bluuebunny/crossref_metadata_2025 huggingface dataset:
Glutamate‐induced increase in intracellular Ca2+ concentration in isolated hippocampal neurones
Authors: Kudo Yoshihisa , Ogura Akihiko
Published: July 2012

A system for real‐time quantitative monitoring of intracellular free calcium ion concentration ([Ca2+]i) on a single cell basis was developed by the combination of a fluorescent Ca2+ indicator fura‐2, a fluorescence microscope, a video‐camera and photometrical devices. It was applied to rat individual hippocampal neurones under culture for detection of L‐glutamate‐induced alterations in the [Ca2+]i level.

L‐Glutamate (0.01–100 μM) induced a dose‐dependent elevation of the [Ca2+]i. The [Ca2+]i in the rat hippocampal neurone was found to be around 30 nM in the resting state, and was increased up to 500 nM by the application of 100 μM L‐glutamate. N‐methyl‐D‐aspartate, kainate and quisqualate in a concentration of 10 μM also increased the [Ca2+]i level in the same single neurone, but their efficacy varied between individual cells.

The L‐glutamate‐induced [Ca2+]i elevation was abolished after removal of extracellular Ca2+ and was much reduced by Mg2+ (3 mM). The increase was, however, still observed in a Na+‐free medium.

The L‐glutamate‐induced [Ca2+]i elevation was not affected substantially after treatment with nitrendipine (10 μM) which blocked the increase in [Ca2+]i induced by an isotonic high KCl‐medium (50 mM).

The present results suggest that the L‐glutamate‐induced [Ca2+]i elevation in the hippocampal neurone is due to an influx of Ca2+ through both L‐glutamate receptor‐coupled and voltage‐sensitive ionic channels.
Atriopeptin II‐induced relaxation of rabbit aorta is potentiated by M&B 22,948 but not blocked by haemoglobin
Authors: Martin William , Morgan Robert O. , Smith Jerry A. , White David G.
Published: July 2012

We examined the effects of haemoglobin (which inhibits the vascular responses to stimulation of soluble guanylate cyclase) and of M&B 22,948 (which selectively inhibits cyclic GMP phosphodiesterase) on the relaxation induced in rabbit aorta by the atrial natriuretic peptide, atriopeptin II (which stimulates particulate guanylate cyclase).

Pretreatment with M&B 22,948 (100 μM) produced a 2.3 fold potentiation of atriopeptin II‐induced relaxation of endothelium‐denuded rings of rabbit aorta.

Pretreatment with haemoglobin (10 μM) had no effect on the relaxation or the 10.9 fold increase in cyclic GMP content induced by atriopeptin II in endothelium‐denuded rings of rabbit aorta.

The potentiation by M&B 22,948 suggests a causal role for cyclic GMP in mediating atriopeptin II‐induced vasodilatation of rabbit aorta.

The inability of haemoglobin to block the atriopeptin II‐induced rise in cyclic GMP suggests that it does not block stimulation of particulate guanylate cyclase. Thus, it is unlikely that a ferrous haem‐containing receptor site is involved in the activation of the particulate form of guanylate cyclase as it is with soluble guanylate cyclase.
Effects of calcium channel blockers on gastric emptying and acid secretion of the rat in vivo
Authors: Brage R. , Cortijo J. , Esplugues J. , Esplugues J. V. , Martí‐Bonmatí E. , Rodriguez C.
Published: July 2012

Experiments were designed to evaluate the effects of three calcium channel blockers (verapamil, diltiazem and cinnarizine) on gastric emptying and secretion in the rat

Pretreatment with the calcium blockers delayed gastric emptying of phenol red in a dose‐dependent manner. Verapamil was the most effective of the agents tested.

Verapamil and diltiazem inhibited gastric acid secretion in the pylorus‐ligated rat without affecting pepsin output. Cinnarizine was ineffective in this model.

When the perfused lumen of the anaesthetized rat was used, verapamil was found to inhibit responses to carbachol or histamine more than those to pentagastrin. Further, we found a greater sensitivity to verapamil for basal compared with vagal‐stimulated (2‐deoxy‐D‐glucose) acid secretion. Neither diltiazem nor cinnarizine modified gastric acid secretion in this experimental model.

These findings are discussed in relation to the role of extracellular calcium in gastric motility and secretion, and the existence of a regional and functional selectivity for calcium blockers is proposed.
Muscarinic receptor modulation of release of [Met5]enkephalin immunoreactive material and catecholamines from the bovine adrenal gland
Authors: Barron B.A. , Hexum T.D.
Published: July 2012

Muscarinic receptor modulation of secretion from the adrenal medulla was studied using retrogradely perfused bovine tissue.

Atropine, at a dose not affecting 1,1 dimethyl‐4‐phenylpiperizinium (DMPP)‐stimulated release, inhibitied the acetylcholine (ACh)‐stimulated release of noradrenaline and [Met5]enkephalin‐immunoreactive material (ME‐IRM).

DMPP‐stimulated release of catecholamines and ME‐IRM was potentiated by the addition of methacholine.

Pilocarpine significantly potentiated the release of noradrenaline only.

Methacholine, pilocarpine or muscarine, when infused alone, had no stimulatory affect on the basal release of ME‐IRM.

These findings suggest that the muscarinic receptors in the bovine adrenal medulla function by potentiating the release of ME‐IRM and catecholamines induced by nicotinic receptor stimulation.
Regional variation in the characteristics of histamine H1‐agonist mediated breakdown of inositol phospholipids in guinea‐pig brain
Authors: Carswell H. , Young J.M.
Published: July 2012

The position of dose‐response curves for histamine‐induced accumulation of [3H]‐inositol 1‐phosphate ([3H]‐IP1) in lithium‐treated slices of guinea‐pig brain prelabelled with [3H]‐inositol differed significantly between cerebellum (EC50 5.1 ± 1.0 μM) and cerebral cortex (EC50 16.3 ± 0.7 μM). The Hill coefficients of the curves, 1.33 ± 0.28 and 1.24 ± 0.03, respectively, did not differ significantly.

2‐Methylhistamine, Nα,Nα‐dimethylhistamine and betahistine were partial agonists in both cerebellum and cerebral cortex, but all produced a greater percentage of the maximum response to histamine in cerebellar slices.

In hippocampal slices the response of the partial agonists was intermediate between that in cerebellum and that in cerebral cortex.

The four agonists produced an appreciable accumulation of [3H]‐inositol 1 ‐phosphate in cerebellar slices even in the absence of Li+ ion. The EC50 and Hill coefficients characterizing the dose‐response curves for the four agonists were the same whether 10 mM LiCl was present or not.

The affinity constant for mepyramine inhibition of the histamine‐induced response was similar in cerebellum, 4.2 ± 0.6 × 108 M−1, and cerebral cortex, 4.6 ± 1.0 × 108 M−1. Curves of mepyramine inhibition of the responses to a fixed concentration of histamine gave no indication of any second component in the response to histamine in either cerebellum or cerebral cortex.

The parameters of histamine inhibition of [3H]‐mepyramine binding were similar in homogenates of guinea‐pig cerebellum and cerebral cortex.

These results indicate that H1 ‐agonist‐induced accumulation of IP1 may not be as directly related to agonist‐receptor interaction as simple reaction schemes suggest.
Electrophysiological study of SR 42641, a novel aminopyridazine derivative of GABA: antagonist properties and receptor selectivity of GABAA versus GABAB responses
Authors: Desarmenien M. , Desaulles E. , Feltz P. , Hamann M.
Published: July 2012

A new arylamino‐pyridazine γ‐aminobutyric acid (GABA) derivative, SR 42641, has been tested for its ability to antagonize the actions of GABA on mammalian sensory neurones.

SR 42641 and bicuculline reversibly decreased GABAA‐induced depolarizations and currents recorded intracellularly from dorsal root ganglion neurones (DRG). Dose‐response curves were shifted to the right in a parallel fashion. KB values (determined under voltage clamp conditions) were respectively 0.12 ±0.05 and 0.38 ± 0.08 μm. Similar values were obtained with current clamp recording conditions.

The study of the GABA‐induced Cl− current under voltage‐clamp conditions did not show any voltage‐dependency of the antagonist effect of SR 42641.

In nodose ganglion neurones, SR 42641 (0.4‐4.5 μm) did not alter the (‐)‐baclofen‐induced shortening of the calcium component of action potentials. At concentrations higher than 10 μm, SR 42641 itself prolonged calcium‐dependent action potentials.

Patch‐clamp recordings from DRG cultured neurones indicated that SR 42641 did not affect the calcium current responsible for sustained calcium entry into cells.

We conclude that SR 42641 is a potent competitive GABA antagonist, specific for the GABAA receptor. It does not act at the level of the chloride ionophore.
Acetylcholinesterase activity rises in rat cerebrospinal fluid post‐ictally; effect of a substantia nigra lesion on this rise and on seizure threshold
Authors: Appleyard Margaret E. , Green A. Richard , Greenfield Susan A.
Published: July 2012

The activity of acetylcholinesterase (AChE) in the cerebrospinal fluid (CSF) of rats increased by 53% following an electroconvulsive shock (ECS) while non‐specific cholinesterase (nsChE) activity was unchanged.

A flurothyl‐induced seizure failed to elicit a change in the AChE activity of CSF.

A bilateral lesion of the substantia nigra pars reticulata abolished the rise in AChE activity in the CSF but did not diminish the increase of seizure threshold which follows a convulsion.

These data suggest that AChE is released from the substantia nigra following a seizure but indicate that the change is not associated with the rise in seizure threshold which occurs.
Recovery of prostacyclin synthesis by rabbit aortic endothelium and other tissues after inhibition by aspirin
Authors: Frazer C.E. , Ritter J.M.
Published: July 2012

The effect of aspirin on prostacyclin (PGI2) and thromboxane B2 (TXB2) synthesis was studied in rabbits. Tissues were removed from animals killed at intervals after injection of aspirin, and incubated with Hanks' solution. PGI2 synthesis was monitored by radioimmunoassay of its hydrolysis product, 6‐ oxo‐prostaglandin F1α (6‐oxo‐PGF1α). TXB2 production in clotted blood, also measured by radioimmunoassay, was determined as an index of platelet cyclo‐oxygenase activity.

6‐oxo‐PGF1α and TXB2 production 0.5 h after aspirin were similarly inhibited to less than 5% of control in all incubations. Subsequent recovery of PGI2 synthesis occurred more rapidly in aortic endothelium than in other tissues, including aorta denuded of endothelium. Recovery of TXB2 production was slower than that of PGI2.

Intravenous cycloheximide prevented the partial recovery of PGI2 synthesis that otherwise occurred 6 h after aspirin, while intravenous epidermal growth factor increased recovery.

It is concluded that in the rabbit, cyclo‐oxygenase is synthesized more rapidly in aortic endothelium than in deeper layers of aorta, or in the other tissues studied.
Blockade by nifedipine of responses to intravenous bolus injection or infusion of α1‐and α2‐adrenoceptor agonists in the pithed rat
Authors: McGrath J.C. , O'Brien J.W.
Published: July 2012

Nifedipine was tested against pressor responses in the pithed rat to ten agonists with varying selectivity for α1‐and α2‐adrenoceptors, injected as a bolus or infused intravenously: i.e. amidephrine, azepexole, cirazoline, indanidine, M7, methoxamine, noradrenaline (NA), oxymetazoline, phenylephrine and xylazine. Nifedipine, administered before the agonists, inhibited responses initiated by all agonists, usually for both the bolus and infusion responses.

With a bolus, blockade was significantly greater against the more prolonged, secondary components of the pressor responses. This demonstrates that calcium‐entry occurs during the secondary component of the a‐adrenoceptor‐mediated response and can be initiated by either α1‐or α2‐adrenoceptor subtypes.

The time courses of responses to infusion varied. Selective α1‐adrenoceptor agonists, with the exception of indanidine, did not produce a stable pressor response during the 20 min infusion time but α2‐adrenoceptor agonists did. Nifedipine reduced responses to infusion with no preference for α1‐or α2‐agonists. Phenylephrine and NA produced pressor responses which reached a peak and then declined during the remainder of the infusion.

The levels of NA in arterial and venous plasma were measured by h.p.l.c. during the infusion of NA. Arterial NA levels rose throughout the infusion whereas venous levels remained relatively unaffected. The absolute levels of plasma NA suggest that a large proportion of intravenously administered NA is removed in the pulmonary circulation and the remainder is removed in the systemic circulation with negligible recirculation.

The consequences of these results, for assessment of the mechanisms of action of adrenoceptor agonists and calcium entry blockers, are discussed.
Evidence that the mechanism of the inhibitory action of pinacidil in rat and guinea‐pig smooth muscle differs from that of glyceryl trinitrate
Authors: Bray Katharine M. , Newgreen D.T. , Small R.C. , Southerton J.S. , Taylor S.G. , Weir Sheila W. , Weston A.H.
Published: July 2012

The effects of pinacidil have been compared with those of glyceryl trinitrate (GTN) using the aorta and portal vein of the rat and the trachealis and taenia caeci of the guinea‐pig.

In aorta, both pinacidil and GTN inhibited responses to noradrenaline and showed some selective inhibition of contractions to 20 mm K+. Responses to 80 mm K+ were little affected.

In trachealis, both pinacidil and GTN inhibited spontaneous tone and selectively relaxed spasms to 20 mm K+. Responses to 80 mm K+ were unaffected.

In portal vein, pinacidil completely inhibited spontaneous electrical and mechanical activity. GTN reduced the amplitude of tension waves and extracellularly‐recorded discharges, but increased the frequency of spontaneous electrical and mechanical activity.

In portal vein, pinacidil inhibited contractions to noradrenaline and selectively inhibited responses to 20 mm K+. GTN had little inhibitory effect on responses to either noradrenaline or K+.

In portal veins loaded with 86Rb as a K+‐marker, pinacidil significantly increased the 86Rb efflux rate coefficient whilst GTN had no effect on 86Rb exchange.

In taenia caeci, both pinacidil and GTN inhibited the spontaneous tone of the preparation. These inhibitory effects were not antagonized by apamin.

It is concluded that pinacidil and GTN do not share a common relaxant mechanism. Evidence has been obtained that pinacidil exerts its inhibitory effects by the opening of apamin‐insensitive, 86Rb‐permeable K+ channels.
Relaxant effect of the H2‐receptor antagonist oxmetidine on guinea‐pig and human airways
Authors: Advenier Charles , Gnassounou Jean Pierre , Scarpignato Carmelo
Published: July 2012

The effects of three different H2‐receptor antagonists (cimetidine, ranitidine and oxmetidine) were tested on isolated preparations of guinea‐pig trachea and human bronchus against contractions induced by acetylcholine, histamine and potassium chloride (KCl). In addition, their influence on calcium concentration‐response curves in guinea‐pig tracheal spirals was examined in a potassium‐rich solution (30 mM). Finally, their effects were studied in vivo against acetylcholine and histamine‐induced bronchoconstriction in anaesthetized guinea‐pigs.

In guinea‐pig isolated trachea, oxmetidine—in contrast to cimetidine and ranitidine, which were completely inactive—induced a concentration‐dependent relaxation regardless of the excitatory stimulus: its—log EC50 values (i.e. the negative log concentration that caused a 50% relaxation) were 3.46 ± 0.11, 4.61 ± 0.09 and 4.20 ± 0.12 against acetylcholine, histamine and KCl, respectively. In Ca2+‐free, K+‐enriched solution, the compound was able to inhibit Ca2+‐induced contractions at concentrations close to those needed to counteract the spasmogenic effect of histamine in normal Krebs solution. Results obtained in the human bronchus preparation were similar to those observed in guinea‐pig tracheal spirals.

When tested against acetylcholine or histamine‐induced bronchoconstriction in vivo, oxmetidine (10 and 30 mg Kg−1 intravenously) significantly reduced the increase in pulmonary airway resistance (Raw) induced by both agents. Once again, cimetidine and ranitidine were completely ineffective.

In summary, oxmetidine displayed non‐specific antispasmogenic activity on guinea‐pig and human airways. This effect, which is independent of H2‐receptor blockade, represents a side‐effect of the drug which may be connected to its interference with Ca2+ influx and the action or release of intracellular Ca2+.
Effects of morphine on cardiovascular responses to acute myocardial ischaemia in rats
Authors: Chan Mo‐Yin , Dai Soter , Ko Wendy W.W.
Published: July 2012

The effects of acute coronary artery ligation on cardiac rhythm and haemodynamics were studied in rats receiving either acute or chronic morphine‐treatment.

In chronic opiate‐treated animals, increasing concentrations of morphine sulphate were administered in drinking water over a 3 week period, and the development of morphine tolerance and dependence was verified by decreased analgesic responses to morphine in the tail‐immersion test and the occurrence of naloxone‐precipitated withdrawal syndromes, respectively.

Acute coronary artery ligation induced a decrease in blood pressure, a slight increase in heart rate, and ventricular tachycardia or fibrillation in anaesthetized rats.

The changes in blood pressure and heart rate following acute coronary artery ligation were not significantly altered by acute or chronic morphine administration.

The incidence and the time of onset of ventricular tachycardia or fibrillation were found to be significantly reduced and prolonged, respectively, in chronically morphine‐treated rats, but were not significantly affected by acute morphine administration in naïve animals.

These findings suggest that chronic morphine treatment lessens the occurrence of early ventricular arrhythmias caused by acute myocardial ischaemia in rats. The mechanism of this effect is unclear.
High and concentration‐proportional accumulation of [3H]‐nitrendipine by intact cardiac tissue
Authors: Lüllmann Heinz , Mohr Klaus
Published: July 2012

The binding of [3H]‐nitrendipine to intact, electrically driven isolated left atria of guinea‐pigs was investigated over the concentration range 10−10 m to 3 × 10−5 m.

A high affinity binding site saturable in the nm range as found in ventricular homogenates could not be detected. Instead the accumulation of nitrendipine in intact atria was found to be proportional to the concentration from 10−10 m to 10−6 m; beyond 10−6 m the binding started to become saturated.

Nitrendipine was highly accumulated in atrial tissue. The cell: medium ratios amounted to about 120 in the range from 10−10 m to 10−6 m.

The concentration‐response curve for the negative inotropic action of nitrendipine yielded an ED50 of 3 × 10−7 m, thus lying within the range of concentration‐proportional accumulation.

The reduction of the contractile force proceeded faster (t1/2 10 min) than the uptake process (t1/2 ∼ 40 min) suggesting that it is the binding of nitrendipine into a superficial compartment, which interferes with the excitation‐contraction coupling.

The results suggest that the high concentration of nitrendipine present in hydrophobic cellular compartments such as the plasmalemma might be involved in its pharmacological action.
BW A575C, a chemically novel agent with angiotensin converting enzyme inhibitor and β‐adrenoceptor‐blocking properties
Authors: Allan G. , Cambridge D. , Hardy G.W. , Follenfant M.J.
Published: July 2012

BW A575C (N‐(1‐(S)‐carboxy‐5‐[4(3‐isopropylamino‐2‐(R, S)‐hydroxypropoxy)indole‐2‐carboxamido]pentyl)‐(R, S)‐alanyl‐(S)‐proline) is a chemically novel agent which exhibits in a single molecule both angiotensin converting enzyme (ACE) inhibition and β‐adrenoceptor‐blocking properties.

BW A575C produced a competitive blockade of heart rate responses to isoprenaline in a guinea‐pig right atrial preparation (pKB 7.18 ± 0.05, cf. pindolol 8.9 ± 0.7). BW A575C inhibited a partially purified preparation of ACE obtained from rabbit lung (IC50 10.7 ± 2.1 nm, cf. enalaprilat, 4.4 ± 0.8 nm).

Intravenous administration of BW A575C (1–100 μg kg−1 min−1) to the pithed rat inhibited in a dose‐dependent fashion both angiotensin I‐induced pressor responses and isoprenaline‐induced tachycardia. Dose‐ratios obtained from such studies demonstrated that, in this preparation, BW A575C was approximately 100 times more active as an ACE inhibitor than as a β‐adrenoceptor blocking agent.

Intravenous administration of BW A575C (1 mg kg−1) to the conscious rat inhibited angiotensin I‐induced pressor responses, being approximately equipotent to enalapril and 10 times more potent than captopril. At the same dose, BW A575C had a similar duration of action as an ACE inhibitor to enalapril.

Intravenous administration of BW A575C (1 mg kg−1) to either conscious dogs or rats inhibited both angiotensin I‐induced pressor responses and isoprenaline‐induced heart rate responses. Dose‐ratios obtained from such studies demonstrated that in these species, BW A575C was 2–10 times more active as an ACE inhibitor than as a β‐adrenoceptor blocking agent.
Muscarinic activity of McN‐A‐343 and its value in muscarinic receptor classification
Authors: Eglen R.M. , Kenny B.A. , Michel A.D. , Whiting R.L.
Published: July 2012

The affinity and potency of McN‐A‐343 (4‐(m‐chlorophenyl‐carbamoyloxy) −2‐butynyltrimethylammonium chloride) has been assessed at a range of M1 and M2 muscarinic receptors. McN‐A‐343 was shown to act as a full agonist at M2 receptors present in the guinea‐pig isolated taenia caeci (–log EC50 = 5.14). McN‐A‐343 exhibited no agonist action in the guinea‐pig ileum, atria, bladder or trachea.

McN‐A‐343 was not selective in terms of affinity since its dissociation constants at M1 and M2 binding sites in the rat cerebral cortex and myocardium respectively, were very similar (cortical pPKi = 5.05; myocardial pKi = 5.22). The selectivity previously reported for the compound may be due to differences in intrinsic efficacy and/or tissue receptor reserve.

Based on differential antagonist affinities, the muscarinic receptor profile of the taenia caeci, trachea and bladder was similar to that observed in the ileum, but dissimiliar to that observed in the atria.
Effects of dantrolene on force development in slow‐and fast‐twitch muscle of euthyroid, hypothyroid, and hyperthyroid rats
Authors: Everts M.E. , van Hardeveld C.
Published: July 2012

The effects of dantrolene on twitch and tetanic force development were determined in soleus and gastrocnemius muscle of euthyroid, hypothyroid, and hyperthyroid rats.

Maximum twitch force of the gastrocnemius muscle was significantly more depressed by dantrolene than that of the soleus muscle in euthyroid and hyperthyroid rats. In hypothyroid rats, the effect of dantrolene on maximum twitch force was similar in soleus and gastrocnemius muscle.

Maximum tetanic force in soleus and gastrocnemius muscle was less depressed by dantrolene than the twitch force in either thyroid state. The effect of dantrolene on maximum tetanic force increased in both muscles in the direction hypothyroid → euthyroid → hyperthyroid.

The results are discussed in terms of an effect of thyroid hormones on Ca2+‐cycling during force development, as a result of thyroid hormone‐induced proliferation of the sarcoplasmic reticulum.
Comparison of the effects of indomethacin, RHC80267 and R59022 on superoxide production by 1,oleoyl‐2,acetyl glycerol and A23187 in human neutrophils
Authors: Dale M. Maureen , Penfield Adrienne
Published: July 2012

Indomethacin (10−4 m) causes marked augmentation of O−2release from human neutrophils when these are stimulated by either 1,oleoyl‐2,acetylglycerol or the divalent cation ionophore, A23187, the concentration‐response curve for each agent being shifted to the left and the maximum response to each increased.

The diacylglycerol kinase inhibitor, R59022 (10−5 m) has effects very similar to those of indomethacin on both the 1,oleoyl‐2,acetylglycerol‐induced and the A23187‐induced concentration‐response curves for O2‐ generation.

The diacylglycerol lipase inhibitor, RHC80267 (10−5 m) on the other hand, has a similar effect to indomethacin on 1,oleoyl‐2,acetylglycerol‐induced O−2 generation but, unlike indomethacin, has no effect on A23187‐induced O−2 generation.

Comparison of the effects of these three agents provides a clue to the locus of the action of indomethacin in increasing superoxide release, suggesting that it may act as a diacylglycerol kinase inhibitor. A component of diacylglycerol lipase inhibition may also be present. It is suggested that these results could have relevance for the use of indomethacin as an anti‐inflammatory agent in chronic rheumatoid diseases.
Individual variations of prostanoid agonist responses in rabbit aorta: evidence for the independent regulation of prostanoid receptor subtypes
Authors: Keith Richard A. , Salama Andre I.
Published: July 2012

The frequency and selectivity of individual variations of prostanoid agonist responses in aortic strips from a population of male rabbits was studied. Three levels of responsiveness to the thromboxane mimetic U46619 occurred: responders (R), intermediate responders (IR), and non‐responders (NR). R could be subdivided into R1 and R2 based on an enhanced potency of prostaglandin F2α (PGF2α) in R2. In the total population (n = 92), the phenotype frequency was: R, 69%; IR, 11%; and NR, 20%. In a subgroup of this population in which R1 and R2 phenotypes were determined (n = 63), the phenotype frequency was: R1, 54%; R2, 19%; IR, 6%; and NR, 21%.

The four rabbit aorta phenotypes, R1, R2, IR, and NR, were characterized with respect to the rank orders of prostanoid agonist potency, agonist intrinsic activities, and the effects of the thromboxane receptor antagonist SQ29548. The rank order of prostanoid agonist potency was U46619 > PGF2α > PGE2 in R1 and R2, and PGF2α > PGE2 > U46619 in IR and NR. For each prostanoid agonist, the intrinsic activity was highest in R (R1 ⋍ R2), intermediate in IR, and lowest in NR. In R1, SQ29548 inhibited all prostanoid agonist responses equally. The contractile effects of PGF2α and PGE2 were partially resistant to inhibition by SQ29548 in R2. Prostanoid agonist responses were not inhibited by SQ29548 in IR.

The potency of histamine was equivalent in R1, R2, IR, and NR.

It is concluded that there are individual variations in the functional expression of thromboxane receptor sensitivity, i.e., prostanoid agonist responses inhibited by SQ29548. Also, there are individual variations in the functional expression of the sensitivity of a non‐thromboxane receptor or receptors, i.e., prostanoid agonist responses not inhibited by SQ29548. It has been proposed by others that prostanoid receptors be termed P‐receptors and that the prostanoid agonist to which they are most sensitive be indicated by a preceding letter, e.g., TP‐for thromboxane receptor and FP‐for PGF2α‐selective receptor. Accordingly, we proposed a working hypothesis that suggests the four phenotypes could result from the independent regulation of the functional expression of TP‐and FP‐receptor subtypes with (a) R2 containing both the TP‐and FP‐receptor subtypes in a fully functional state; (b) R1 containing only the functional TP‐receptor; (c) IR containing only the functional FP‐receptor; and (d) NR containing only a low efficacy FP‐receptor system.

The mechanisms underlying the observed individual variations are unknown but could include changes in receptor number or affinity, changes in receptor‐effector coupling, changes in a second messenger system, or changes in tissue degradative or uptake processes. Further study is needed to differentiate between these possibilities.
Release of endogenous ATP during sympathetic nerve stimulation
Authors: Lew M.J. , White T.D.
Published: July 2012

Vas deferens from guinea‐pig was stimulated with a suction electrode and both contractions and release of endogenous ATP monitored

Release of ATP was tetrodotoxin‐sensitive and increased when the number of stimuli was increased.

Release of ATP was not due to contraction of the muscle and persisted following block of contractions with prazosin and α,β‐methylene ATP.

These results indicate that stimulation of the sympathetic nerves in the vas deferens releases endogenous ATP presynaptically, supporting a cotransmitter function for ATP with noradrenaline.
Increase by oestrogen of calcium entry and calcium channel density in uterine smooth muscle
Authors: Batra S.
Published: July 2012

The effect of in vivo oestrogen treatment on both 45Ca influx in myometrial strips and the kinetics of [3H)‐nitrendipine binding in the isolated plasma membrane (PM) was studied.

After four days of continuous oestrogen treatment of ovariectomized rats, 45Ca influx in both resting (unstimulated) and K‐stimulated myometrium was substantially increased.

Oestrogen treatment significantly increased the density in PM of nitrendipine binding sites and also caused a slight and insignificant increase in the affinity for nitrendipine.

The data suggest that the increase in Ca entry following oestrogen treatment prol ably results from an increase in calcium channel density.
Effect of angiotensin‐converting enzyme inhibitor YS980 on prostaglandin synthesis in rabbit kidney medulla slices
Authors: Fujimoto Yohko , Wada Kohichiro , Kaneko Mika , Fujita Tadashi
Published: July 2012

The effect of YS980, an angiotensin‐converting enzyme inhibitor, on the generation of medullary prostaglandins E2 and F2α was examined. At concentrations of 0.2 mm and below, YS980 enhanced prostaglandin F2α synthesis at the expense of prostaglandin E2. At concentrations of 0.4 mm or more, YS980 inhibited synthesis of both prostaglandins E2 and F2α markedly. These results suggest that YS980 has the potential to modulate prostaglandins E2 and F2α synthesis by the kidney and that this effect may represent some pharmacological action of the drug.
Comparison of autonomic responses in the trachea isolated from normal and albumin‐sensitive guinea‐pigs
Authors: McCaig Dorothy J.
Published: July 2012

Mechanical and electrical responses to stimulation of the parasympathetic and sympathetic nerves were compared in the trachea isolated from normal guinea‐pigs and from guinea‐pigs sensitized to albumin and exposed repeatedly to inhaled albumin (a model of bronchial asthma).

Sensitized trachealis exhibited mechanical hyper‐responsiveness to vagal stimulation characterized by a shift to the left of the frequency‐response relationship and a 71% increase in the maximum response.

Transmembrane potential was significantly less negative in sensitized trachealis cells.

The amplitude of the depolarization evoked by vagal stimulation (4 or more pulses) was significantly greater in sensitized tissues. Vagally‐mediated depolarization was associated with the appearance of regenerative electrical activity (spikes) in sensitized but not in control tissues.

Spontaneous discharge of slow waves occurred in cells from both control and sensitized trachea but the proportion of spontaneously active cells was higher in sensitized tissues. Spontaneous depolarization, like nerve‐mediated depolarization, gave rise to abortive spikes only in sensitized trachealis.

Inhibitory responses to stimulation of the sympathetic stellate ganglion, mediated by β‐adrenoceptors, were unaltered in sensitized trachealis.

Possible explanations for the hyper‐responsiveness to vagal input in sensitized trachealis are discussed.
Independent regulation of β1‐ and β2‐adrenoceptors
Authors: Beer Margaret , Hacker Stephen , Poat Judith , Stahl Stephen M.
Published: July 2012

The down‐regulation of β‐adrenoceptors has been postulated as a biochemical marker of antidepressant efficacy. Here we demonstrate that chronic treatment with desipramine down‐regulates β1‐adrenoceptors in rat cerebral cortex and that β‐adrenoceptor subtypes can be independently regulated by treatment with different β‐adrenoceptor agonists.

Desipramine, (±)‐clenbuterol, prenalterol, corwin (20 mg kg−1 daily) and corwin (10 mg kg−1 daily) were administered to male, Sprague‐Dawley rats, over eight days, by means of osmotic Alzet pumps placed subcutaneously and removed 24 h before analysis. Control rats received vehicle only. The β1‐ and β2‐adrenoceptor populations were measured in cerebral cortex by a modified (–)‐[125I]‐pindolol receptor binding assay.

The conventional antidepressant, desipramine, preferentially down‐regulated β1‐adrenoceptors whereas the non‐selective β‐adrenoceptor agonist (±)‐clenbuterol preferentially down‐regulated β2‐adrenoceptors. The β1‐selective partial agonist, prenalterol, up‐regulated β1‐adrenoceptors perhaps acting more as an antagonist than as an agonist. Finally, neither dose of corwin had any significant effect on β‐adrenoceptor number.
Hypothermia induced by baclofen, a possible index of GABAB receptor function in mice, is enhanced by antidepressant drugs and ECS
Authors: Gray Julian A. , Goodwin Guy M. , Heal David J. , Green A. Richard
Published: July 2012

Intraperitoneal injection to mice of the γ‐aminobutyric acidB (GABAB) receptor agonist (±)‐baclofen induces a dose‐dependent decrease in rectal temperature.

Injection of (–)‐baclofen intracerebroventricularly at doses that had no effect when given peripherally induced a marked hypothermia. (+)‐Baclofen was without effect.

The decrease in rectal temperature induced by (–)‐baclofen when injected intraperitoneally was highly correlated with an increase in sedation.

Repeated administration of amitriptyline (10 mg kg−1 daily for 14 days) resulted in mice displaying an enhanced temperature and sedation response to injection of (±)‐baclofen (5 mg kg−1) 24 h after the last dose of antidepressant.

An enhanced hypothermic response was also seen following repeated administration of zimeldine, mianserin or desipramine (all 10 mg kg−1 daily for 14 days) or repeated electroconvulsive shock (ECS; 5 ECS over 10 days) 24 h after the last treatment.

A single administration of any of the antidepressant drugs or ECS or repeated administration of the anxiolytic drug flurazepam (20 mg kg−1 daily for 14 days) did not alter the baclofen‐induced hypothermic response.

Administration of (±)‐baclofen (5 mg kg−1) daily for 5 or 14 days attenuated the baclofen‐induced hypothermic response. However, one pretreatment dose did not alter the response.

It has previously been reported that repeated baclofen administration decreases GABAB receptor number in the brain while repeated administration of antidepressant drugs and ECS increases the density of this receptor. The current data therefore suggest that baclofen‐induced hypothermia may provide a simple index of GABAB receptor function in the brain and strengthens the evidence that GABAB receptor function is enhanced by antidepressant drugs and ECS.
Electrophysiological studies of the effects of the general anaesthetic etomidate on frog myelinated nerve fibre
Authors: Benoit E. , Carratù M.R. , Dubois J. M. , Mitolo‐Chieppa D. , Preziosi P.
Published: July 2012

The effects of the general anaesthetic etomidate (0.1 to 1 mmM) upon the node of Ranvier of frog isolated nerve fibres were investigated under current and voltage clamp conditions.

When added to the external solution, etomidate reversibly decreased the amplitude of the action potential. The action potential block, induced by the drug, was reversed by increasing the membrane potential.

Etomidate rapidly and reversibly blocked the Na current with an apparent dissociation constant of 0.6 mM. In the presence of the drug, the steady‐state inactivation‐voltage curve of the Na current was shifted towards negative voltages.

The block of Na current by etomidate was partially removed by repetitive depolarization preceded by a 50 ms period of hyperpolarization. In contrast, the block was enhanced when the repetitive depolarization was not preceded by hyperpolarization. This suggests that Na channels were preferentially blocked by the drug in the inactivated state.

The K current was reversibly blocked by etomidate with an apparent dissociation constant of 0.2 mM. In the presence of the drug, the K current showed an apparent fast inactivation suggesting that K channels were blocked in the open state.

We conclude that at higher concentrations than those attainable in the mammalian brain following single anaesthetic doses the general anaesthetic etomidate has a ‘local anaesthetic‐like’ action on the peripheral nervous system.
Nerve pathways involved in adrenergic regulation of electrical and mechanical activities in the chicken rectum
Authors: Komori Seiichi , Ohashi Hidenori
Published: July 2012

Peripheral nerve pathways responsible for adrenergic inhibition of mechanical and electrical activities in the chicken rectum and receptors mediating the adrenergic inhibition were investigated in isolated extrinsically‐innervated rectum of the chicken.

Electrical stimulation of the anal end (Ra) or the ileal cut end (Ri) of Remak's nerve, or perivascular nerves (P) elicited relaxation of the rectum pretreated with atropine (0.5 μm) and hexamethonium (0.3 mm) to block the cholinergic and non‐cholinergic, non‐adrenergic excitatory innervations. Ri stimulation was much less effective than Ra and P stimulations. The relaxation was shown to be related to cessation of spontaneous spike discharge of the longitudinal muscle which was accompanied by membrane hyperpolarization.

The inhibitory effects elicited by Ra and P stimulations, which were prolonged beyond the period of the stimulation, were converted to transient ones by propranolol (3.4 μm). Phentolamine (2.6 μm) reduced effectively the residual effects. In contrast, the effects of Ri stimulation were little affected by these drugs.

The present results provide evidence for the existence of two nerve pathways responsible for direct adrenergic inhibitory innervation to the chicken rectum, one running orally in Remak's nerve trunk, leaving it and descending in the branches to the rectum, and the other running as the perivascular nerves along the arterial supplies of the rectum. The direct innervation is mediated predominantly by β‐adrenoceptors.
Purinoceptors in the rat heart
Authors: Fleetwood Gillian , Gordon John L.
Published: July 2012

The effects of an intracoronary bolus of adenosine triphosphate (ATP), α,β‐methylene ATP (APCPP), β,γ‐methylene ATP (APPCP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and adenosine on coronary tone and ventricular myocardial contraction were investigated in the perfused rat heart.

Adenine nucleotides, given by bolus injection were negatively inotropic in amounts >3 × 10−7 mol. The potency order was ATP > ADP > AMP. Adenosine (< 1 × 10−5 mol) had no effect on ventricular myocardial contraction.

Adenine nucleotides and adenosine (1 × 10−10–1 × 10−7 mol) reduced coronary tone. The potency order was ATP > ADP > AMP = adenosine. The ATP analogue APPCP was less active than ATP at reducing coronary tone, and APCPP had no vasodilator effect. This suggests the presence of a P2‐purinoceptor, subclass P2Y, which mediates vasodilatation.

ATP and ADP increased the concentration of prostacyclin (measured as 6‐keto prostaglandin F1α) in the perfusate, but only after injection of > 3 × 10−7 mol, suggesting that the vasodilator responses to ATP and ADP were not mediated by prostacyclin. AMP and adenosine had no effect, even at 1 × 10−5mol.

At a dose of 3 × 10−9 mol, approximately 40% of ATP and 70% of ADP was converted to AMP and adenosine whilst passing through the heart. The amounts of AMP and adenosine formed, however, were insufficient to account for the vasodilator effects of ATP and ADP.

Vasodilatation mediated by AMP and adenosine was inhibited by an infusion of 8‐phenyltheophyllin (8‐PT; 2 × 10−5 m) indicating interaction with a P1‐purinoceptor. Vasodilatation induced by ATP (at doses at which AMP and adenosine had no action) was also depressed by 8‐PT indicating either an action of ATP on P1‐purinoceptors, or an effect of 8‐PT on P2Y receptors.

Vasodilatation induced by AMP was unaltered during an infusion of α,β‐methylene ADP (2 × 10−6 m, which inhibited breakdown of AMP to adenosine by 54.2 ± 1.5%, n = 4). This suggests that AMP acted directly, and it did not require conversion to adenosine to induce vasodilatation.

The ATP analogues APCPP (1 × 10−9 −1 × 10−8 mol) and APPCP (1 × 10−8−1 × 10−7 mol) increased coronary tone, as did high doses (1 × 10−5 mol) of ATP and ADP, indicating the presence of an additional P2‐purinoceptor, subclass P2X, mediating vasoconstriction.
Contractile effects of substance P and neurokinin A on the rat stomach in vivo and in vitro
Authors: Holzer‐Petsche Ulrike , Lembeck Fred , Seitz Helmut
Published: July 2012

Substance P and neurokinin A (substance K) were infused into the coeliac artery of anaesthetized rats at doses of 0.06–20 nmol min−. Both tachykinins caused contractions of the stomach, the threshold dose of neurokinin A being 10 times lower than of substance P. The dose‐response curve for substance P was flatter than that for neurokinin A.

On circular muscle strips from the rat gastric corpus in vitro, the dose‐response curves for both tachykinins were parallel, neurokinin A being 10 times more potent than substance P. The contractions in response to 10 μm neurokinin A and to 30 μm substance P were 58 and 54%, respectively, of the maximal contraction to bethanechol (1 mm).

The effect of substance P was reduced by atropine both in vivo and in vitro. In vitro, the contractions to substance P were also reduced by tetrodotoxin but left unaffected by methysergide. The action of neurokinin A was not affected by these drugs.

It is concluded that neurokinin A contracts rat stomach by a direct action on the circular smooth muscle, whereas the action of substance P is mediated, at least in part, by cholinergic interneurones.
Morphine withdrawal in cortical slices: suppression by Ca2+‐channel inhibitors of abstinence‐induced [3H]‐noradrenaline release
Authors: Pellegrini‐Giampietro Domenico E. , Bacciottini Lucia , Carlà Vincenzo , Moroni Flavio
Published: July 2012

The effects of morphine withdrawal were evaluated in vitro by monitoring the actions of naloxone on the depolarization‐induced release of [3H]‐noradrenaline (NA) in cortical slices taken from naïve or dependent rats. The effects of dihydropyridine molecules acting on Ca2+‐channels (nimodipine and Bay K 8644) were also studied in this model.

Naloxone (10−8‐10−5 M) dose‐dependently enhanced the K+ induced release of [3H]‐NA in slices taken from dependent rats, but failed to modify the [3H]‐NA release from ‘naïve’ slices.

The naloxone‐induced potentiation of release was significantly reversed by nimodipine (10−8‐10−6 M). These doses of nimodipine did not change [3H]‐NA release (both basal and K+ induced) in preparations obtained from naive rats.

Bay K 8644 potentiated the K+‐induced [3H]‐NA release from cortical slices taken from naïve rats to a similar extent as that of naloxone in dependent rats.

These results suggest that the naloxone potentiation of the depolarization‐induced [3H]‐NA release in slices taken from dependent rats may be considered a model of morphine withdrawal in vitro. In this model dihydropyridine Ca2+‐channel antagonists suppress morphine‐withdrawal effects in a similar manner to observations made in vivo.
A comparison between atria from control and streptozotocin‐diabetic rats: The effects of dietary myoinositol
Authors: Kofo‐Abayomi A. , Lucas P.D.
Published: July 2012

Atria, isolated from control rats, six‐week streptozotocin‐diabetic rats and from similarly diabetic rats treated with myo‐inositol (MI) were compared. The MI treatment was shown to reverse the depressed sciatic nerve MI which was observed in the untreated diabetic group.

Spontaneously beating atria from the untreated diabetic animals beat more slowly, and with greater force than tissues from the control group. When electrically driven at 4 Hz they were found to be less sensitive to the negative inotropic effect of acetylcholine. No differences between the two groups were observed in responses to isoprenaline.

Intramural nerve stimulation in the presence of 10−6 m propranolol (vagal stimulation) had a greater negative inotropic effect in the untreated diabetic rat atria than in the controls. Positive inotropic responses to nerve stimulation in the presence of 10−6 m atropine (sympathetic stimulation) were not significantly different between the two groups.

Atria from the MI‐treated diabetic animals were found to have a lower spontaneous contractile force and greater sensitivity to acetylcholine than tissues from the untreated diabetic animals. The values obtained in both cases were similar to those from the controls. No significant effect of MI treatment on spontaneous contractile rate or on responses to nerve stimulation was demonstrated.

Atrial (mainly myocardial) MI was measured in additional control, six‐week diabetic and six‐week MI‐treated diabetic animals. A significantly higher concentration was observed in the MI supplemented group compared to the untreated diabetic group. The mean MI content in the latter group was lower than that obtained from control tissues but not significantly so.

The results implicate MI depletion either in the neurones or in the myocardium in at least some of the changes observed. Possible mechanisms involved are discussed.
Endothelium‐derived relaxing factor and atriopeptin II elevate cyclic GMP levels in pig aortic endothelial cells
Authors: Martin William , White David G. , Henderson Andrew H.
Published: July 2012

Two directly‐acting stimulants of soluble guanylate cyclase, glyceryl trinitrate (0.1 μm) and sodium azide (10 μm), and a receptor‐mediated stimulant of particulate guanylate cyclase, atriopeptin II (10 nm), each elevated the cyclic GMP content of primary cultures of pig aortic endothelial cells without affecting the cyclic AMP content.

Two receptor‐mediated stimulants of adenylate cyclase, glucagon (1 μm) and isoprenaline (10 μm), had no effect on the cyclic AMP or cyclic GMP content of these cells, but the directly acting stimulant, forskolin (30 μm), induced a small increase in cyclic AMP content.

Three agents that release endothelium‐derived relaxing factor (EDRF); bradykinin (0.1 μm), ATP (10 μm) and ionophore A23187 (0.1 μm), each markedly elevated the cyclic GMP content of pig aortic endothelial cells, but acetylcholine (1 μm) had no effect. None of these agents had any effect on cyclic AMP content.

Two agents that potentiate the actions of EDRF; M & B 22948 (100 μm) and superoxide dismutase (30 units ml−1), each elevated the cyclic GMP content of pig aortic endothelial cells without affecting the cyclic AMP content. Pretreating cells with catalase (100 units ml−1) did not affect the rise in cyclic GMP content induced by superoxide dismutase (30 units ml−1).

Pretreatment of pig aortic endothelial cells with haemoglobin (10 μm) reduced the resting content of cyclic GMP and blocked the increase in cyclic GMP content induced by glyceryl trinitrate (0.1 μm), sodium azide (10 μm), bradykinin (0.1 μm) ATP (10 μm), ionophore A23187 (0.1 μm), M & B 22948 (100 μm) and superoxide dismutase (30 units ml−1), but not that induced by atriopeptin II (10 nm).

Pretreatment of pig aortic endothelial cells with an inhibitor of soluble guanylate cyclase, methylene blue (20 μm), had no effect on the resting content of cyclic GMP. Methylene blue (20 μm) blocked the increase in cyclic GMP content induced by glyceryl trinitrate (0.1 μm), M & B 22948 (100 μm) and bradykinin (0.1 μm), but not that induced by atriopeptin II (10 nm).

The data show that soluble guanylate cyclase, particulate guanylate cyclase and adenylate cyclase are present in pig aortic endothelial cells. They further suggest that EDRF, produced spontaneously or in response to vasoactive agents, elevates endothelial cyclic GMP content by stimulating soluble guanylate cyclase. It is possible that this may serve as a feedback loop by which the endothelial cell modulates EDRF production.