bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of tachykinin receptors in isolated basilar arteries of guinea‐pig
Authors: Edvinsson Lars , Jansen Inger 
Published: July 2012

In circular lengths cut from the basilar artery of guinea‐pig (0.2‐0.3 mm o.d.) relaxations induced by substance P and neurokinin A were highly susceptible to mechanical damage of the endothelium by rubbing. The precontraction induced by prostaglandin F2α but not that of 124 mm potassium was reduced considerably by the rubbing procedure.
Concentration‐dependent relaxations were evoked by tachykinin agonists in the following order of potency: substance P = physalaemin > neurokinin A > eledoisin. Physalaemin was, however, a partial agonist, giving only half the maximum relaxation as compared to the other tachykinins.
The two putative tachykinin receptor antagonists, spantide ([d‐Arg1, d‐Trp7,9, d‐Leu11] substance P) and [d‐Pro2, d‐Trp7,9] substance P, shifted the concentration‐dependent relaxations of substance P to the right in a parallel manner. Calculation of pA2 values and Schild plot analysis revealed pA2 values of 7.4–7.6 for spantide and 6.9‐7.0 for [d‐Pro2, d‐Trp7,9] substance P, irrespective of whether substance P or neurokinin A was used as agonist. The pA2 values and the Schild plot analysis suggest a specific interaction between tachykinin agonists and antagonists that follow a simple bimolecular process.
The results suggest the presence of tachykinin receptors of the ‘SP‐P’ type in guinea‐pig basilar arteries which, for induction of relaxation, involves the release of an endothelium‐derived relaxing factor.
Effects of repeated intravenous administration of haem arginate upon hepatic metabolism of foreign compounds in rats and dogs
Authors: Tokola Olavi 
Published: July 2012

Haem arginate is a new haem compound, recently introduced for the treatment of acute hepatic porphyrias. Porphyrias are characterized biochemically by decreased formation of haem due to defects in certain enzyme activities involved in the haem biosynthesis.
Haem is essential for cell respiration and oxidative biotransformation. Hepatic drug metabolism, haem biosynthesis and catabolism were investigated after repeated intravenous administration of haem arginate in connection with toxicity studies.
The daily doses of haem for rats were 4, 12 and 40 mg kg−1 and for dogs 3 and 9 mg kg−1 for 30 days and for 28 days, respectively.
Hepatic microsomes were used in the assay of the following drug metabolizing enzymes: cytochrome P‐450 and b5, aminopyrine N‐demethylase, ethoxyresorufin O‐deethylase and UDP‐glucuronyl transferase. The assay of NADPH‐cytochrome C‐reductase and the enzymes reflecting synthesis and metabolism of haem in the liver (δ‐aminolaevulinic acid synthase, δ‐aminolaevulinic acid dehydratase, uroporphyrinogen I‐synthase, uroporphyrinogen decarboxylase, haem synthase, haem oxygenase and biliverdin reductase) were performed from 20,000 g supernatants.
The lowest dose administered to rats and dogs did not cause any significant changes compared to controls in the parameters measured.
The highest doses significantly increased the activities of haem oxygenase and uroporphyrinogen I‐synthase but decreased concentrations or activities of other enzymes, e.g. cytochrome P‐450 and ethoxyresorufin O‐deethylase.
The results show that it is important to avoid overdosage of haem when restoration of mixed function oxygenase activity is needed.
Endothelium‐derived relaxing factor inhibits in vitro platelet aggregation
Authors: Furlong B. , Henderson A.H. , Lewis M.J. , Smith J.A. 
Published: July 2012

We studied the effects of endothelium‐derived relaxing factor (EDRF), bovine retractor penis muscle inhibitory factor and sodium nitroprusside, three stimulants of guanylate cyclase, on the in vitro aggregation of washed human platelets.
Platelet aggregation induced either by collagen or by the thromboxane A2 analogue U46619 was inhibited by all three agents.
The anti‐aggregatory effect of each agent was inhibited by haemoglobin.
The anti‐aggregatory effect of EDRF was potentiated by superoxide dismutase.
These findings are discussed in relation to a potential role for EDRF in haemostasis.
Inhibition of the rate of GABA synthesis in regions of rat brain following a convulsion
Authors: Green A. Richard , Metz Alan , Minchin Michael C.W. , Vincent Nigel D. 
Published: July 2012

The rate of synthesis of γ‐aminobutyric acid (GABA) in the cortex, hippocampus and striatum of rat brain was assessed by measuring the linear rate of accumulation of GABA following injection of amino‐oxyacetic acid (AOAA).
Five min after a single electrically induced seizure there was a rise in GABA content in these brain regions and an almost total inhibition of the rate of synthesis.
Five min after seizure induced by the inhalant convulsant flurothyl there was no rise in GABA content in these brain regions but a similar marked degree of inhibition of GABA synthesis.
Two hours after the convulsion the rate of GABA synthesis had returned to control values in all three brain regions.
A single convulsion did not alter the glutamic acid decarboxylase activity in these brain regions either in the absence or presence of added co‐factor (pyridoxal phosphate).
Evidence for an inhibition of GABA release following a convulsion which may be associated with the inhibition of GABA synthesis is presented in the following paper.
The effect of repeated electroconvulsive shock on GABA synthesis and release in regions of rat brain
Authors: Green A. Richard , Vincent Nigel D. 
Published: July 2012

The release of endogenous γ‐aminobutyric acid (GABA) from slices of rat cortex, hippocampus and striatum prepared both 30 min and 24 h after the last of a series of electroconvulsive shocks (5 seizures given spread out over 10 days) has been investigated.
No change in spontaneous (basal) release was observed. However, 30 min after the last convulsion, K+‐evoked GABA release above basal release was inhibited in both hippocampus (20%) and striatum (33%) but not in the cortex. Release was still inhibited in striatum (22%) 24 h after the last seizure.
In confirmation of an earlier report, chronic electroconvulsive shock was found to increase basal GABA content in striatum and inhibit synthesis by 34%. The synthesis rate was also inhibited in the hippocampus (44%) but not in the cortex.
Glutamic acid decarboxylase activity was unchanged in all regions after repeated electroconvulsive shock treatment.
It is proposed that repeated electroconvulsive shocks lead to a substantial inhibition of release in the striatum and hippocampus and a long‐term inhibition of GABA synthesis in these regions. Such changes may be associated with the altered monoamine biochemistry and function observed after repeated electroconvulsive shock and with the mechanism of the antidepressant action of electroconvulsive therapy.
The effects of single and repeated electroconvulsive shock administration on the release of 5‐hydroxytryptamine and noradrenaline from cortical slices of rat brain
Authors: Green A. Richard , Heal David J. , Vincent Nigel D. 
Published: July 2012

A method is described of measuring the K+‐evoked release of endogenous 5‐hydroxytryptamine (5‐HT) and noradrenaline (NA) from slices prepared from rat cortex.
There was no difference in either the spontaneous (basal) or K+‐evoked release of 5‐HT or NA from cortical slices prepared from handled animals and those given a single electroconvulsive shock (ECS) either 30 min or 24 h earlier.
In chronic studies, rats were either handled or given an ECS 5 times over 10 days and cortical slices prepared. There was no difference in 5‐HT or NA release between the groups 30 min after the last treatment other than a modest attentuation of spontaneous NA release following ECS treatment. However 24 h after the last treatment K+‐evoked release (above basal release) of 5‐HT and NA was inhibited by 84% and 48%, respectively.
These data demonstrate that following a single ECS, normal 5‐HT and NA release is seen at a time when GABA release is markedly inhibited. After repeated ECS the release of both monoamines was markedly inhibited. These 5‐HT changes may be involved in the enhanced 5‐HT‐receptor function seen after repeated ECS.
Resting, and rate‐dependent depression of of guinea‐pig ventricular action potentials by amiodarone and desethylamiodarone
Authors: Pallandi Regan T. , Campbell Terence J. 
Published: July 2012

The cellular electrophysiological effects of amiodarone and its metabolite desethylamiodarone (DEA) were studied in guinea‐pig ventricular myocardium by use of standard microelectrode techniques.
Both compounds produced significant increases in action potential duration (Class III antiarrhythmic effect) and decreases in maximum rate of depolarization (Class I effect), at clinically relevant concentrations.
The Class I effects were rate‐dependent, with small (0–16%) falls in maximum depolarization rate in the absence of stimulation (‘resting block’) and progressively larger effects at decreasing interstimulus intervals (range 1200‐300 ms).
The kinetics of onset and offset of the Class I effect in response to a step change in driving rate were quite fast for both drugs (comparable to those reported for Class Ib agents).
It is concluded that this unique combination of Class III action plus Class I effects with fast onset and offset kinetics may help explain the great efficacy of amiodarone in antiarrhythmic therapy.
Effect of cholera toxin on the production of eicosanoids by rat jejunum
Authors: Autore Giuseppina , Capasso Francesco , Di Carlo Giulia , Mascolo Nicola 
Published: July 2012

Cholera toxin injected i.v. into rats stimulated the production of prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and LTC4 by segments of jejunum, but it had no effect when added to the tissue in vitro.
Pretreatment of the animals with the compound BW 755C reduced the increased production of PGE2, LTB4 and LTC4 by i.v. cholera toxin. Pretreatment with indomethacin reduced the production of PGE2.
These findings are consistent with the hypothesis that arachidonate metabolites are involved in the diarrhoea induced by cholera toxin.
Comparative pharmacology of endothelium‐derived relaxing factor, nitric oxide and prostacyclin in platelets
Authors: Radomski M.W. , Palmer R.M.J. , Moncada S. 
Published: July 2012

The pharmacological effects of endothelium‐derived relaxing factor (EDRF), nitric oxide (NO) and prostacyclin on human and rabbit platelets were examined.
EDRF is released from porcine aortic endothelial cells, cultured on microcarriers and treated with indomethacin, in sufficient quantities to inhibit platelet aggregation induced by 9,11‐dideoxy‐9α,11α‐methano epoxy‐prostaglandin F2α (U46619) and collagen.
The anti‐aggregating activity of EDRF was potentiated by M&B 22948, a selective inhibitor of cyclic GMP phosphodiesterase, and by superoxide dismutase (SOD) and was inhibited by haemoglobin and Fe2+.
Both NO and prostacyclin inhibited platelet aggregation.
The anti‐aggregatory activity of NO, but not that of prostacyclin, was potentiated by M&B 22948 and by SOD and was inhibited by haemoglobin and Fe2+. Thus NO is a potent inhibitor of platelet aggregation whose activity on platelets mimics that of EDRF.
It is likely that the inhibitory effect of NO on platelets represents the action of endogenous EDRF and therefore this substance, together with prostacyclin, is a regulator of platelet‐vessel wall interactions.
Neuropharmacological and neurochemical properties of N‐(2‐cyanoethyl)‐2‐phenylethylamine, a prodrug of 2‐phenylethylamine
Authors: Baker Glen B. , Coutts Ronald T. , Rao Tadimeti S. 
Published: July 2012

N‐(2‐cyanoethyl)‐2‐phenylethylamine (CEPEA) was examined as a possible prodrug of 2‐phenylethylamine (PEA).
Pharmacokinetics of PEA and CEPEA were investigated in rat brain, blood and liver by gas chromatography with electron‐capture detection (GC‐ECD). Interactions of PEA and CEPEA with putative neurotransmitter amines were investigated by use of high performance liquid chromatography with electrochemical detection (h.p.l.c.‐e.c.).
Administration of PEA caused transient increases in PEA concentrations which decreased rapidly in brain and blood and at a slower rate in liver. Administration of CEPEA caused sustained elevations of PEA concentrations and elimination of PEA was markedly decreased in these tissues relative to the situation after administration of PEA itself.
Administration of CEPEA caused more prolonged decreases in brain noradrenaline, dopamine and 5‐hydroxytryptamine concentrations than those observed after PEA administration, although values increased to control levels eventually.
Origin of 5‐hydroxytryptamine‐induced hyperpolarization of the rat superior cervical ganglion and vagus nerve
Authors: Ireland S.J. 
Published: July 2012

5‐Hydroxytryptamine (5‐HT)‐induced membrane potential changes were recorded extracellularly from rat superior cervical ganglia (SCG) and cervical vagus nerves in vitro.
On the SCG, low concentrations of 5‐HT (1 × 10−8‐3 × 10−7 m) induced concentration‐related hyperpolarization responses. Higher concentrations of 5‐HT (1 × 10−6‐1 × 10−4 m) induced complex responses which typically consisted of an initial hyperpolarization, followed by a depolarization and subsequent after‐hyperpolarization. The depolarization, but not the initial hyperpolarization, was blocked by metoclopramide (3 × 10−5 m), quipazine (1 × 10−6 m) or MDL 72222 (1 × 10−5 m).
5‐HT‐induced hyperpolarization of the SCG was potentiated when the amount of calcium chloride added to the superfusion medium was reduced from 2.5 to 0.15 mmol l−1. Hyperpolarization responses recorded from SCG preparations superfused with this low‐calcium medium were unaffected by the substitution of lithium chloride for sodium chloride and were potentiated by the omission of potassium ions. Ouabain (1 × 10−3 m) abolished both the hyperpolarization and the depolarization induced by 5‐HT.
On the vagus nerve, 5‐HT (1 × 10−7‐3 × 10−5 m) did not induce initial hyperpolarization in either normal or low‐calcium Krebs‐Henseleit medium. However, in the latter solution only, depolarization responses induced by 5‐HT at concentrations of 1 × 10−6 m or greater were followed by hyperpolarization. Both the depolarization and the post‐5‐HT hyperpolarization were blocked by metoclopramide (3 × 10−5 m) but were unaffected by spiperone (1 × 10−7 m).
On the vagus nerve, post‐5‐HT hyperpolarization responses were selectively and reversibly inhibited by ouabain, and by superfusion with Krebs‐Henseleit medium that was either potassium‐free or contained lithium chloride in place of sodium chloride.
These results demonstrate the generation in the rat SCG of a 5‐HT‐induced hyperpolarization response that is not mediated through 5‐HT3 receptors and is unlikely to be a consequence of depolarization. In contrast, on the rat vagus nerve, the post‐5‐HT hyperpolarization observed in the present study had the characteristics expected of depolarization‐dependent activation of a sodium ion pump.
An investigation of the actions of diltiazem on rat aorta exposed to acute hypoxia followed by re‐oxygenation
Authors: Marriott J.F. 
Published: July 2012

The effects of diltiazem and removal of extracellular Ca2+ were examined on contractions, of the rat isolated aorta, to noradrenaline (NA) and high K+, during exposure to oxygenated conditions and hypoxia followed by re‐oxygenation.
Exposure to hypoxia caused a similar reduction of contractile responses to NA and KCl, while re‐oxygenation restored contractile activity.
Ca2+‐free conditions abolished responses to KCl but a transient response to NA remained which was resistant to hypoxia.
Diltiazem produced similar reductions of responses to NA during both oxygenated conditions and hypoxia, whereas during re‐oxygenation the effects of diltiazem upon responses to NA were enhanced.
Diltiazem produced a more pronounced reduction of responses to KCl than of responses to NA. However, the reduction of responses to KCl by diltiazem was not modified by the changes in Po2 examined in the present study.
The present study indicates that contractions of the rat aorta mediated by intracellular Ca2+ are resistant to the hypoxic conditions studied in the present investigation, whereas those responses mediated by an influx of Ca2+ are reduced. The increase in the contractile response to NA following re‐oxygenation may result from an increased influx of extracellular Ca2+ since such responses show an enhanced sensitivity to diltiazem.
Voltage‐independent catecholamine release mediated by the activation of muscarinic receptors in guinea‐pig adrenal glands
Authors: Nakazato Y. , Ohga A. , Oleshansky M. , Tomita U. , Yamada Y. 
Published: July 2012

The differences between the mechanisms of muscarinic and nicotinic receptor‐mediated catecholamine secretion with respect to their dependence on voltage changes and extracellular Ca were examined using perfused adrenal glands of the guinea‐pig.
Acetylcholine (ACh, 10−6 to 10−3 m) caused a dose‐dependent increase in catecholamine secretion. The ED50 value for ACh was 7 × 10−5 m. In the presence of atropine (10−5 m), the dose‐response curve for ACh was shifted to the right. Hexamethonium (5 × 10−4 m) preferentially reduced the responses to higher concentrations of ACh (> 10−5 m). Pilocarpine (5 × 10−4 m) and nicotine (3 × 10−5 m) also stimulated catecholamine release.
During perfusion with isotonic KCl solution, ACh and pilocarpine, but not nicotine, evoked catecholamine secretion. These responses were abolished by atropine (10−6 m). Pilocarpine‐stimulated catecholamine secretion was enhanced during perfusion with isotonic KCl solution. Under these conditions, hexamethonium (10−3 m) significantly augmented ACh‐evoked catecholamine release.
During perfusion with either Ca‐free isotonic KCl or Ca‐free Locke solution, ACh and pilocarpine caused a partial increase in catecholamine secretion whereas nicotine and high K solution (56 mm) did not. The responses to ACh and pilocarpine were completely inhibited by atropine but not by hexamethonium.
When guinea‐pig adrenal glands were perfused with isotonic KCl solution containing 2.2 mm Ca which was subsequently removed and replaced with EGTA, ACh‐induced catecholamine secretion was similar in magnitude to that observed during perfusion with Locke solution.
We conclude that both nicotinic and muscarinic receptors are involved in ACh‐induced catecholamine secretion from guinea‐pig adrenal chromaffin cells. Activation of muscarinic or nicotinic receptors appears to stimulate catecholamine release through different mechanisms with respect to both voltage‐dependence and Ca requirements.
Cardiovascular effects of apamin and BRL 34915 in rats and rabbits
Authors: Cook Nigel S. , Hof Robert P. 
Published: July 2012

The cardiovascular effects of apamin, a selective blocker of certain calcium‐activated potassium channels, and BRL 34915, a vasodilator thought to act by opening of potassium channels, have been investigated in vivo in rats and rabbits.
In anaesthetized normotensive rats, apamin (0.05 and 0.15 mg kg−1, i.v.) potentiated angiotensin II pressor responses but did not modify baseline blood pressure or heart rate.
Apamin (0.15 mg kg−1, i.v.) was without cardiovascular effects in rabbits.
BRL 34915 (0.1 and 0.3 mg kg−1, i.v.) lowered blood pressure in rats dose‐dependently and caused reflex tachycardia. The heart rate increase was abolished by prior administration of the β‐adrenoceptor blocker bopindolol (0.1 mg kg−1, i.v.).
In anaesthetized rabbits, regional blood flow measurements (with radioactive tracer microspheres) showed that BRL 34915 (3 to 30 μg kg−1, i.v.) caused marked vasodilatation in the stomach, with increases in flow also to the heart and small intestine. Brain blood flow also tended to increase. Blood flow to the kidneys was reduced by BRL 34915, whereas flow to skeletal muscle was unchanged.
Apamin pretreatment did not modify the blood pressure lowering activity of BRL 34915 in rats. The site at which BRL 34915 acts to cause vasodilatation in vivo thus appears to be apamin‐insensitive.
A study of the renal actions of amlodipine in the normotensive and spontaneously hypertensive rat
Authors: Johns Edward J. 
Published: July 2012

Normotensive Sprague‐Dawley and spontaneously hypertensive rats anaesthetized with sodium pentobarbitone were used to determine the systemic and renal actions of amlodipine, a new calcium channel blocking drug.
Amlodipine, 200 μg kg−1 plus 50 μg kg−1 h−1, decreased blood pressure by 12 ± 3 mmHg in normotensive rats, although the fall was not statistically significant in the hypertensive rats; did not change renal haemodynamics and caused significant increases in urine flow, absolute and fractional sodium excretions of 70%, 91% and 113%, respectively, in normotensive rats and 65%, 91% and 96%, respectively in hypertensive rats. Fractional lithium excretion was unchanged in the normotensive rats but increased by 28% in the hypertensive animals while absolute fluid reabsorption in the proximal tubule did not change in either group. Absolute water and sodium reabsorption in the segments beyond the proximal tubule were unchanged in the normotensive rats but increased in the hypertensive animals by 24% and 22%, respectively, while fractional sodium excretion in this portion of the nephron increased by 88% and 51% in the normotensive and hypertensive rats, respectively.
Amlodipine, 400 μ kg−1 plus 100 μg kg−1 h−1, decreased blood pressure by 12 ± 4 mmHg in the normotensive and by 27 ± 5 mmHg in the hypertensive rats. Renal blood flow was not changed in either group of rats and glomerular filtration rate increased by 25% in the spontaneously hypertensive animals. There were significant increases in urine flow, absolute and fractional sodium excretions of 105%, 145% and 142%, respectively, in the normotensive rats and 224%, 421% and 259%, respectively, in the hypertensive rats. Fractional lithium excretion was elevated by 29% and 38%, in the normotensive and hypertensive rats, respectively, but absolute fluid reabsorption at the proximal tubule remained unchanged. At the same time there were significant increases in absolute water and sodium reabsorption beyond the proximal tubule of 26% and 18%, respectively, in the normotensive animals and of 63% and 60%, respectively, in the hypertensive animals. Fractional excretion of water and sodium in the nephron regions after the proximal tubule were increased by 55% and 88%, respectively, in the normotensive rats and by 84% and 121%, respectively, in the hypertensive rats.
These doses of amlodipine caused modest reductions in blood pressure, minimal changes in renal haemodynamics and a natriuresis and diuresis. Proximal sodium and water reabsorption was not affected by the drug and it is suggested that the changes in tubular fluid handling were compatible with depression of reabsorption further along the tubule.