bluuebunny/crossref_metadata_2025 huggingface dataset:
Aortic vascular and atrial responses to (±)‐1‐O‐octadecyl‐2‐acetyl‐glyceryl‐3‐phosphorylcholine
Authors: Cervoni P. , Herzlinger H.E. , Lai F.M. , Tanikella T.K.
Published: July 2012

The effects of (±)‐1‐O‐octadecyl‐2‐acetyl‐glyceryl‐3‐phosphorylcholine (octadecyl‐AGPC) were studied in three types of aortic vascular smooth muscle preparations, namely, strips, rubbed and unrubbed rings, and an atrial preparation in normotensive rats.

In the resting tension state, octadecyl‐AGPC did not elicit significant contractions in either rubbed or unrubbed ring preparations at concentrations lower than 1 × 10−4m. However, at a concentration of 3 × 10−4 m, octadecyl‐AGPC markedly contracted both types of ring preparations. This contractile response was partially antagonized by pretreatment with reserpine and completely blocked by phentolamine (1 × 10−6m).

In preparations contracted with noradrenaline (NA), octadecyl‐AGPC elicited biphasic responses in intact ring preparations; an initial relaxation followed by contraction. Octadecyl‐AGPC induced only a slight contraction in strips and a slight relaxation in the rubbed ring preparation.

Octadecyl‐AGPC did not elicit any significant effect on chronotropy or inotropy at concentrations up to 3 × 10−5 m. When the concentration was 1 × 10−4 m, octadecyl‐AGPC produced significant positive chronotropic and inotropic effects on spontaneously beating right and electrically driven left atrial preparations, respectively. Both effects were blocked by propranolol (5 × 10−8m); reserpine pretreatment antagonized only the chronotropic response.

In [3H]‐dihydroalprenolol ([3H]‐DHA) binding studies, octadecyl‐AGPC had a Kd of 427.85 μm and thus was much less potent than isoprenaline (Kd = 465.10 nm) or propranolol (Kd = 4.4 nm) in displacing [3H]‐DHA in rat cardiac membrane preparations.

In conclusion, relaxation and contraction induced by octadecyl‐AGPC in aortic preparations is an indirect rather than a direct effect. An unknown factor released from endothelial cells is responsible for aortic smooth muscle relaxation by octadecyl‐AGPC while released NA appears to be responsible for aortic vascular contraction and for the positive chronotropic and inotropic effects in the atrial preparations.
Platelet β‐adrenoceptors
Authors: Kerry Roger , Scrutton Michael C.
Published: July 2012

Inhibition by isoprenaline of the aggregatory response of human and rat platelets induced by various excitatory agonists is blocked by β2‐adrenoceptor antagonists, β1‐Adrenoceptor antagonists are ineffective.

β2‐Adrenoceptor agonists cause inhibition of the response of human platelets to various excitatory agonists. The maximal extent of inhibition is less than that observed for isoprenaline. β1‐Adrenoceptor agonists fail to cause detectable inhibition of this response. Neither β1 nor β2‐adrenoceptor agonists cause inhibition of the response of rat platelets to excitatory agonists. Only β2‐adrenoceptor agonists block the inhibitory response to isoprenaline.

The extent of inhibition by isoprenaline is a function of the excitatory agonist used and in human platelets is correlated with the ability of that agonist to suppress elevated platelet cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels.

Inhibition by isoprenaline is prevented in the presence of an inhibitor of adenylate cyclase.

Isoprenaline increases platelet cyclic AMP levels with an EC50 similar to that required to observe inhibition of the aggregatory response.

These data indicate that human platelets carry β2‐adrenoceptors whose occupancy causes inhibition of the response to excitatory agonists as a consequence of elevation of platelet cyclic AMP. The β‐adrenoceptor present on rat platelets also appears to be of the β2‐subtype.
Cardiovascular responses of rats to intrahypothalamic injection of carbachol and noradrenaline
Authors: Poole S.
Published: July 2012

Carbachol (0.1–2 μg) and noradrenaline (5–20 μg) injected into the anterior hypothalamus of unanaesthetized unrestrained rats evoked dose‐dependent falls in heart rate and increases in arterial blood pressure.

When the above amine injections were repeated in rats anaesthetized with chloral hydrate, sodium pentobarbitone or halothane the evoked bradycardias were usually smaller and the changes in arterial blood pressure more variable.

The cardiovascular responses to carbachol (1 μg) and to noradrenaline (10 μg) were antagonized by intrahypothalamic injection of atropine (1 μg) and phentolamine (10 μg), respectively.

The bradycardias evoked by carbachol (1 μg) and by noradrenaline (10 μg) were abolished by pretreatment with intra‐arterial injection of methyl atropine (100 μg 100 g−1).

The hypertensive responses to carbachol (1 μg) and to noradrenaline (10 μg) were reduced by pretreatment with intra‐arterial injection of thymoxamine (500 μg 100 g−1).
The effect of adenyl compounds on the rat heart
Authors: Burnstock Geoffrey , Meghji Parviz
Published: July 2012

The effects of adenyl compounds were examined on the rat atrium and ventricle.

Adenosine, adenosine 5′‐monophosphate, adenosine 5′‐diphosphate, adenosine 5′‐triphosphate (ATP) and β, γ‐methylene ATP (APPCP) produced negative inotropic effects on the rat atrium. These inhibitory effects were antagonized by 8‐phenyltheophylline (8‐PT), a P1‐purinoceptor antagonist, and potentiated by erythro‐9‐(2‐hydroxy‐3‐nonyl) adenine (EHNA), an adenosine deaminase inhibitor, but were not affected by dipyridamole, which blocks adenosine uptake.

α, β‐Methylene ATP (APCPP), which is resistant to degradation, did not produce a similar inhibitory response in the rat atrium.

Adenosine did not affect the basal developed force of the rat ventricle nor did it affect the β‐adrenoceptor‐mediated positive inotropic effect.

Very high concentrations of ATP (0.1–3 mM) produced negative inotropic effects in the rat ventricle. APPCP (0.3 mM) also produced an inhibitory response, which was significantly smaller than that produced by ATP (0.3 mM). APCPP elicited excitation rather than the expected inhibitory response.

The inhibitory effect of ATP in the rat ventricle was not blocked by indomethacin, 8‐PT or atropine.

It impossible that the action of ATP in the rat ventricle is mediated via P2‐purinoceptors and that the lack of inhibitory action of APCPP on the rat ventricle is due to the difference in structural conformation between ATP and APCPP.

It seems likely that inhibitory P1‐purinoceptors are present in the rat atrium and that the inhibitory responses produced by ATP in the rat ventricle may be mediated via P2‐purinoceptors.
The effect of modification of sympathetic activity on responses to ligation of a coronary artery in the conscious rat
Authors: Botting J.H. , Johnston Kathleen M. , Macleod B.A. , Walker M.J.A.
Published: July 2012

Ligation of a coronary artery was performed in conscious rats whose sympathetic system activity had been altered by various treatments.

β‐Adrenoceptor blockade with acute (0.2 mg kg−1 plus 0.1 μg kg−1 min−1) or chronic (50–60 mg kg−1 daily for 12 days) propranolol treatment had little effect on arrhythmias, or other responses to ligation.

Abrupt withdrawal of chronic propranolol two days before ligation was also without effect.

Reduction of sympathetic activity acutely with labetalol (5 mg kg−1), or chronically with adrenomedullectomy and 6‐hydroxydopamine treatment, accentuated the adverse effects of ligation.

The results of this study suggest that, while activity of the sympathetic system is not detrimental during ligation in the conscious rat, it may be important for survival.
Influence of dopamine receptor agonists on gastric acid secretion induced by intraventricular administration of thyrotropin‐releasing hormone in the perfused stomach of anaesthetized rats
Authors: Maeda‐Hagiwara Masaki , Watanabe Kazuo
Published: July 2012

The influence of dopamine receptor agonists on gastric acid secretion stimulated by thyrotropin‐releasing hormone (TRH) was studied in the perfused stomach of anaesthetized rats.

Intraventricular TRH produced a dose‐dependent stimulation of basal gastric acid secretion.

Pretreatment with apomorphine, bromocriptine or methamphetamine inhibited the TRH‐stimulated gastric acid secretion; these drugs did not influence bethanechol‐induced acid secretion.

Haloperidol and metoclopramide prevented the antisecretory effects of apomorphine, bromocriptine and methamphetamine.

The present study suggests that central dopamine receptor stimulation inhibits intraventricular TRH‐induced gastric acid secretion in rats.
Dose‐dependent reduction in renal magnesium clearance by amiloride during frusemide‐induced diuresis in rats
Authors: Devane John , Ryan Michael P.
Published: July 2012

The effects of the potassium‐sparing diuretic, amiloride, on fractional magnesium excretion were investigated at four doses (0.02, 0.08, 0.20 and 2.00 mg kg−1h−1) during frusemide‐induced diuresis.

Amiloride caused a dose‐dependent reduction in the fractional excretion of both magnesium and potassium, whereas the effects of amiloride, over the same dose range, on fractional sodium and calcium excretion were not dose‐dependent.

The results indicate that amiloride exerted a specific renal action to alter magnesium and potassium transport dissociated from effects on sodium excretion.
Gastric juice electrolyte secretion in conscious dogs with gastric fistulae and its modification by FPL 52694, a mast cell stabilizing agent
Authors: Canfield S.P. , Curwain B.P.
Published: July 2012

Studies have been made of the electrolyte output in the gastric juice of conscious dogs equipped with gastric fistulae during stimulation by intravenous infusion of either pentagastrin (2 μg kg−1 h−1), histamine (30 μg kg−1 h−1) or insulin (0.1 u kg−1 h−1).

The mast cell stabilizing agent, FPL 52694 (4.35 mg ml−1) was instilled into the stomach for 30 min and caused a marked reduction of H+ output, H+ concentration and osmotic strength of the juice during stimulation with pentagastrin, histamine, or insulin. There was also a marked increase in the rate of Na+ output into the juice.

When pentagastrin‐stimulated acid secretion was inhibited by cimetidine (4 μmol kg−1 i.v.) acid output was reduced but there were no sustained changes in ion concentrations, osmolality or Na+ output of the type seen following inhibition with FPL 52694.

It is concluded that FPL 52694 may have a dual mode of action in this preparation; a direct reduction of the output of hydrochloric acid and a smaller effect to increase gastric NaHCO3 output leading to a post‐secretory neutralization of the juice.
Myocardial inotropic responses and adrenoceptors in protein‐deficient rats
Authors: Benfey B.G. , Varma D.R. , Yue T.L.
Published: July 2012

Inotropic effects of isoprenaline, phenylephrine and calcium were studied in left atria of 5 weeks old rats fed a low (5%) or a normal (21%) protein diet for 3 weeks. Rats maintained on a low (5%) protein diet consume about half the amount of food eaten by the same rats maintained on a normal (21%) protein diet and thus suffer from protein‐calorie malnutrition (PCM).

Body weight did not increase in PCM, but heart weight adjusted to body weight was slightly increased compared to normal rats.

Atrial resting tension and peak developed tension in response to isoprenaline, phenylephrine or calcium were not diminished by PCM.

The number of a and β‐adrenoceptors and the receptor affinity in ventricular membranes were not reduced by PCM.
The spasmogenic action of potassium chloride in guinea‐pig trachealis
Authors: Foster R.W. , Small R.C. , Weston A.H.
Published: July 2012

Tissue bath experiments showed that potassium chloride (KCl) at 10–40 mmol l−1 evoked spasm of guinea‐pig trachealis which was unaffected by atropine (1 μmol l−1), mepyramine (1 μmol l−1), tetrodotoxin (3 μmol l−1) or indomethacin (2.8 μmol l−1).

Spasm evoked by KCl was depressed in Ca2+‐free Krebs solution or by exposure of tissues to LaCl3 (0.25–1 mmol l1).

Extracellular electrical; recording showed that the spasm evoked by KCl 10 mmol l−1 was associated with promotion of electrical slow wave activity. Higher concentrations of KCl abolished slow wave activity but caused further tension development.

Intracellular recording confirmed the ability of KCl 10 mmol l−1 transiently to promote slow wave activity in individual trachealis cells. This action was associated with depolarization and tension development. Higher concentrations of KCl evoked further tension development but slow waves were suppressed as the depolarization evoked by KCl increased.

KCl (10–40 mmol 1−1) increased the lanthanum‐resistant calcium fraction of muscle‐containing strips of trachea.

It is concluded that KCl acts directly on the smooth muscle of guinea‐pig trachea. The spasmogenic action is associated with transient promotion of slow wave activity and a fall in resting membrane potential. The spasm involves the cellular influx of Ca2+ and is dependent on the presence of Ca2+ in the extracellular fluid.
Motoneurone excitability after administration of a thyrotrophin releasing hormone analogue
Authors: Clarke K.A. , Stirk G.
Published: July 2012

Recordings have been made of motoneurone field potentials at vertebral level L1 to stimulation of the ventral root, in rats anaesthetized with urethane.

Injection of thyrotrophin releasing hormone (TRH) analogue RX77368 (2 mg kg−1) produced an increase in the amplitude of the field potential within 1 min of injection, reaching peak amplitude of 51–69% above control values 6–12 min after injection; the duration of the elevation was 30–65 min.

Arguments are presented which show that this effect is compatible with an RX77368‐induced depolarization of the motoneurone, allowing the antidromic volley to invade more cell bodies.
Interactions between alinidine and responses to acetylcholine, dopamine and 5‐hydroxytryptamine of specific Helix central neurones
Authors: Bokisch Anita J. , Walker R.J.
Published: July 2012

Intracellular recordings were made from identified neurones in the brain of the snail, Helix aspersa. The effect of alinidine on the excitatory and inhibitory responses to acetylcholine and dopamine and on the excitatory response to 5‐hydroxytryptamine (5‐HT) was investigated.

Alinidine was found to reduce the responses to acetylcholine and 5‐HT and the excitatory response to dopamine but had no effect on the dopamine inhibitory response. pA2 values were determined for alinidine antagonism to indicate relative potency. The pA2 values against the excitatory responses of acetylcholine, dopamine and 5‐HT were 5.8, 5.6 and 5.5 respectively. The pA2 value against acetylcholine inhibition was 3.5.

From these studies it is suggested that alinidine interacts preferentially with the sodium ionophore, to a lesser degree with the chloride ionophore and not at all with the potassium ionophore on Helix central neurones.
Effect of 781094, a new selective α‐adrenoceptor antagonist, on the aggregatory responses of human blood platelets and on binding of [3H]‐dihydroergocryptine to these cells
Authors: Kerry Roger , Scrutton Michael C.
Published: July 2012

781094 (2‐(2(1, 4‐benzodioxanyl))‐2‐imidazoline hydrochloride) is a potent competitive inhibitor of the aggregatory responses of human platelets induced by adrenaline (pA2 = 7.3) and UK‐14304.

781094 is a more potent inhibitor of the pro‐aggregatory response to clonidine than of that to methoxamine. The α2/α1‐adrenoceptor selectivity ratio is 11.4.

781094 is a potent inhibitor of the binding of [3H]‐dihydroergocryptine to platelet lysates.

781094 has no effect on the aggregatory responses of human platelets induced by adenosine‐5′‐pyrophosphate (ADP), 5‐hydroxytryptamine, thrombin, U‐46619, or arginine‐vasopressin provided that the platelet‐rich plasma does not exhibit enhanced responsiveness. In some instances high concentrations of 781094 potentiate the aggregatory response to collagen.

In platelet‐rich plasma which exhibits enhanced responsiveness, 781094 causes partial inhibition of the aggregatory responses to 5‐hydroxytryptamine, ADP and vasopressin at concentrations similar to those required to inhibit the response to adrenaline.

781094 acts as a specific antagonist for the responses mediated by human platelet α‐adrenoceptors and exhibits moderate selectivity for the α2‐adrenoceptors on this cell.
Cyclic adenosine 3′,5′‐monophosphate and β‐effects in rat isolated superior cervical ganglia
Authors: Brown D.A. , Dunn P.M.
Published: July 2012

Isoprenaline (0.01–1 μm) increased the amount of cyclic adrenosine 3′,5′‐monophosphate (cyclic AMP) in rat isolated superior cervical ganglia by up to 10 times after 10 min application. Cyclic AMP levels returned to control values after 20 min washing.

Salbutamol, in concentrations (1–100 μm) that depolarized the ganglion and facilitated submaximal transmission, did not significantly raise ganglionic cyclic AMP levels.

The action of isoprenaline was antagonized by butoxamine (apparent KI≅0.14 μm) and weakly by practolol (apparent KI≅9.1 μm).

The effect of 0.1 μm isoprenaline was also inhibited 94% by 100 μm of the adenylate cyclase inhibitor, 9‐(tetrahydro‐2‐furyl)adenine (SQ 22,536).

Exogenous dibutyryl cyclic AMP did not replicate the effects of isoprenaline on ganglionic d.c. potentials or submaximal transmission.

The phosphodiesterase inhibitors theophylline, isobutylmethylxanthine or 4‐(3,4‐dibutoxybenzyl)‐2‐imidazolidinone (Ro 20–1724) did not potentiate these electrical responses to isoprenaline.

The adenylate cyclase inhibitor, SQ 22,536, did not inhibit the electrical responses to isoprenaline.

It is concluded that available evidence does not support the view that the ganglion depolarization or facilitation of submaximal transmission in rat isolated ganglia produced by isoprenaline are likely to be mediated by cyclic AMP.
The effects of altered thyroid state upon responses mediated by atrial muscarinic receptors in the rat
Authors: Ishac E.J.N. , Pennefather Jocelyn N.
Published: July 2012

Untreated rats, and rats treated with methimazole (0.05% w/v in drinking water) or thyroxine (1 mg/kg, s.c., three times weekly) for 4–6 weeks to induce hypo‐ and hyperthyroidism respectively, were used to study the influence of thyroid hormone upon negative chronotropic and inotropic responses mediated by cardiac muscarinic receptors, and upon the affinity of these receptors for atropine.

Negative chronotropic effects of methacholine were investigated by establishing partial concentration‐response curves for isolated preparations of right atria. Methacholine was least potent in tissues from thyroxine‐treated rats.

Isolated left atria paced at 3 Hz, and spontaneously beating right atria, were used in studies of the negative inotropic effects of methacholine. This agonist was least potent in atria from the thyroxine‐treated rats in which it also produced the smallest maximal responses.

The negative inotropic effects of carbachol were examined on left atria paced at 3, 5 and 5.8 Hz to approximate the basal contraction rates of isolated right atria from methimazole‐treated, untreated control and thyroxine‐treated rats, respectively. At each of these frequencies, carbachol was most potent in atria from methimazole‐treated rats, and least potent in atria from thyroxine‐treated rats. Maximal responses were smallest in the latter group.

pA2 values for atropine with methacholine as the agonist were obtained by the method of Arunlakshana & Schild (1959) for spontaneously beating right atria (negative chronotropic and inotropic effects) and left atria paced at 3 Hz (negative inotropic effects). Slopes of Schild plots did not differ from minus one in tissues from each of the experimental groups; pA2 values were similar, indicating that thyroid status is without effect upon the affinity of this antagonist for muscarinic receptors mediating both negative inotropic and chronotropic effects.

The results are discussed in the light of reports that hypothyroidism increases, and hyperthyroidism decreases the numbers of high affinity muscarinic receptor binding sites in the rat myocardium.
Temperature‐induced changes in dissociation constants (KA) of agonists at cardiac β‐adrenoceptors determined by use of the irreversible antagonist Ro 03–7894
Authors: Broadley Kenneth J. , Williams Russell G.
Published: July 2012

The positive inotropic responses of guinea‐pig left atria and papillary muscles and positive chronotropic responses of right atria to sympathomimetic amines were examined at 38° and 30°C.

At the lower temperature, supersensitivity to orciprenaline and isoprenaline was exhibited as shifts of the dose‐response curves to the left and significant reductions in EC50 values.

This supersensitivity could not be attributed to reduced metabolism since the experiments were performed in the presence of metanephrine (10−5m) and U‐0521 (3×, 4×‐dihydroxy‐2‐methylpropiophenone) (10−4m) as inhibitors of extraneuronal uptake and catechol‐O‐methyltransferase (COMT) respectively, and the agonists are not susceptible to neuronal uptake.

After incubation of the tissues with Ro 03–7894 (1‐(5‐chloracetylaminobenzfuran‐2‐yl)‐2‐isopropylaminoethanol), followed by its prolonged washout (> 2h), the maximum responses to isoprenaline and orciprenaline were depressed, confirming the apparently irreversible β‐adrenoceptor antagonism.

Dissociation constants (KA) for isoprenaline and orciprenaline were determined from the equiactive concentrations obtained before (A) and after (A′) incubation with Ro 03–7894, plotted as 1/A against 1/A′ (KA = (slope — 1)/intercept).

KA values were the same for orciprenaline in the three cardiac preparations and for isoprenaline in the atria. This applied at 38° and 30°C and indicates that the β‐adrenoceptors mediating the inotropic and chronotropic responses of the guinea‐pig heart do not differ.

The KA values of both agonists were, however, consistently and significantly lower at 30° than at 38°C, indicating an increase in affinity.

It is concluded that hypothermia‐induced supersensitivity of cardiac tissue to sympathomimetic amines is associated with an increase in their affinity for the β‐adrenoceptors.
Modulation of the concentration of noradrenaline at the neuro‐effector junction in human saphenous vein
Authors: Janssens Walter , Verhaeghe Raymond
Published: July 2012

We studied the importance of neuronal and extraneuronal uptake and of the pre‐junctional α‐adrenergic feed‐back mechanism for the junctional noradrenaline concentration in the human saphenous vein. All major metabolites of the enzymatic breakdown of noradrenaline were detected in the overflow of superfused veins loaded with [3H]‐noradrenaline. The efflux of 3,4‐dihydroxyphenylglycol (DOPEG) was drastically reduced in preparations labelled after neuronal uptake blockade indicating its neuronal origin; the other metabolites are formed extraneuronally since they behaved distinctly differently from DOPEG under several experimental conditions.

Extraneuronal uptake followed by enzymatic breakdown removes the same amount of noradrenaline from the biophase during nerve activity as that diffusing intact out of the tissue, whereas neuronal uptake appears only half as effective since the overflow of intact noradrenaline increases by only 48% in the presence of desmethylimipramine (DMI). However, in preparations mounted for isometric tension recording, neuronal uptake blockade potentiated contractions to α‐adrenergic activation, emphasizing the functional importance of the neuronal disposition mechanism. By contrast, no evidence was found for a hydrocortisone‐sensitive extraneuronal uptake compartment, suggesting that extraneuronal removal may have little, if any, functional importance.

During nerve stimulation, yohimbine increased the amount of labelled noradrenaline present in the superiusate, while exogenously added noradrenaline decreased it in the presence of cocaine. Thus, prejunctional α‐adrenoceptors can modulate the junctional concentration of neurotransmitter in the human saphenous vein.
Specificity and inhibition of glucocorticoid‐induced macrocortin secretion from rat peritoneal macrophages
Authors: Blackwell Geoffrey J.
Published: July 2012

The secretion of the phospholipase A2‐inhibitor macrocortin and the binding of dexamethasone were studied in suspensions of rat peritoneal macrophages.

Corticosteroid‐induced macrocortin secretion was specific for glucocorticoids and did not occur in response to glucocorticoid antagonists or other steroids or in response to non‐steroid macrophage activators (formyl‐methionyl‐leucyl‐phenylalanine f‐MLP), the calcium ionophore A23187, phorbol myristate acetate (PMA) and lipopolysaccharide‐E.‐coli(LPS)).

The apparent potency of competition by secretory glucocorticoids for dexamethasone binding to the macrophage parallelled their ability to induce secretion, implying that these binding sites represent the receptors by which macrocortin secretion is initiated.

Agents which interfere with microtubule assembly (colchicine, vinblastine and trimethylcol‐chicinic acid) and prostacyclin and dibutyryl cyclic AMP inhibit macrocortin secretion.

Inhibition studies of glucocorticoid‐induced macrocortin secretion also suggest dependence upon metabolic energy, a source of Ca2+ and proteolysis and glycosylation prior to secretion.
Effect of metoprolol on 24‐hour urinary excretion of adrenal steroids and kallikrein in patients with essential hypertension
Authors: Fritschka E. , Gotzen R. , Kittler R. , Schöneshöfer M.
Published: July 2012

Treatment of fifteen patients with essential hypertension over four weeks using the β‐adrenoceptor blocking agent, metoprolol, resulted in a decrease in 24 h urinary excretion of kallikrein and aldosterone along with a decrease in plasma renin activity.

There was no significant change in 24 h excretion rates of the free adrenal steroids deoxycorticosterone, 18‐OH‐deoxycorticosterone, corticosterone, cortisol or 18‐OH‐corticosterone during treatment, which were not significantly different from excretion rates of normal males, thus excluding inhibitory effects of adrenal steroids on urinary kallikrein activity.

A positive correlation was found between plasma renin activity and urinary excretion of kallikrein during the control period and after 2 weeks on metoprolol, supporting the assumption of a preserved link between the renin‐angiotensin‐aldosterone system and the renal excretion of kallikrein in these patients.

The decrease in kallikrein excretion during β1‐adrenoceptor blockade in patients with essential hypertension may be explained by a reduction in sympathetic tone and by reduced activity of the renin‐aldosterone system.
Inhibitory effects of centrally acting drugs on the neonatal imprinting of sex differences in the hepatic metabolism of a dimethylated epoxide in the rat
Authors: Finnen Michael J. , Hassall Kenneth A.
Published: July 2012

The effects of the neonatal administration of reserpine, chlorpromazine, phenobarbitone and morphine on the development of sex differences in hepatic drug metabolism in the rat have been investigated.

Treatment of neonatal male rats with reserpine or chlorpromazine for the first two weeks post‐partum significantly inhibited the development of sex differences in drug metabolism in adult life.

Similar treatment of neonatal female rats with reserpine or chlorpromazine had no effect on the development of hepatic drug metabolism in adulthood.

Morphine or phenobarbitone treatment of neonatal rats of either sex had no effect on the development of sex differences in hepatic drug metabolism in adult life.
Are there α‐adrenoceptors in the young chick atria?
Authors: Tayo Fola M.
Published: July 2012

The effect of noradrenaline and isoprenaline were studied in the 15‐day old chick atria. Noradrenaline increased both the rate and force of atrial contractions whilst isoprenaline only slightly increased force at very high concentrations.

The increase in force after noradrenaline and isoprenaline was reduced by phentolamine, an α‐adrenoceptor antagonist. The β‐antagonist, propranolol and the cardioselective β1‐adrenoceptor antagonist, atenolol, did not reduce the positive inotropy. Noradrenaline‐induced positive chronotropy was, however, resistant to both α‐ and β‐adrenoceptor blockade.

It is concluded that the force of contraction of the chick atria may be α‐adrenoceptor‐mediated whilst the rate seems to be mediated by a mechanism sensitive to noradrenaline but insensitive to α‐and β‐adrenoceptor blockade.
The effects of arachidonic acid and non‐steroidal anti‐inflammatory drugs on intrapulmonary airways of the guinea‐pig
Authors: Clay T. P. , Fenske D. C.
Published: July 2012

A method is described in which changes in intrapulmonary airway tone of guinea‐pig isolated lungs are reflected by changes in intraluminal perfusion pressure.

A supramaximal dose of arachidonic acid (AA) (61 μm) was found to have little on no action on baseline perfusion pressure. However, following elevation of perfusion pressure with histamine, AA caused a dose‐dependent pressure decrease. This was also mimicked by prostaglandin E1 (PGE1) and PGE2.

AA induced a reduction of histamine elevated perfusion pressure which was inhibited, dose‐dependently, by several non‐steroidal anti‐inflammatory agents including indomethacin, phenylbutazone, aspirin, benoxaprofen, BW755C and phenidone. Their respective rank order of potency appeared to correlate with their activity against microsomal cyclo‐oxygenase.

Indomethacin, phenylbutazone and aspirin induced augmentation of the elevated perfusion pressure due to histamine, whereas BW755C did not.

We suggest that the primary arachidonate metabolite present in intrapulmonary airways following histamine‐induced constriction is probably a relaxant of the E series. However, our data suggest that both cyclo‐oxygenase and lipoxygenase products are associated with the maintenance of airway tone.
Effect of cyclosporin A and inhibitors of arachidonic acid metabolism on blood flow and cyclo‐oxygenase products in rat skin allografts
Authors: Fan T.‐P.D. , Lewis G.P.
Published: July 2012

Using skin blood flow as a measurement of skin graft rejection in rats, it has been shown that in both isografts and allografts the blood flow at first increases above the normal, after which the flow in isografts returns to normal while that in allografts ceases at the onset of rejection.

Cyclosporin A (CSA) 5–40 mg kg−1 intramuscularly produced a dose‐related inhibition of graft rejection and the pattern of blood flow in the treated allografts became similar to that in isografts in that it remained about 20% above normal throughout the period of treatment.

Indomethacin (Indo), inhibitor of cyclo‐oxygenase and benoxaprofen (Ben), inhibitor of cyclo‐oxygense and lipoxygenase, caused an enhancement of the onset of rejection and an early cessation of blood flow in allografts.

The total content of 4 cyclo‐oxygenase products (COP), (prostaglandin E2 (PGE2), PGF2α, 6‐oxo‐PGF1α and thromboxane B2 (TxB2)) increased both in isografts and allografts, but when individual COP were expressed as a percentage of the total, only 6‐oxo‐PGF1α (the stable metabolite of prostacyclin) increased in allografts.

This increased proportion was reduced to normal by a dose of CSA which prolonged graft survival. Indo and Ben partially inhibited COP formation and in particular that of 6‐oxo‐PGF1α. In addition, CSA caused a dose‐related inhibition of the prostacyclin produced by zymosan‐activated macrophages.

These findings in the rat suggest that prostacyclin is partly responsible for the increase in blood flow in allografts prior to rejection; that CSA inhibits both the recruitment of prostacyclin‐producing macrophages and prostacyclin formation directly; and that inhibitors of cyclo‐oxygenase enhance skin graft rejection by abrogating the immunoregulatory activity of prostacyclin.
Comparative effects of verapamil and sodium nitroprusside on contraction and 45Ca uptake in the smooth muscle of rabbit aorta, rat aorta and guinea‐pig taenia coli
Authors: Karaki H. , Nakagawa H. , Urakawa N.
Published: July 2012

The effects of verapamil and sodium nitroprusside on muscle tension and 45Ca uptake activated in different ways were compared in rabbit aorta, rat aorta and guinea‐pig taenia coli.

In rabbit aorta, K‐induced contraction was specifically inhibited by verapamil and noradrenaline‐induced contraction by sodium notroprusside. In rat aorta, both K‐induced and noradrenaline‐induced contractions were inhibited by verapamil or by sodium nitroprusside also. In taenia, both K‐ and histamine‐induced sustained contractions were inhibited by verapamil but not by sodium nitroprusside. The effect of varapamil was competitively antagonized by external Ca, while that of sodium nitroprusside was not.

High K, noradrenaline and histamine increased the rate of 45Ca uptake in aortae and taenia. In rabbit aorta the increment in response to high K was specifically inhibited by verapamil and the increment induced by noradrenaline was specifically inhibited by sodium nitroprusside. In rat aorta, increments induced by both high K and noradrenaline were inhibited by verapamil and by sodium nitroprusside. In taenia, the increments induced by high K and by histamine were inhibited by verapamil but not by sodium nitroprusside.

These results suggest different characteristics of Ca entry systems in these smooth muscles. In rabbit aorta, there seem to be two Ca channels, one of which is activated by high K and inhibited by verapamil, while the other is activated by noradrenaline and inhibited by sodium nitroprusside. In rat aorta, both K‐ and noradrenaline‐activated Ca pathways are sensitive to both verapamil and sodium nitroprusside whereas, in taenia, both K‐ and histamine‐activated Ca pathways are sensitive only to verapamil.
Phentolamine—an unexpected agonist in the rabbit
Authors: Angus J. A. , Lew M. J.
Published: July 2012

Phentolamine (0.1–10 μm) caused an anomalous right‐ward shift of the relationship between the number of electrical field pulses and tachycardia in the rabbit isolated right atrium. Phentolamine was apparently acting as a presynaptic agonist on sympathetic nerve endings to inhibit transmitter release. The effect was prevented by benextramine treatment and antagonized 10 fold by yohimbine (1 μm) but not by prazosin (0.1 μm). In ganglion‐blocked (mecamylamine) conscious or anaesthetized rabbits, phentolamine (3–1000 μg kg−1) caused a dose‐related rise in blood pressure that was antagonized by yohimbine (1 mg kg−1). These pressor and inhibitory cardiac sympathetic nerve effects of phentolamine are not found in similar preparations from the guinea‐pig or rat. Therefore, these rabbit‐specific agonist effects of phentolamine at sites similar to α2‐adrenoceptors make this drug unsuitable as an α‐adrenoceptor antagonist in rabbits.
Effects of KCl on 45Ca uptake and efflux in the rat vas deferens
Authors: Hay D.W.P. , Wadsworth R.M.
Published: July 2012

The effects of KCl 160 mm on 45Ca uptake and efflux in the rat isolated vas deferens were investigated using a modification of the lanthanum method and a superfusion system respectively.

In the prostatic half, basal cellular 45Ca uptake was 679 ± 21 nmol g−1 tissue wet weight and KCl 160 mm increased this by 155%. In the epididymal half, basal cellular 45Ca uptake was 730 ± 28 nmol 45Ca g−1 and KCl 160 mm increased this by 46%.

Verapamil 2.04 JAM or nifedipine 0.29 μm had no or little effect on basal 45Ca efflux or on basal 45Ca uptake. The KCl‐induced increase in 45Ca uptake in both halves was inhibited by verapamil 2.04 μm or nifedipine 0.29 μm, concentrations which markedly reduce the contractile response. It is concluded that high K+ contracts the rat vas deferens by stimulation of the entry of extracellular Ca2+ to the intracellular compartment.

KCl 160 mm produced a large, rapid and reversible increase in the rate of 45Ca efflux into Ca2+‐containing and Ca2+‐free Krebs‐Henseleit solutions, which was not inhibited by verapamil 2.04 μm, nifedipine 0.29 μm or nitroprusside 1,678 μm.

The relative size of the slow component of 45Ca efflux was larger in the prostatic half compared to the epididymal half of bisected tissues, suggesting that the postulated high affinity binding sites are predominant in this region. However, the rates of the fast and slow components of 45Ca efflux from prostatic and epididymal halves were identical. KCl 160 mm produced a similar increase in 45Ca efflux in prostatic and epididymal halves.
Influence of plasma protein on the inhibitory effects of indocyanine green and bromcresol green on pulmonary prostaglandin E1 extraction
Authors: Dawson Christopher A. , Linehan John H. , Rickaby David A. , Roerig David L.
Published: July 2012

The purpose of this study was to examine the influence of plasma protein on the inhibitory effects of the anionic dyes indocyanine green and bromcresol green on prostaglandin E1 (PGE1) uptake by the lungs.

Dog lung lobes were isolated and perfused with either autologous plasma or Krebs‐Ringer bicarbonate solution (KRB) containing no protein but with dextran used as a colloid.

PGE1 uptake was determined by injecting a bolus, containing radiolabeled PGE1 into the lobar artery and then analysing ethanolic extracts of the venous effluent for radioactivity in PGE1 and PGE1 metabolites by thin layer chromatography and scintillation counting.

When the lobes were perfused with KRB, bromcresol green at an average initial concentration of 28.5 μm, reduced PGE1 by an average of 56%. When the lobes were perfused with plasma, similar concentrations of bromcresol green reduced the uptake by less than 2%.

A similar result was obtained with indocyanine green, which at an average initial concentration of 17.5 μm reduced uptake by about 70% when the lobes were perfused with KRB, but when the lobes were perfused with plasma similar concentrations of the dye reduced uptake by less than 3.5%.

The results suggest that plasma protein binding interferes with the inhibitory effects of these dyes on PGE1 uptake in the lungs.
Mediators of arachidonic acid‐induced contractions of indomethacin‐treated guinea‐pig airways: leukotrienes C4 and D4
Authors: Burka John F. , Saad Maan H.
Published: July 2012

Arachidonic acid (AA) (66 μm) induced contractions of indomethacin‐treated (8.4 μm) guinea‐pig tracheal and lung parenchymal preparations. Mepacrine (210 μm) treatment did not affect the magnitude of contraction induced by AA.

Normal and ovalbumin‐sensitized tissues responded identically to AA, and released equivalent amounts of the contractile mediators.

Nordihydroguaiaretic acid (100 μm) markedly reduced release of the contractile mediators and reduced AA‐induced contractions of the airways.

The mediators of AA‐induced, calcium ionophore A23187‐induced, and antigen‐induced contraction of the trachea and lung parenchyma were purified and identified by reverse‐phase high performance liquid chromatography to be leukotrienes C4 and D4, being present in an approximate ratio of 20:1.

Mepacrine‐treated trachea exhibited a smaller contractile response to stimuli (A23187 for normal tissues and ovalbumin for sensitized tissues). Addition of exogenous AA (66 μm) increased the magnitude of contraction, although not to the level observed on tissues not treated with mepacrine. There was no observable effect of AA on the response of mepacrine‐treated parenchyma to the ionophore or antigen.

It was concluded that (a) immunological sensitization does not alter AA metabolism via the lipoxygenase pathway in guinea‐pig airways and (b) the mediators of AA‐induced contraction are leukotrienes C4 and D4.
Differences between the prejunctional effects of phenylephrine and clonidine in guinea‐pig isolated atria
Authors: Ledda Fabrizio , Mantelli Laura
Published: July 2012

The prejunctional effects of clonidine and phenylephrine were studied in guinea‐pig isolated atria by means of field stimulation of the sympathetic nerve terminals during the cardiac refractory period, in the presence of 1 μm atropine.

Clonidine (10–100 nm) produced a dose‐dependent decrease in the stimulus‐inotropic response curve; the IC50 for clonidine was increased about 70 times by the pretreatment of the preparations with 1 μm yohimbine. The effect of clonidine was not modified by 0.5 μm prazosin.

Unlike clonidine, phenylephrine (1–10 μm) induced a statistically insignificant increase in the contractile force of preparations stimulated at 4 Hz.

The inhibitory effect of phenylephrine (1–10 μm) was partially prevented by either 1 μm yohimbine or 0.5 μm prazosin. However, it was antagonized, to about the same degree as that observed with clonidine, by the pretreatment of the preparations with both 1 μm yohimbine and 0.5 μm prazosin.

The results seem to indicate that one component of the prejunctional effects of phenylephrine may be mediated by presynaptic α‐adrenoceptors belonging to the α1‐subtype.
Hyperalgesia produced by intrathecal substance P and related peptides: desensitization and cross desensitization
Authors: Moochhala S.M. , Sawynok J.
Published: July 2012

The hyperalgesic effect of intrathecally administered substance P (SP), physalaemin, eledoisin and eledoisin‐related peptide (ERP) was investigated in the rat tail flick test.

Hyperalgesia produced by SP (2.5–15 μg, 1.9–11 nmol) was maximal 10–20 min after injection, lasted 30 min and was dose‐related. The effect was mimicked by all of the peptides examined. The rank order of potency was physalaemin > SP > eledoisin > ERP.

Desensitization to the hyperalgesic effect of SP was produced by three repeated intrathecal injections. Rats desensitized to SP no longer responded to physalaemin or ERP, indicating cross‐desensitization. Phentolamine continued to produce hyperalgesia following such desensitization.

The demonstration of a hyperalgesic effect for SP provides further support for a role for SP in nociceptive transmission. The receptor mediating this effect appears to be a SP‐P subtype. Cross‐desensitization between peptides suggests an action on the same receptor.
A study of [d‐Pro2, d‐Phe7, d‐Trp9]‐substance P and [d‐Trp7,9]‐substance P as tachykinin partial agonists in the rat colon
Authors: Bailey S. J. , Jordan C.C.
Published: July 2012

Two substance P (SP) analogues, [d‐Pro2, d‐Phe7, d‐Trp9‐SP (DPDPDT) and [d‐Trp79]‐SP (DT7,9), previously described as tachykinin antagonists, have been shown to contract the rat colon muscularis mucosae preparation. The maximum response exhibited by these analogues was about 30% that of the SP maximum, suggesting that they were acting as partial agonists relative to SP.

The responses to DPDPDT were unaffected by pretreatment with mepyramine, methysergide or [Sar1, Ile5, Ala8]‐angiotensin II, which abolished the responses to histamine, 5‐hydroxytryptamine (5‐HT) and angiotensin II, respectively. Methysergide also did not affect the responses to DT79; the other antagonists were not tested against this analogue. Indomethacin and cimetidine also had no inhibitory effect. Atropine (2 μm) was present in all experiments to prevent indirect muscarinic effects.

Phenoxybenzamine did not affect the dose‐response curves to SP, eledoisin‐related peptide (ERP), kassinin, eledoisin or physalaemin, nor did it affect the responses to individual doses of DPDPDT or DT79. However, in the absence of atropine, it shifted the carbachol dose‐response curve markedly to the right, and reduced its maximum.

The tachykinin antagonist [d‐Pro4, d‐Trp7,9,10]‐SP4–11 reduced the responses to individual matched doses of DPDPDT, DT79 and SP to the same degree, whilst leaving responses to 5‐HT or angiotensin II unaffected. This suggested that DPDPDT and DT79 were acting at the same receptor as SP.

The inhibitory effects of DPDPDT on responses to SP, ERP and kassinin, and that of DT79 on responses to SP, were analysed. All four combinations yielded data compatible with an interaction at only one receptor, although DPDPDT appeared slightly more potent at inhibiting responses to kassinin.

The results are discussed in the light of the proposed existence of multiple tachykinin receptor subtypes. The possible influence of differential metabolism of tachykinin analogues is also considered.
Neuronal responses to noradrenaline in the cerebral cortex: evidence against the involvement of α2‐adrenoceptors
Authors: Bradshaw C.M. , Sheridan R.D. , Szabadi E.
Published: July 2012

The technique of microelectrophoresis was used to test the hypothesis that α2‐adrenoceptors are involved in mediating the excitatory responses of single neurones to noradrenaline in the somatosensory cerebral cortex of the rat.

In the first series of experiments the effects of two α2‐adrenoceptor antagonists, yohimbine and idazoxan (RX‐781094), were compared on excitatory responses to noradrenaline, phenylephrine and acetylcholine. The response to noradrenaline was not more susceptible to antagonism by these drugs than the response to the α1‐adrenoceptor stimulant, phenylephrine. Yohimbine antagonized responses to all three agonists equally, while idazoxan antagonized responses to noradrenaline and phenylephrine equally with relative preservation of responses to acetylcholine.

In the second series of experiments the effects of the selective α2‐adrenoceptor stimulant, UK‐14304, were examined. UK‐14304 produced weak and inconsistent excitations on a small number of cells; however, most of the cells did not respond to this drug. When applied continuously using low ejection currents, UK‐14304 selectively and reversibly antagonized responses to noradrenaline and phenylephrine without affecting responses to acetylcholine.

These results suggest that, in the somatosensory cortex of the rat, neuronal excitation to noradrenaline is unlikely to be mediated either wholly or partly by α2‐adrenoceptors. The antagonism of neuronal responses to noradrenaline and phenylephrine by idazoxan probably reflects the α1‐adrenoceptor antagonistic properties of the drug which is known to occur at higher concentrations. The low agonistic potency of UK‐14304 and the antagonism of responses to noradrenaline and phenylephrine by UK‐14304 suggest that this drug, like clonidine, may act as a partial agonist at α1‐adrenoceptors.
3‐Hydroxy‐N,N‐dimethylpiperidinium: a precursor of a false cholinergic transmitter
Authors: Hemsworth B.A. , Shreeve S.M. , Veitch G.B.A.
Published: July 2012

A cyclic choline analogue, 3‐hydroxy‐N,N‐dimethylpiperidinium, has been shown to be transported into a crude preparation of synaptosomes by high and low affinity transport mechanisms. Under conditions favouring the high affinity system the synaptosomes metabolized approximately 50% of the accumulated analogue to 3‐acetoxy‐N,N‐dimethylpiperidinium, which was detected by paper electrophoresis.

The phrenic nerve endplate region of a mouse hemidiaphragm accumulated 3‐hydroxy‐N,N‐dimethylpiperidinium on nervous stimulation. This tissue metabolized approximately 60% of the accumulated analogue to the acetylated derivative which was released on nervous stimulation into the bathing medium.

Compared to acetylcholine, 3‐acetoxy‐N,N‐dimethylpiperidinium was shown to be 57 times less potent an agonist at the nicotinic receptors of the frog rectus abdominis muscle and 162 times less potent an agonist at the muscarinic receptors of the guinea‐pig ileum.

It is concluded that 3‐hydroxy‐N,N‐dimethylpiperidinium is a precursor of a false cholinergic transmitter.