaxed established contractions in intact tissues. These effects were antagonized by idazoxan or by pre‐incubation with haemoglobin.

In intact preparations, idazoxan had no effect on the spasmogenic sensitivity and responsiveness to UK 14304.

Pre‐incubation with haemoglobin augmented the spasmogenic actions of noradrenaline, U46619 or UK 14304 in intact tissues, but had no effect on these responses in rubbed preparations.

Tissue concentrations of cyclic GMP were greater in intact than in rubbed tissues. A concentration of acetylcholine (10 μM) evoking just maximal mechanical inhibition produced a significant increase in cyclic GMP concentration in intact preparations. However, no detectable changes in cyclic GMP concentration were produced by UK 14304 (10 μM) or by acetylcholine (30 nM), concentrations which were equi‐effective in inhibiting mechanical activity.

In the presence of threshold spasmogenic concentrations of noradrenaline, the contractile effects of angiotensin II were augmented and became comparable to those observed in rubbed preparations. In the presence of greater concentrations of noradrenaline, angiotensin II always produced an additional contraction.

It is concluded that the presence of the vascular endothelium limits the spasmogenic action of a variety of agonists. Although spasmogens like noradrenaline and UK 14304 can stimulate the release of endothelium‐derived relaxing factor (EDRF) via α2‐adrenoceptors, the inhibitory effects of EDRF largely result from the spontaneous release of this substance.
Muscarinic and nicotinic mechanisms in the responses of the adrenal medulla of the dog and cat to reflex stimuli and to cholinomimetic drugs
Authors: Critchley J.A.J.H. , Ellis P. , Henderson C.G. , Ungar A. , West Christine P.
Published: July 2012

In isolated perfused adrenal glands of the cat, muscarinic and nicotinic agonists selectively released adrenaline and noradrenaline respectively.

In isolated perfused adrenal glands of the dog, the output of adrenaline and noradrenaline remained in a fixed ratio at rest and when stimulated by muscarinic or by nicotinic agonists.

In the anaesthetized dog, a combination of muscarinic and nicotinic antagonists was needed to block reflex responses of the adrenal medulla. A nicotinic antagonist was more effective in blocking the baroreceptor reflex response than the chemoreceptor reflex response.
Stereospecific antiarrhythmic effect of opioid receptor antagonists in myocardial ischaemia
Authors: Parratt James R. , Sitsapesan Rebecca
Published: July 2012

The effects of the stereoisomers of two different antagonists at opioid receptors were examined on the ventricular arrhythmias that result from acute coronary artery ligation in anaesthetized male rats. (−)−Mr 1452 (but not the (+)‐isomer, Mr 1453) reduced, in a dose‐dependent manner, the number of ventricular ectopic beats and the incidence or duration of both ventricular tachycardia and fibrillation. (−)−WIN 44,441–3 (but not its (+)‐isomer, WIN 44,441–2) had a similar protective effect in ischaemia. These results suggest that antagonism of the effects of endogenous opioid peptides at specific receptors results in reduced severity of arrhythmias in myocardial ischaemia.
Vascular responses to leukotriene B4, C4 and D4 following FPL 55712, indomethacin, saralasin, phentolamine and verapamil in the conscious rat
Authors: Filep János , Földes‐Filep Éva , Frölich Jürgen C.
Published: July 2012

The pressor and vascular permeability effects of leukotrienes B4 (LTB4), C4 and D4 were investigated in conscious unrestrained rats.

Leukotrienes C4 and D4 (3.2–51 nmol kg−1 i.v.) caused an acute dose‐dependent elevation of the mean arterial pressure, which was maximal after 2 min and returned to control levels within 14 min. Heart rate was significantly reduced by the higher doses of LTC4 and LTD4. LTB4 (up to a dose of 51 nmol kg−1) was essentially inactive.

These effects of LTC4 and LTD4 were abolished by FPL 55712, a putative antagonist of sulphidopeptide leukotrienes and by verapamil, a calcium channel blocker.

Indomethacin, phentolamine or saralasin pretreatment failed to modify the pressor response to LTC4 and LTD4.

LTC4 and LTD4 furthermore caused an increase in haematocrit values, which was significantly attenuated by FPL 55712, indomethacin and verapamil.

The present findings show that the pressor effect of LTC4 and LTD4 is not related to prostanoid release and can be reversed by calcium channel blockade; whereas the effect on vascular permeability seems to require the presence of both cyclo‐oxygenase product(s) and calcium.
Inhibition of myocardial Ca2+ channels by three dihydropyridines with different structural features: potential‐dependent blockade by Ro 18–3981
Authors: Holck Mark , Osterrieder Wolfgang
Published: July 2012

Inhibition of myocardial Ca2+ channels was investigated for three dihydropyridines with different structural features: Ro 18–3981, darodipine (PY 108‐068) and nifedipine. Ro 18–3981 contains a sulphamoyl acetyl side‐chain.

In voltage‐clamp experiments with isolated cardiac myocytes of guinea‐pig, Ro 18‐3981 caused a concentration‐dependent inhibition of the Ca2+ current, which was influenced by the membrane holding potential. A markedly greater inhibition by Ro 18‐3981 was observed when myocytes were depolarized (to + 10 mV) from a holding potential (Vh) of −20 mV (IC50 = 2.3 nm) than at −50 mV (IC50 = 100 nm).

The three dihydropyridines caused a concentration‐dependent reduction in contractile force of isolated, electrically‐stimulated left atria of the guinea‐pig. Elevation of the extracellular K+ concentration from 5.9 to 24 mm resulted in a significant reduction in negative inotropic IC50 values for Ro 18‐3981 (137 fold), darodipine (8 fold) and nifedipine (20 fold).

The affinity of these drugs for the high‐affinity (+)‐[3H]‐PN 200‐110 binding site was determined in guinea‐pig cardiac membranes. The KD value of Ro 18‐3981 (1.0 nm) was similar to the IC50 value for blockade of ICa at a Vh of − 20 mV (2.3 nm), i.e. at a level of near‐maximal depolarization.

Thus, structurally‐different dihydropyridines exert potential‐dependent inhibition of myocardial Ca2+ channel activity consistent with the modulated receptor hypothesis. These results demonstrate that blockade of myocardial excitation‐contraction coupling by Ca2+ entry blockers is also potential‐dependent.
The role of calcium in the cyclic AMP response to histamine in rabbit cerebral cortical slices
Authors: Al‐Gadi M. , Hill S.J.
Published: July 2012

The effect of calcium on the H1‐and H2‐receptor components of the cyclic AMP response to histamine in rabbit cerebral cortical slices has been investigated.

Removal of calcium ions from the incubation medium during the preparation, preincubation and final incubation of brain slices significantly reduced the cyclic AMP responses to adenosine, histamine and the H2‐selective agonist, impromidine.

Removal of calcium ions from the incubation medium during only the final incubation with agonists did not influence the responses to adenosine, histamine, impromidine and the H1‐selective agonist, 2‐thiazolylethylamine.

Final incubation of rabbit cerebral cortical slices in calcium‐free buffer containing EGTA (1 mm) however, selectively reduced the cyclic AMP responses to the H1‐agonists histamine and 2‐thiazolylethylamine without affecting the response to impromidine or adenosine.

These latter incubation conditions significantly reduced the maximal extent of the augmentation of impromidine‐or adenosine‐stimulated cyclic AMP accumulation produced by H1‐receptor stimulation, without affecting the EC50 values of the H1‐agonists. Calcium‐free/EGTA conditions did not, however, alter the dose‐response parameters for the response to the H2‐agonist, impromidine.

These data provide further evidence that the two histamine receptor systems affect cyclic AMP accumulation in rabbit cerebral cortical slices by different mechanisms.
Human calcitonin gene‐related peptide activates adenylate cyclase and releases prostacyclin from human umbilical vein endothelial cells
Authors: Crossman D. , McEwan J. , MacDermot J. , MacIntyre I. , Dollery C.T.
Published: July 2012

Endothelial cells of human umbilical vein were isolated and cultured in vitro.

In these cells there was a concentration‐dependent release of prostacyclin and activation of adenylate cyclase by human calcitonin gene‐related peptide (hCGRP). The concentration of hCGRP for half‐maximum activation of adenylate cyclase (Kact) by hCGRP was 190 nm.

Bradykinin induced a ten fold greater release of prostacyclin than CGRP, but did not activate adenylate cyclase.

hCGRP may exert its potent vasodilator properties by stimulating release of vasorelaxant substances, including prostacyclin from endothelial cells.