bluuebunny/crossref_metadata_2025 huggingface dataset:
THE INFLUENCE OF HORMONAL AND NEURONAL FACTORS ON RAT HEART ADRENOCEPTORS
Authors: KUNOS GEORGE , MUCCI LUCIA , O'REGAN SEANA
Published: July 2012

The influence of hormonal and neuronal factors on adrenoceptors mediating increased cardiac force and rate of contraction were studied in rat isolated atria. The pharmacological properties of these receptors were deduced from the relative potencies of agonists and from the effects of selective α‐and β‐adrenoceptor antagonists. The numbers and affinities of α‐ and β‐adrenoceptors were also determined by radioligand binding to ventricular membrane fragments.

Hypophysectomy reduced the inotropic potency of isoprenaline and increased the potency of phenylephrine and methoxamine in left atria. The effect of phenylephrine was inhibited by propranolol less effectively and by phentolamine or phenoxybenzamine more effectively in hypophysectomized than in control rats. The difference in block was smaller at low than at high antagonist concentrations. Similar but smaller changes were observed for chronotropic responses of right atria.

The decreased β‐ and increased α‐receptor response after hypophysectomy was similar to that observed earlier in thyroidectomized rats (Kunos, 1977). These changes developed slowly after hypophysectomy (> 2 weeks), they were both reversed within 2 days of thyroxine treatment (0.2 mg/kg daily), but were not affected by cortisone treatment (50 mg/kg every 12 h for 4 days).

Treatment of hypophysectomized rats for 2 days with thyroxine increased the density of [3H]‐dihydroalprenolol ([3H]‐DHA) binding sites from 27.5 ± 2.7 to 45.5 ± 5.7 fmol/mg protein and decreased the density of [3H]‐WB‐4101 binding sites from 38.7 ± 3.1 to 18.7 ± 2.5 fmol/mg protein. The affinity of either type of binding site for agonists or antagonist was not significantly altered by thyroxine treatment and the sum total of α1‐ and β‐receptors remained the same.

Sympathetic denervation of thyroidectomized rats by 6‐hydroxydopamine increased the inotropic potency of isoprenaline and noradrenaline and the blocking effect of propranolol, and decreased the potency of phenylephrine and the blocking effect of phenoxybenzamine to or beyond values observed in euthyroid controls. The density of [3H]‐DHA binding sites was higher and that of [3H]‐WB‐4101 binding sites was lower in the denervated than in the innervated hypothyroid myocardium. Depletion of endogenous noradrenaline stores by reserpine did not significantly alter the adrenoceptor response pattern of the hypothyroid preparations and did not influence the density or affinity of [3H]‐DHA and [3H]‐WB‐4101 binding sites.

These results indicate that thyrotropin or steroids do not contribute to the reciprocal changes in the sensitivity of cardiac α1‐ and β‐adrenoceptors in altered thyroid states. These thyroid hormone‐dependent changes are probably due to a parallel, reciprocal change in the numbers but not the affinities of α1‐ and β‐adrenoceptors. Reciprocal regulation of cardiac α1‐ and β‐adrenoceptors by thyroid hormones requires intact sympathetic innervation but not the presence of normal stores of the neurotransmitter.
THE INHIBITORY ACTION OF TWO THROMBIN INHIBITORS (TI‐189 AND TI‐233) ON THE CONTRACTILE RESPONSES TO 5‐HYDROXYTRYPTAMINE AND PROSTAGLANDIN ENDOPEROXIDE ANALOGUE (U‐44069) IN ISOLATED VASCULAR STRIPS
Authors: HO WILLIAM K.W. , NAKAO K. , SHIBATA S.
Published: July 2012

Two arginine derivatives that were developed as thrombin inhibitors (TI‐189 and TI‐233) selectively inhibited the 5‐hydroxytryptamine (5‐HT)‐induced contraction of rabbit aortic strips in a competitive manner. The pA2 values of TI‐189 and TI‐233 were 5.24 ± 0.21 and 6.23 ± 0.32 respectively.

Even at 10−4 m they had no inhibitory effect on the contractile response to noradrenaline (NA), histamine, prostaglandin E2 (PGE2), PGF2α, arachidonic acid or potassium in rabbit aortic strips.

In dog basilar and coronary arterial strips and also in rat fundus, both agents inhibited the 5‐HT response in a non‐competitive manner.

At 10−5 m, TI‐233 but not TI‐189 antagonized effects of NA and KC1 in the dog basilar and coronary arteries.

These arginine derivatives decreased the contractile responses induced by a prostaglandin endoperoxide analogue (U‐44069) in rabbit aorta and in dog basilar and coronary arteries but there was no evidence for competitive antagonism.

These results indicate that the arginine derivatives are competitive antagonists selective for 5‐HT receptors in rabbit aorta.
ERRORS IN THE MEASUREMENT OF AGONIST POTENCY‐RATIOS PRODUCED BY UPTAKE PROCESSES: A GENERAL MODEL APPLIED TO β‐ADRENOCEPTOR AGONISTS
Authors: KENAKIN TERRY P.
Published: July 2012

The sensitization of guinea‐pig atria and trachea to noradrenaline, isoprenaline, and salbutamol, produced by an inhibitor of neuronal (cocaine) and extraneuronal (metanephrine) uptake, was studied quantitatively. The data were compared to a theoretical model.

Cocaine produced near maximal sensitization to noradrenaline in guinea‐pig atria (5 fold) at concentrations which produced only partial sensitization in guinea‐pig trachea (4.7 fold sensitization of a maximum 11 fold). These results agreed with the model which predicts that there is a direct relationship between the amount of uptake inhibitor required to produce full sensitization and the magnitude of maximal sensitization demonstrable in the tissue. This makes extrapolation of uptake inhibition concentrations from tissue to tissue a potentially erroneous practice.

In normal trachea, salbutamol is 20 times more potent than noradrenaline but this difference is abolished (to 0.9 times) by cocaine (100 μm). This reduction of potency‐ratio is due to the selective cocaine‐induced sensitization of trachea to noradrenaline and raises a serious objection to the classification of salbutamol as a β2 selective agonist.

Metanephrine produced very little sensitization of trachea to isoprenaline. Experiments with salbutamol showed metanephrine to be a simple competitive antagonist of β‐adrenoceptors (pKb = 4.3) and that this receptor antagonism masked sensitization to isoprenaline.

A theoretical model indicates that an inhibitor of agonist uptake requires a remarkable degree of selectivity for the uptake mechanism (i.e. Kb for receptors 104 × K1 for uptake sites) to demonstrate tissue sensitization to the agonist. This analysis and the data with metanephrine indicate that a sinistral shift of the concentration‐response curve is a poor indicator of the importance of uptake mechanisms in an isolated tissue.

An alternate method to determine the importance of agonist‐uptake effects on concentration‐response curves is described which utilizes agonist potency ratios. Agonist potency ratios in guinea‐pig atria and trachea showed that the bronchoselectivity demonstrated by salbutamol (with respect to isoprenaline) is reduced from 54 to 7.8 by metanephrine reflecting the importance of extraneuronal uptake in trachea.
MYOTONIA AS A SIDE EFFECT OF DIURETIC ACTION
Authors: BRETAG A.H. , DAWE S.R. , KERR D.I.B. , MOSKWA A.G.
Published: July 2012

Commonly used loop diuretics produce side effects in man which are similar to chemically induced myotonia. These diuretics have structural affinity with known myotonic agents.

We have observed EMG myotonia in vivo in leg muscles of rats treated with intravenous frusemide.

In the presence of several different diuretics, rat isolated diaphragm, soleus and extensor digitorum longus muscles as well as frog sartorius muscles produce typically myotonic contractions with relaxation times up to several seconds.

Intracellular recording of action potentials from diuretic‐treated muscles reveals long lasting after‐discharges following a brief electrical stimulus, again typical of chemically induced myotonia.

Having demonstrated a myotonic action of several diuretics we suggest a need for caution in using these drugs in persons with hereditary myotonia and a need to be aware of possible provocation of myotonia in subclinical cases. Myopathies and neuropathies which are known to result from chronic exposure to myotonic agents also need to be considered.

In our study, the diuretic, acetazolamide, unmasked subthreshold myotonia. This seems to be at variance with reports of its usefulness in the treatment of myotonia.

Diuretics should probably not be employed in the treatment of herbicide intoxication where their myotonic activity would be expected to add to the known myotonic activity of the herbicide.
A COMPARISON OF THE ABILITY OF TWO ANGIOTENSIN II RECEPTOR BLOCKING DRUGS, 1‐SAR, 8‐ALA ANGIOTENSIN II AND 1‐SAR, 8‐ILE ANGIOTENSIN II, TO MODIFY THE REGULATION OF GLOMERULAR FILTRATION RATE IN THE CAT
Authors: JOHNS E.J.
Published: July 2012

Modest stimulation of the renal nerves in the anaesthetized unilaterally nephrectomized cat resulted in a 15% fall in renal blood flow, no change in glomerular filtration rate and significant falls in both the absolute and fractional rates of sodium excretion.

The haemodynamic responses to nerve stimulation were not modified by angiotensin II blockade with 1‐Sar, 8‐Ala angiotensin II although the fall in absolute, but not fractional sodium excretion was significantly larger. In contrast, stimulation of renal nerves following administration of 1‐Sar, 8‐Ile‐angiotensin II caused a significant fall in glomerular filtration rate. The reductions in both absolute and fractional sodium were of the same magnitude as in the absence of drug.

Both renal blood flow and glomerular filtration rate were autoregulated during the reduction of renal perfusion pressure and this was associated with reductions in both absolute and fractional sodium excretions.

In the presence of 1‐Sar, 8‐Ala angiotensin II, the haemodynamic and sodium excretory responses to reductions in renal perfusion pressure were not significantly different from those recorded in the absence of drug. However, following administration of 1‐Sar, 8‐Ile angiotensin II, renal blood flow but not glomerular filtration rate, was autoregulated during reduction in renal perfusion pressure. The falls in absolute and fractional sodium excretions caused by this manoeuvre were of similar magnitude to those obtained in the absence of drug.

The results obtained using the 1‐Sar, 8‐Ile angiotensin II are consistent with angiotensin II having an important intra‐renal site of action to regulate glomerular filtration rate, possibly via an action at the efferent arteriole. Administration of 1‐Sar, 8‐Ala angiotensin II was without effect on the regulation of renal haemodynamics which it is suggested reflects a limitation in the use of this particular compound as an intrarenal angiotensin II antagonist.
EVIDENCE THAT CELL BODIES OF NON‐CHOLINERGIC, EXCITATORY NEURONES WHICH SUPPLY THE SMOOTH MUSCLE OF THE CHICKEN RECTUM ARE LOCATED IN THE GANGLIA OF REMAK'S NERVE
Authors: KANAZAWA T. , OHASHI H. , TAKEWAKI T.
Published: July 2012

A pharmacological investigation of the distribution of non‐cholinergic excitatory nerve cell bodies was performed on the chicken's isolated perfused rectum with attached Remak's nerve supply.

Electrical stimulation of Remak's nerve trunk produced a contraction and a discharge of action potentials in the nerve branches which supply the smooth muscle of the rectum. Both responses were virtually blocked by hexamethonium when applied via the caudal mesenteric artery.

The contractile effect following stimulation of the nerve trunk was inhibited more effectively by hexamethonium when application was restricted to the trunk rather than to the intestine.

The contractile effect of stimulating the nerve branches was unaffected by hexamethonium.

It is concluded that ganglionic transmission, which is mediated by nicotinic receptors, occurs in the ganglia of Remak's nerve but not in ganglia of the enteric plexuses. Therefore, cell bodies of the postganglionic neurones which are considered to be non‐cholinergic are located in Remak's nerve ganglia.
PRAZOSIN DOES NOT ALTER CANINE RENIN RELEASE IN RESPONSE TO SYSTEMIC HYPOTENSION OR INTRARENAL ISOPRENALINE AND PROSTAGLANDIN I2 INFUSION
Authors: GERBER JOHN G. , NIES ALAN S. , OLSON RICHARD D.
Published: July 2012

The effect of a hypotensive dose of intravenous prazosin (0.2 mg/kg) on heart rate and plasma renin activity was evaluated in anaesthetized mongrel dogs pretreated with indomethacin.

The effect of prazosin on the renin release elicited by the β‐adrenoceptor agonist isoprenaline and by prostaglandin I2 was also evaluated.

Prazosin administration was associated with a significant increase in heart rate and increase in plasma renin activity.

Prazosin did not interfere with the increase in plasma renin activity in response to either isoprenaline or prostaglandin I2.

We conclude that prazosin is not a unique peripheral vasodilator since hypotensive doses are associated with an increase in heart rate and plasma renin activity. In addition, prazosin does not inhibit the release of renin induced by either isoprenaline or prostaglandin I2.
A STUDY OF γ‐AMINOBUTYRIC ACID UPTAKE IN NORMAL AND DOWN'S SYNDROME PLATELETS
Authors: ENNS LOUISE , McCOY E.E.
Published: July 2012

Initial uptake rates of γ‐aminobutyric acid (GABA) were compared in Down's syndrome (D.S.) and normal platelets. GABA uptake was decreased in D.S. platelets (1.10 ± 0.10 nmol h−1 10−9) compared to uptake by normal platelets (1.89 ± 0.21 nmol h−1 10−9), P < 0.005.

The effect of varying the Na+ concentration was similar on D.S. and normal platelets. Increasing the media Na+ concentration resulted in increased rates of GABA uptake in both D.S. and normal platelets.

GABA uptake in the presence of 2,4‐dinitrophenol or at 2°C is approximately 56% of the uptake at 37°C for both D.S. and normal platelets.

Extrapolation of a reciprocal plot indicates a two affinity uptake system: a high affinity and a low affinity mechanism.

A significant defect in GABA uptake exists in D.S. platelets.
ACCUMULATION AND OVERFLOW OF 3H FOLLOWING INCUBATION OF THE GUINEA‐PIG GALL BLADDER WITH [3H]‐NORADRENALINE
Authors: DOGGRELL SHEILA A. , VINCENT LYNN
Published: July 2012

Strips of guinea‐pig gall bladder readily accumulate 3H following incubation in the presence of 5 times 10−8 m (‐)‐[3H]‐noradrenaline. This accumulation was reduced by lowering the incubation temperature (from 37° to 23°C), by cocaine (10−6 m), by nortriptyline (10−8, 10−6 and 10−4 m) and following incubation of the tissues with 6‐hydroxydopamine (10−3 m for 3 h). At 10−6 m, (‐)‐noradrenaline and (‐)‐adrenaline, but not (‐)‐isoprenaline, inhibited the accumulation of 3H.

Following preloading of strips of guinea‐pig gall bladder with 3.6 times 10−7 m (‐)‐[3H]‐noradrenaline for 1 h, the spontaneous overflow of 3H was observed. Cocaine (10−4 m), nortriptyline (10−6 m), (‐)‐isoprenaline (10−5 m), acetylcholine (10−5 m) and adenosine 5′‐triphosphate (ATP, 10−4 m) had no effect on the spontaneous overflow of 3H. KCl (10−1 m), (‐)‐noradrenaline (10−5 m), (‐)‐adrenaline (10−5 m), and tyramine (10−5 m) increased the overflow of 3H. These results illustrate similar characteristics of the guinea‐pig gall bladder to other noradrenergically‐innervated tissues in accumulating and releasing 3H following incubation in the presence of [3H]‐noradrenaline.

Following incubation in the presence of 3.6 times 10−7 m (‐)‐[3H]‐noradrenaline, field stimulation, at 5 Hz, of strips of gall bladder, in the absence or presence of 10−6 m atropine, increased the overflow of 3H and, simultaneously, induced contractions. The contractile responses to 5 Hz were smaller in the presence than in the absence of 10−4 m lignocaine. Lignocaine (10−4 m) reduced the overflow of 3H evoked by field stimulation at 5 Hz. It is suggested that the contractile responses to 5 Hz are due to nerve stimulation and that the increased overflow of 3H is due to the stimulation of noradrenergic nerves.

The overflow of 3H evoked by field stimulation at 5 Hz was unaltered and increased by propranolol (10−6 m) and phentolamine (10−6 m), respectively. Clonidine (5 times 10−5 m) had no effect in the absence but reduced the amount of 3H which overflowed in response to field stimulation at 5 Hz in the presence of 10−6 m atropine. The contractile responses to field stimulation at 5 Hz were reduced by phentolamine (10−6 m) or clonidine (5 times 10−6, 10−5 and 5 times 10−5 m) whether or not atropine (10−6 m) was present. These results illustrate the presence of postsynaptic α‐adrenoceptors and suggest the presence of presynaptic α‐adrenoceptors in the gall bladder of the guinea‐pig.
CHLORPROMAZINE, HALOPERIDOL, METOCLOPRAMIDE AND DOMPERIDONE RELEASE PROLACTIN THROUGH DOPAMINE ANTAGONISM AT LOW CONCENTRATIONS BUT PARADOXICALLY INHIBIT PROLACTIN RELEASE AT HIGH CONCENTRATIONS
Authors: BESSER G.M. , DELITALA G. , GROSSMAN ASHLEY , STUBBS W.A. , YEO T.
Published: July 2012

The effects of chlorpromazine, haloperidol, metoclopramide and domperidone on the release of prolactin from perfused columns of dispersed rat anterior pituitary cells were studied.

Chlorpromazine, haloperidol, metoclopramide and domperidone antagonized the dopamine‐mediated inhibition of prolactin release at low concentrations.

Each dopamine antagonist displaced the dose‐response curve for dopamine‐induced suppression of prolactin release to the right in a parallel manner.

At higher concentrations, the four drugs became less effective as dopamine antagonists.

At high concentrations in the absence of dopamine, chlorpromazine, haloperidol, metoclopramide and domperidone paradoxically suppressed prolactin secretion by an unknown mechanism.
CHARACTERISTIC CONTRACTILE RESPONSE TO THE CALCIUM IONOPHORE, A23187, IN GUINEA‐PIG VAS DEFERENS
Authors: ISHIDA YUKISATO , SHIBATA SHOJI
Published: July 2012

In the guinea‐pig isolated vas deferens, the calcium ionophore, A23187, initially caused a phasic contraction followed by rhythmic activity.

Treatment with atropine, phentolamine, tetrodotoxin and reserpine modified neither of the components of the contraction induced by the ionophore. Verapamil and nifedipine abolished the rhythmic activity but had no effect on the phasic contraction.

In a calcium‐free solution, both components of the contraction were abolished.

It is suggested that A23187 is able to cause contraction by a direct action on the smooth muscle of guinea‐pig vas deferens.
PROPHYLACTIC LIGNOCAINE AND EARLY POST‐CORONARY ARTERY OCCLUSION DYSRHYTHMIAS IN ANAESTHETIZED GREYHOUNDS
Authors: MARSHALL R.J. , PARRATT J.R.
Published: July 2012

Lignocaine (1 mg kg−1 min−1 infused intravenously for 30 min) greatly reduced the incidence of ventricular ectopic beats that resulted from acute coronary artery ligation in anaesthetized greyhound dogs. However, the incidence of ventricular fibrillation was only slightly reduced by this treatment which caused significant myocardial depression.

There is no good evidence from this study that lignocaine is a particularly effective prophylactic in acute myocardial infarction.
SUBSTANCE P INCREASES HYPOTHALAMIC BLOOD FLOW VIA AN INDIRECT ADRENERGIC‐CHOLINERGIC INTERACTION
Authors: KLUGMAN K.P. , LEMBECK F. , MARKOWITZ S. , MITCHELL G. , ROSENDORFF C.
Published: July 2012

Hypothalamic blood flow (HBF) was measured in conscious rabbits by the 133xenon washout technique.

Substance P in a dose of 50 or 500 ng increases HBF while 5 ng is without effect.

Cholinoceptor blockade, with either atropine or mecamylamine abolishes the vasodilator effect of substance P.

Chemical sympathectomy of the hypothalamus with 6‐hydroxydopamine, or adrenoceptor blockade with either propranolol or phenoxybenzamine abolishes the effect of substance P on HBF.

Destruction of the intracerebral noradrenergic pathway (INP), or blockade of its vasodilator action, with barbiturate or bicarbonate, likewise prevent the vasodilator action of substance P.

These results suggest that substance P may cause an increase in HBF via the release of endogenous acetylcholine, which in turn stimulates the INP.
INVESTIGATION OF THE ANTIFIBRILLATORY ACTIVITY OF SOME ANTICONVULSANT γ‐AMINOBUTYRIC ACID‐TRANSAMINASE INHIBITORS IN THE RABBIT ISOLATED HEART: COMPARISON WITH PHENYTOIN AND MEXILETINE
Authors: ALMOTREFI A.A. , BAKER J.B.E.
Published: July 2012

The electrical stimulation and ventricular fibrillation thresholds were measured in the Langendorff‐perfused rabbit heart by application of rectangular impulses of 3 ms duration and increasing current at frequencies of 4 and 20 Hz respectively.

Perfusion with either phenytoin or mexiletine produced significant dose‐dependent increases in both thresholds.

Perfusion with four anticonvulsant inhibitors of γ‐aminobutyric acid (GABA)‐transaminase, amino‐oxyacetic acid, γ‐acetylenic GABA, γ‐vinyl GABA and sodium valproate, up to a concentration of 20 μg/ml, had no significant effect on either threshold.

The results suggest that these compounds, unlike phenytoin and mexiletine, are devoid of antifibrillatory activity.
THE EFFECT OF CHRONIC MORPHINE TREATMENT ON EXCITATORY JUNCTION POTENTIALS IN THE MOUSE VAS DEFERENS
Authors: NORTH R.A. , VITEK L.V.
Published: July 2012

Intracellular recordings were made from smooth muscle cells of vasa deferentia in vitro. Vasa from two groups of mice were studied; the first were naive and the second had been chronically pretreated with morphine for 3 days. The vasa from morphine‐pretreated mice were maintained in Krebs solution containing normorphine (300 nm).

The resting membrane potentials of the smooth muscle cells were the same in both groups of mice.

The excitatory junction potentials (e.j.ps) evoked by stimulation of the intramural nerves were depressed by normorphine in both groups of mice. The EC50 for this action of normorphine was 560 nm for the naive group and 6.6 μm for the morphine‐pretreated group.

The EC50 for adenosine in depressing e.j.p. amplitude was the same in the two groups.

Naloxone did not change the resting membrane potential in cells from either group of mice. In morphine‐pretreated mice, naloxone caused a marked increase in the amplitude of the evoked e.j.p.

The EC50 for noradrenaline in causing a contractile response of the isolated vas deferens was the same in both groups of mice.

The results indicate that changes in postsynaptic sensitivity to transmitter do not occur following morphine pretreatment.
ESTIMATION OF pKB VALUES FOR HISTAMINE H2‐RECEPTOR ANTAGONISTS USING AN in vitro ACID SECRETION ASSAY
Authors: ANGUS J.A. , BLACK J.W. , STONE M.
Published: July 2012

Histamine H2‐receptor antagonism by burimamide, metiamide and cimetidine was analysed under apparent equilibrium conditions in the lumen‐perfused isolated stomach preparation of the mouse.

The behaviour of these compounds was not incompatible with simple competitive antagonism but the estimated pKB values (−log KB) were all significantly lower, by about 1 log unit, than reference values reported for guinea‐pig atrium or rat uterus.

There seems no need to propose that the parietal cell receptors are somehow different from the others; metiamide continually appears in the gastric juice so that a steady‐state but not equilibrium can presumably be reached with respect to the bath concentration and this could keep the antagonist concentration artificially low in the region of the receptors.
PARASYMPATHOMIMETIC INFLUENCE OF CARBACHOL ON LOCAL CEREBRAL BLOOD FLOW IN THE RABBIT BY A DIRECT VASODILATOR ACTION AND AN INHIBITION OF THE SYMPATHETIC‐MEDIATED VASOCONSTRICTION
Authors: AUBINEAU PIERRE , SERCOMBE RICHARD , SEYLAZ JACQUES
Published: July 2012

Two sorts of effect of carbachol on local cerebral blood flow (caudate nucleus) have been studied: (a) a direct action on the arterial smooth muscle; (b) an interaction with the adrenergic (sympathetic) constrictor system which innervates the vascular system of this nucleus.

Continuous measurements of the following variables were performed in lightly anaesthetized rabbits: local blood flow (caudate nucleus), arterial blood pressure, PaO2, PaCO2.

After blockade of the nicotinic synapses in the superior cervical sympathetic ganglion by local hexamethonium injection, carbachol was infused into the common carotid artery, thus minimizing systemic effects of this drug. Infusions of 0.6, 1.3 and 2.5 μg kg−1 min−1 induced mean increases in caudate blood flow of about 8, 17 and 37% respectively, without notable modifications of other variables measured.

The dilator effect of 2.5 μg kg−1 min−1 carbachol was reduced to a mean of 12% after intravenous injection of 0.5 mg/kg atropine, and could be totally abolished by higher doses (1 to 1.5 mg/kg).

Administration of 2.5 μg kg−1 min−1 of carbachol diminished by more than 50% the reduction in caudate blood flow induced by postganglionic stimulation of the cervical sympathetic chain, but did not affect the reduction of flow obtained by intravenous infusion of noradrenaline (2.5 to 5.0 μg kg−1 min−1). This inhibition of the adrenergic (sympathetic) system by carbachol was not modified by high doses of atropine (1 mg/kg i.v.).

We conclude that: (a) the local cerebral blood flow of a deep structure can be significantly modified by activation of vascular muscarinic receptors; (b) activation of non‐muscarinic prejunctional cholinoceptors can cause inhibition of the sympathetic fibres innervating the vascular bed of the same structure.
EFFECTS OF DOPAMINE ON ADRENERGIC NEUROMUSCULAR TRANSMISSION IN THE GUINEA‐PIG VAS DEFERENS
Authors: BELL G.
Published: July 2012

In the isolated vas deferens of the guinea‐pig, contractile responses to adrenergic nerve stimulation at 2 Hz were depressed by exogenous dopamine (5 μm) and this effect was abolished in the presence of phentolamine (0.3 μm), suggesting that it was due to an agonist action of dopamine on α‐adrenotors.

The depression by dopamine (5 μm) of contractile responses to nerve stimulation was correlated with reduction in amplitude of single excitatory junction potentials (e.j.ps) evoked by nerve stimulation, but not with depression of spontaneous junction potentials.

By contrast, during repetitive nerve stimulation at 1 Hz the depressant effect of dopamine on e.j.p. amplitude became less pronounced, due to the amount of facilitation being greater than that occurring under control conditions in the same cell.

The α‐adrenoceptor antagonist, phentolamine (10 μm), also increased the amount of facilitation during repetitive nerve stimulation.

In the presence of phentolamine (10 μm), the depressant effect of dopamine (5 μm) on single e.j.ps was abolished but its enhancing effect on facilitation was not reduced.

It is suggested that the enhancement of facilitation during repetitive stimulation by both dopamine and phentolamine is independent of their actions on presynaptic α‐adrenoceptors.
ATTENUATED DEPRESSOR RESPONSE TO ARACHIDONIC ACID AND PROSTAGLANDINS IN UNCLIPPED RENAL HYPERTENSIVE RATS
Authors: TEN BERG R.G.M. , DE JONG W. , NIJKAMP F.P.
Published: July 2012

In renal hypertensive rats (one‐clip, two‐kidney type) blood pressure returned to a normotensive level within 24 h after the removal of the renal artery clip (unclipping).

The decrease in blood pressure caused by intravenous administration of arachidonic acid, prostaglandin E2 and prostaglandin I2 was significantly reduced in these unclipped rats.

The hypotensive response to bradykinin and acetylcholine was the same in unclipped rats and in control rats.

Nephrectomy abolished the difference in blood pressure response to arachidonic acid and the two prostaglandins between unclipped and control rats.

An enhanced secretion of renin, as indicated by the absence of an increase in plasma renin activity, did not seem to be involved in the attenuated blood pressure response to arachidonic acid in unclipped rats.
INHIBITORY EFFECT OF ADENOSINE AND ADENINE NUCLEOTIDES ON POTASSIUM‐EVOKED EFFLUX OF [3H]‐NORADRENALINE FROM THE RAT ISOLATED HEART: LACK OF RELATIONSHIP TO PROSTAGLANDINS
Authors: KHAN MOHAMMAD T. , MALIK KAFAIT U.
Published: July 2012

In the isolated heart of the rat prelabelled with [3H]‐noradrenaline (NA) and perfused with Krebs solution, administration of potassium (K+ 60 μmol) increased the efflux of total radioactivity and of [3H]‐NA in the perfusate.

Adenosine triphosphate (ATP), adenosine diphosphate (ADP) and adenosine, but not inosine, dibutyryl cyclic adenosine 3′5′‐monophosphate (db cyclic AMP) or db cyclic GMP reduced the K+‐evoked overflow of total radioactivity and of intact [3H]‐NA, in concentrations too low to cause release of prostaglandins. ATP, ADP and adenosine did not affect tyramine‐evoked overflow of tritium.

Blockade of prostaglandin synthesis with indomethacin did not alter the inhibitory effect of either ATP, ADP or adenosine on K+‐induced overflow of tritium, thereby indicating that these nucleotides inhibit adrenergic transmission by a mechanism unrelated to stimulation of prostaglandin synthesis.

Theophylline which increases entry of calcium (Ca2+) across the cell membrane and reduces its binding in the cell, enhanced K+‐evoked overflow of tritium and diminished the inhibitory effect of ATP, ADP and adenosine on K+‐evoked overflow of tritium from the heart, presumably by interfering with transneuronal Ca2+ metabolism.
DIFFERENTIAL EFFECTS OF PROSTAGLANDINS ON CANINE INTRAPULMONARY ARTERIES AND VEINS
Authors: ALTURA BURTON M. , CHAND NARESH
Published: July 2012

The sensitivity and contractility of isolated canine intrapulmonary arteries and veins to a variety of primary prostaglandin compounds was studied.

Intrapulmonary arteries produced no measurable contractile responses to prostaglandin A1 (PGA,), PGA2, PGB1, PGD2, PGE,1, PGE2 or to PGFlα. However, high concentrations of both PGB2 (> 10−7 m) and PGF2α (> 10−6 m) elicited concentrated‐related, but weak, contractile responses, measuring only 5–25% of KCl‐induced maximum contractions.

Intrapulmonary arteries, partially contracted by 5‐hydroxytryptamine (5‐HT), exhibited concentration‐related relaxations in response to PGE,1 PGE2, PGA1, or PGA2 produced only weak superimposed contrtactions.

In contrast to intrapulmonary arteries, intrapulmonary veins contracted in a concentration‐related fashion to all prostaglandins tested, where the contractile sensitivity was (based on EC50 s and threshold concentrations): PGB2 > PGB1, > PGD2 > PGF2α > PGA2 »PGA1, > PGF1α > PGE2 > PGE1.

In terms of the ability to generate maximum contractile responses on intrapulmonary veins, the prostaglandins were also variable, with PGA2 and PGB2 being the most potent and PGD2 the least potent.

Intrapulmonary veins, partially contracted by 5‐HT, exhibited concentration‐related relaxations to PGE1 at low concentrations, followed by secondary contractile responses at higher concentrations.

Neither PGA1 nor PGA2 (3.4 × 10−8 to 3.4 × 10−5 m) inhibited or potentiated 5‐HT responses of intrapulmonary arteries.

These data suggest that there are species, regional and major qualitative and quantitative, differences in the responsiveness of intrapulmonary arteries and veins to prostaglandin.
ATROPINE AND MICTURITION RESPONSES BY RATS WITH INTACT AND PARTIALLY INNERVATED BLADDER
Authors: CARPENTER F.G.
Published: July 2012

Micturition responses by a group of 17 rats were recorded during a water diuresis. During a 2 h period, uniform volumes of urine were passed at regular intervals; the mean of the voiding responses by each animal was consistent from one water loading period to another. Residual urine volumes were physiologically insignificant.

Atropine treatment did not compromise seriously micturition by water‐loaded rats. Treated animals micturated more frequently; the mean volume was 68% of control. The residual urine volume was equal to that of controls.

Several weeks after the surgical removal of half the motor innervation of the bladder, there was no significant effect on micturition. Mean voiding volumes were not different from those of controls; residual urine volumes were the same as before denervation.

After half the innervation of the bladder had been destroyed, the effect of atropine on micturition was enhanced. Volumes passed were 50% of control; large residual volumes remained when micturition was over. Only in this group could bladder distension be found.

It is concluded that functional responses of the rat urinary bladder are not only resistant to atropine but also to the sizeable reduction in the number of neuroeffector units in the bladder itself. The functional reserve of the rat bladder musculature is remarkably high when assessed by its ability to empty adequately.
ISOPRENALINE‐ AND NORADRENALINE‐INDUCED HYPER‐POLARIZATION OF GUINEA‐PIG LIVER CELLS
Authors: KARASHIMA TSUYOSHI
Published: July 2012

Effects of pretreatment with isoprenaline (Isop) or noradrenaline (NA) and various ionic environments on the NA‐induced or Isop‐induced hyperpolarization of guinea‐pig liver cells were investigated by means of a microelectrode technique.

NA (5.9 × 10−6 m) decreased the membrane resistance, and hyperpolarized the membrane with or without generation of an initial transient small depolarization. The NA‐induced initial depolarization was not dependent on the membrane potential and was increased by Isop (4.0 × 10−6 m) or glucagon (10−7m).

In Ca‐free solution, the NA‐induced hyperpolarization became transient and a continuous depolarization followed in the presence of NA. Repetitive application of NA resulted in a complete disappearance of the NA‐induced hyperpolarization and was replaced by a slowly developing depolarization with or without generation of the initial transient depolarization. In excess [Ca]0, the NA or Isop‐induced hyperpolarization was increased.

Both Isop and glucagon hyperpolarized the membrane and decreased the membrane resistance, to various degrees. Repetitive application of Isop or glucagon resulted in the disappearance of both Isop and glucagon‐induced hyperpolarizations. Pretreatment with NA not only resulted in a recovery of both Isop and glucagon‐induced hyperpolarizations, but also extensively enhanced the hyperpolarization.

After pretreatment with Isop, the NA‐induced hyperpolarization was decreased in amplitude and duration and was followed by a slowly developing depolarization. After repetitive application of Isop, NA produced only depolarization of the membrane, and in these conditions, Isop, glucagon or ATP also depolarized the membrane. These depolarizations were reversed to hyperpolarizations by pretreatment with excess [Ca]0.

After treatment with Na‐deficient solution, NA depolarized the membrane and decreased the membrane resistance. Excess [Ca]0 restored the NA‐induced membrane response from one of depolarization to one of hyperpolarization.

In the presence of tetraethylammonium 10mM, the NA‐induced hyperpolarization became transient or ceased and depolarization occurred with a reduction in the membrane resistance.

It is postulated that both NA and Isop increase the free [Ca]i by releasing bound Ca from storage sites and consequently an increase in K conductance follows. NA but not Isop promotes Ca‐influx which replenishes the storage site. In Ca‐depleted conditions, NA does not elevate the free [Ca]i to a threshold concentration required for hyperpolarization, probably because NA induces a small release of Ca from storage sites.
DISTRIBUTION OF P1 AND P2‐PURINOCEPTORS IN THE GUINEA‐PIG AND FROG HEART
Authors: BURNSTOCK GEOFFREY , MEGHJI PARVIZ
Published: July 2012

The effects of adenyl compounds were examined on the guinea‐pig and frog heart in terms of the P1/P2‐purinoceptor hypothesis.

The effects of two slowly degradable adenosine 5′‐triphosphate (ATP) analogues; β, γ‐methylene adenosine 5′‐triphosphate (APPCP) and α, β‐methylene adenosine 5′‐triphosphate (APCPP) were also examined.

Adenosine, adenosine 5′‐monophosphate (AMP), adenosine 5′‐diphosphate (ADP), ATP and APPCP produced inhibitory effects in guinea‐pig atria. These inhibitory effects were antagonized competitively by theophylline and potentiated by dipyridamole. APCPP did not produce a similar inhibitory response.

Guinea‐pig ventricles were insensitive to adenyl compounds.

ATP and ADP produced initial excitatory effects in frog atria which were followed by inhibitory effects. Adenosine and AMP produced inhibitory effects alone whereas APCPP produced excitatory effects only. The inhibitory effects were antagonized competitively by theophylline and potentiated by dipyridamole.

ATP, ADP, APPCP and APCPP evoked excitatory responses in frog ventricles. These responses were not affected by theophylline or dipyridamole. Adenosine and AMP were inactive on frog ventricles.

It is concluded that only P1‐receptors are present in guinea‐pig atria; that both P1‐ and P2‐receptors are present in frog atria; and that only P2‐receptors are present in frog ventricles. No evidence was found for the presence of either P1 or P2‐purinoceptors in guinea‐pig ventricles.
EFFECT OF GENDER ON DEVELOPMENT AND DIURNAL RHYTHM OF PROSTAGLANDIN RECEPTORS IN RAT AORTA
Authors: KARANIAN J.W. , RAMEY E.R. , RAMWELL P.W.
Published: July 2012

The prostaglandin endoperoxide H2 analogue, U‐46619 (15‐hydroxyll, 9‐epoxymethano‐prosta‐5Z, 13E‐enoic acid), was used to determine the effect of gender on the isotonic contractile response of the superfused rat aorta preparation over a 24 h period and at 10 and 16 weeks of age.

The maximal responses of the male aortae were 20 ± 3% and 36 ± 4% (P< 0.001) greater than the female at 10 and 16 weeks, respectively. Similarly, sensitivity of the male aorta to the PGH2 analogue increased with age.

The male but not the female exhibited a diurnal rhythm in which both the maximum contractile response and sensitivity were significantly decreased at night.

We conclude that these gender differences may be related to the secretion of androgen, since reported peak serum testosterone over a 24 h period and testosterone changes with maturation are coincident with the maximum response of male aortae to the PGH2 analogue.
EFFECT OF FATTY ACIDS ON THE VENTRICULAR ARRHYTHMIA THRESHOLD IN THE ISOLATED HEART OF THE RABBIT
Authors: MURNAGHAN MAURICE F.
Published: July 2012

The ventricular arrhythmia threshold (VAT) was measured in the isolated Ringer‐perfused rabbit heart (Langendorff preparation) by applying a single 10 ms square‐wave pulse of current to the left ventricle during the vulnerable period of late systole under normoxic and hypoxic conditions.

The sodium salt of the fatty acid was bound to albumen and incorporated in the Krebs‐Henseleit solution which was maintained at 37°C and gassed with 95% O2 and 5% CO2 (normoxia) or 5% CO2 in air (hypoxia).

Saturated fatty acids failed to alter the VAT under normoxia.

Naturally occurring long‐chained saturated and mono‐unsaturated fatty acids with chain lengths varying from 14 to 20 carbons, but not the 12 carbon lauric acid, potentiated the effect of the hypoxia in lowering the VAT.

Short‐chained 8 and 10 carbon saturated and long‐chained polyunsaturated fatty acids antagonized the effect of hypoxia on the VAT.

In addition the polyunsaturated acids antagonized the potentiating effect of the long‐chained saturated and mono‐unsaturated acids on the hypoxia in lowering the VAT.

The fatty acids did not alter the duration or type of the induced arrhythmia.
THE PARTIAL PURIFICATION AND BIOASSAY OF A TOXIN PRESENT IN EXTRACTS OF THE SEA ANEMONE, Tealia felina (L.)
Authors: ALDEEN SUSAN I. , ELLIOTT R.C. , SHEARDOWN M.
Published: July 2012

Column chromatography with Agarose A50m followed by Sephadex G100 was used to separate a fraction (extract II) in the molecular weight range 12,000 to 14,000 daltons from saline extracts of the sea anemone, Tealia felina.

Extract II inhibited histamine‐induced contractions of the guinea‐pig ileum and produced haemolysis of human blood, effects on which bioassays were based.

The potency of extracts was assayed. A standard unit of activity (= AU) was defined such that 100 AU produced 90% inhibition of histamine‐induced contractions of the guinea‐pig ileum after 30 to 35 min exposure.

The relationship between activity of the extracts measured on the ileum and their haemolytic activity was studied, providing a second assay method based on the latter property.

Based on values from both methods of assay, the calculated yield in AU at the end of the separation procedure was 0.53 AU for each AU present in the original extract. In crude extract there were 5.0 AU/mg dry weight and 36.7 AU/mg protein, and after separation (extract II) there were 11.2 AU/mg dry weight and 312.2 AU/mg protein.

The acute LD50 values determined in mice (i.v.) were: for crude extract 124 mg/kg, for extract I, 76 mg/kg and for extract II, 69 mg/kg.

Extract II (0.18 to 0.72 AU/ml) produced a slowly developing contraction of guinea‐pig ileum. Indomethacin (2.8 × 10−5 m) substantially reduced this response.

Extract II (0.03 AU/ml) reduced the contractile response of the guinea‐pig ileum to acetylcholine by 39 ± 8%, n = 6, and the response to histamine by 26 ± 6.6%, n = 6. The response to 5‐hydroxy‐tryptamine (5‐HT) was not reduced by 0.08 AU/ml of extract II, a concentration that actually increased the contractile response to KCl by 32 ± 11.2%, n = 7.

It is proposed that for future work on the extract a new AU should be used. This AU is defined such that 50 AU produce 50% inhibition of histamine‐induced contractions of the guinea‐pig ileum after 30 to 35 min exposure.
EFFECT OF SUBSTANCE P AND ITS NATURAL ANALOGUES ON GASTRIC EMPTYING OF THE CONSCIOUS RAT
Authors: BERTACCINI G. , DE CASTIGLIONE R. , SCARPIGNATO C.
Published: July 2012

Substance P and its natural analogues were tested for their effect on gastric emptying in the rat.

Substance P and kassinin were virtually inactive even at the maximum dose tested.

The other tachykinins significantly delayed gastric emptying, their effect being quite remarkable with 100 μg/kg. The lowest doses (30 μg/kg) caused a slight and non‐significant increase in emptying rate.

The effect on gastric emptying was most probably correlated with a spasmogenic effect on the gastroduodenal junction, as pointed out in previous work.
5‐HYDROXYTRYPTAMINE INDUCES RELAXATION OF GOAT PULMONARY VEINS: EVIDENCE FOR THE NONINVOLVEMENT OF M AND D‐TRYPTAMINE RECEPTORS
Authors: CHAND NARESH
Published: July 2012

Reactivity of goat isolated pulmonary arteries and veins to a variety of vasoactive agents was investigated.

Bradykinin (Bk), acetylcholine (ACh), noradrenaline (NA), prostaglandin A1 (PGA1), PGE2, PGF2α and histamine induced dose‐dependent contractile responses on veins; 5‐hydroxytryptamine (5‐HT) induced veno‐relaxation. Angiotensin was virtually inactive.

Angiotensin, NA, Bk, histamine and 5‐HT produced concentration‐dependent contractile responses on the arterial strips; these arteries failed to respond to ACh, PGA1, PGE2 or PGF2α.

The pulmonary veno‐relaxant response to 5‐HT was found to be resistant to propranolol, indomethacin, metiamide, cimetidine, methysergide, atropine and morphine. These findings appear to exclude the involvement of adrenergic mechanisms and prostaglandin generation as well as activation of classical M and D‐tryptamine receptors by 5‐HT in the goat pulmonary veins. This response may be mediated via a presynaptic inhibitory 5‐HT receptor.

5‐HT‐induced arterial contractile responses were antagonized by methysergide, showing the occurrence of classical D receptors in the goat pulmonary artery.

It is concluded that differential reactivity of pulmonary arteries and veins to vasoactive agents may play differential role(s) in the pathophysiology of pulmonary disease. 5‐HT may exert an antiinflammatory activity in goat pulmonary veins.
STEREOSPECIFIC DEXTRORPHAN TOLERANCE IN RATS
Authors: CARNEY JOHN M. , SIROCHMAN VICKI L.
Published: July 2012

Levorphanol was 20 times more potent than dextrorphan in decreasing food‐reinforced fixed ratio 15 responding in male Sprague Dawley rats.

Chronic dextrorphan (100 mg/kg, i.p.; every 8 h) resulted in the development of dextrorphan tolerance. The dextrorphan dose‐effect curve was shifted to the right three fold.

In contrast to dextrorphan, nontolerance developed to the effects of levorphanol.

These data support the hypothesis that (+)‐isomers of opioids produce pharmacologically distinct CNS effects.
ANGIOTENSIN RECEPTORS IN BOVINE UMBILICAL ARTERY AND THEIR INHIBITION BY NONSTEROIDAL ANTI‐INFLAMMATORY DRUGS
Authors: GOODFRIEND THEODORE L. , SIMPSON ROBERT U.
Published: July 2012

The contractile effect of angiotensin II on bovine isolated umbilical arteries was compared to [125I]‐angiotensin II binding by a subcellular fraction of that tissue. The ED50 of angiotensin was 3.1 ± 2.8 × 10−8 m, while the apparent dissociation constant was 4.9 ± 1.6 × 10−9 m.

Indomethacin, meclofenamate, and eicosatetraynoic acid inhibited angiotensin‐induced contraction of the isolated artery and binding to a particulate fraction at comparable doses. Phenylbutazone inhibited [125I]‐angiotensin binding more potently than the response. Inhibition by the first three agents was noncompetitive, whereas phenylbutazone inhibited competitively.

Inhibition of angiotensin activity by the nonsteroidal anti‐inflammatory agents was not specific. These agents also inhibited 5‐hydroxytryptamine‐induced contraction, but not the contraction induced by KCl.

The data suggest that the angiotensin binding sites studied include receptors that mediate contraction of the isolated umbilical artery. Our data also indicate that indomethacin, meclofenamate, eicosatetraynoic acid and phenylbutazone are capable of direct inhibitory effects on receptors, as well as their well‐known synthetase actions. The net effect of these activities will determine the change these agents cause in tissue responses to hormones.
A COMPARISON OF STEREOSPECIFICITY AT CENTRAL AND PERIPHERAL ‘MUSCARINE‐SENSITIVE’ ACETYLCHOLINE RECEPTORS: OBSERVATIONS WITH THE ENANTIOMERIC FORMS OF PROCYCLIDINE AND TRICYCLAMOL
Authors: BARLOW R.B. , DAWBARN D. , PYCOCK C.J.
Published: July 2012

Procyclidine resembles hyoscine in enhancing the effects of amphetamine on ipsiversive turning by mice with a unilateral central dopamine lesion.

The stereospecific index for procyclidine is not greater than 10, in contrast to 173 for acetylcholine receptors in ileum from the same mice.

This suggests that although the central effects of procyclidine in this test involve acetylcholine receptors similar to those at peripheral sites, they cannot be identical with them unless there are differences at some secondary site, for example, if the weaker enantiomer were a stronger inhibitor of dopamine uptake or if there were a stereoselective uptake process for procyclidine itself.
THE EFFECTS OF AMILORIDE AND TRIAMTERENE ON URINARY MAGNESIUM EXCRETION IN CONSCIOUS SALINE‐LOADED RATS
Authors: DEVANE JOHN , RYAN MICHAEL P.
Published: July 2012

The potassium‐sparing diuretics, triamterene and amiloride, reduced urinary magnesium excretion in conscious saline‐loaded rats.

Urinary magnesium‐conservation was also detected when amiloride was used in combination with the potent ‘loop‐blocking’ diuretic, frusemide.
EFFECT OF VARIOUS DOSES OF ACETYLSALICYLIC ACID IN COMBINATION WITH DIPYRIDAMOLE ON THE BALANCE BETWEEN PROSTACYCLIN AND THROMBOXANE IN HUMAN SERUM
Authors: VIINIKKA LASSE , YLIKORKALA OLAVI
Published: July 2012

Thirty‐six healthy human subjects were randomly divided into six groups which were treated with a single dose of 75 mg (1.3 mg/kg) of dipyridamole alone, or 75 mg of dipyridamole in combination with 30 mg (0.5 mg/kg), 50 mg (0.8 mg/kg), 160 mg (2.6 mg/kg) and 330 mg (5.7 mg/kg) of acetylsalicylic acid (ASA), or with placebo.

The concentrations of prostacyclin (PGI2) and thromboxane A2 (TxA2) metabolites, 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) and TxB2 respectively, were measured in serum with specific radioimmunoassays before and 1 and 3 h after the ingestion of the test dose.

The basal concentrations of 6‐keto‐PGF1α and TxB2 correlated significantly (r = 0.588, P < 0.001).

Dipyridamole alone did not change PGI2 or TxA2 production.

Dipyridamole‐ASA combinations with ASA doses between 0.5 and 0.8 mg/kg inhibited TxB2 production by 48 to 74%, and with the ASA doses between 2.6 and 5.7 mg/kg by about 90%. None of these combinations changed PGI2 production.

The ratio of 6‐keto‐PGF1α to TxB2 increased 3.5 to 6 times with ASA doses of 0.5 to 0.8 mg/kg and 21 to 29 times with doses between 2.6 to 5.7 mg/kg.

These results suggest that the anti‐thrombotic effect of dipyridamole in vivo is not mediated through direct changes in PGI2 and/or TxA2 production.