bluuebunny/crossref_metadata_2025 huggingface dataset:
β‐Adrenoceptors of the human myocardium: determination of β1 and β2 subtypes by radioligand binding
Authors: Heitz Alain , Schwartz Jean , Velly Jeanne
Published: July 2012

β‐Adrenoceptors of the human myocardium were investigated with binding studies using 125iodocyanopindolol (ICYP) as ligand.

Inhibition of ICYP‐binding by betaxolol (a selective β1‐antagonist) and ICI 118551 (a selective β2‐blocking drug) resulted in non‐linear Scatchard‐plots suggesting that both β‐adrenoceptor subtypes are present in human left atrium and left ventricle.

Computer analysis of the data gave a β1/β2‐adrenoceptor ratio of approximately 65:35 both for left atrium and for left ventricle.
Enhancement by intracerebroventricular thyrotropin‐releasing hormone of indomethacin‐induced gastric lesions in the rat
Authors: Maeda‐Hagiwara Masaki , Watanabe Hiroshi , Watanabe Kazuo
Published: July 2012

Effects of the intracerebroventricular thyrotropin‐releasing hormone (TRH) on gastric mucosa were studied in rats.

TRH (3 and 10 μg rat−1 i.c.v.) produced slight gastric lesions and also aggravated indomethacin‐, aspirin‐ or 5‐hydroxytryptamine (5‐HT)‐induced gastric lesions, while restraint and cold stress‐induced lesions were not influenced by TRH.

Bethanechol used at a dose sufficient to produce acid secretion did not influence the gastric mucosa in intact or indomethacin‐treated rats.

Enhancement of indomethacin‐induced gastric lesions by TRH was not inhibited to any significant degree by atropine 0.1 mg kg−1 s.c., which prevented TRH‐induced gastric acid secretion, but tended to be inhibited by phentolamine, 2.5 mg kg−1 i.p.

It is concluded that the enhancement by TRH of indomethacin‐induced gastric lesions is due to a combination of the central and peripheral actions of the ulcerogenic agents.
Contracture of guinea‐pig ileum on withdrawal of methionine5‐enkephalin is mediated by substance P
Authors: Chahl Loris A.
Published: July 2012

The effects of methionine5‐enkephalin (Met‐enkephalin, ME) 5 × 10−8‐5 × 10−6 moll−1) were investigated on the resting guinea‐pig ileum.

While in contact with the ileum, ME reduced the natural tone and movements, but following washout a contracture occurred which increased with increasing duration of the contact period from 0.5 to 32 min and with increasing concentration of the ME present during the contact period.

The washout contractures after 2 min contact with ME, 10−6 moll−1, were abolished by naloxone, 10−6 moll−1, added prior to the addition of ME, atropine, 5 × 10−6 moll−1 and the substance P (SP) antagonist, (d‐Pro2, d‐Phe7, d‐Trp9)‐SP, 10−5 moll−1 and were reduced by 5‐hydroxytryptamine (5‐HT)‐autodesensitization. Washout contractures following 32 min contact with ME, 10−6moll−1, were significantly inhibited by the SP antagonist and naloxone and were abolished by a combination of atropine and the SP antagonist, but were not significantly reduced by atropine alone or by 5‐HT‐desensitization.

Contractures of ileum occurred on addition of naloxone to ileal segments exposed to ME for 2 or 32 min. These contractures were also inhibited by the SP antagonist but a combination of atropine and SP‐desensitization was required to abolish them.

It was concluded that gut dependence occurs following very brief exposure to an opioid and that SP plays a central role in the withdrawal response precipitated either by washout or addition of naloxone.
Studies on the stereoselectivity of the P2‐purinoceptor
Authors: Burnstock G. , Cusack N.J. , Hills J.M. , MacKenzie I. , Meghji P.
Published: July 2012

ATP, 2‐chloro‐ATP, 2‐methylthio‐ATP, and their unnatural L‐enantiomers, were synthesized and their effects tested on the guinea‐pig taenia coli and urinary bladder, and the stimulated frog ventricle.

The potent P2‐purinoceptor agonists, 2‐chloro‐ATP and 2‐methylthio‐ATP were, respectively, 30 and 200 times more effective than ATP in relaxing the guinea‐pig taenia, but approximately as effective as ATP in contracting the guinea‐pig bladder and augmenting the force of contraction of the frog ventricle.

A high degree of stereoselectivity was observed for relaxations of the guinea‐pig taenia coli produced by the P2‐purinoceptoragonists, and 2‐methylthio‐ATP was over 700 times more effective than its L‐enantiomer. In contrast, stereoselectivity for contraction of the guinea‐pig bladder was observed only at low concentrations with each pair of enantiomers, and a similar low stereoselectivity was displayed by the frog ventricle.

These results show that P2‐purinoceptors mediating inhibitory responses in the guinea‐pig taenia coli can show a high degree of stereoselectivity, while P2‐purinoceptors mediating excitatory responses in the guinea‐pig bladder and in the frog ventricle show little stereoselectivity.

The partial stereoselectivity of the P2‐purinoceptor in smooth muscle contrasts with the absolute stereospecificity of P1‐purinoceptors for adenosine on smooth muscle and autonomic nerve terminals and the absolute stereospecificity of the receptor for ADP on the human platelet.
Effect of inhibition of synthesis and receptor antagonism of SRS‐ A in cardiac anaphylaxis
Authors: Aehringhaus U. , Peskar B.A. , Wittenberg H.R. , Wölbling R.H.
Published: July 2012

The effects of infusions of the lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA, 1.1 × 10−7 mol min−1) and the antagonist of slow‐reacting substance of anaphylaxis (SRS‐A) FPL 55712 (1.2 × 10−7molmin−1) on the coronary constriction and the release of SRS‐A, leukotriene C4‐like immunoreactivity, thromboxane B2 and 6‐keto‐prostaglandin F1α from perfused anaphylactic guinea‐pig hearts were investigated.

Both NDGA and FPL 55712 in the concentrations used induced an increase in basal coronary flow, but did not prevent the coronary flow reduction in the early phase (0–4 min) after antigen injection. On the other hand, NDGA and FPL 55712 inhibited the less pronounced long‐lasting coronary flow reduction in the later phase of cardiac anaphylaxis.

NDGA decreased the release of SRS‐A from the anaphylactic guinea‐pig hearts below or close to the detection limit of the bioassay and simultaneously diminished the release of leukotriene C4‐like immunoreactivity. On the other hand, FPL 55712 did not influence the amounts of leukotriene C4‐like immunoreactivity released in cardiac anaphylaxis.

Neither NDGA nor FPL 55712 affected the release of immunoreactive thromboxane B2 (TXB2) from anaphylactic guinea‐pig hearts. Release of 6‐keto‐prostaglandin F1α after challenge, however, was decreased by NDGA, while FPL 55712 had no significant effect.

These results suggest, that SRS‐A may be a relatively more important mediator in the late phase of coronary constriction occurring during cardiac anaphylaxis, while the effects of other mediators, particularly vasoconstrictor cyclo‐oxygenase products, seem to prevail in the early phase.
Inhibition by purines of the inotropic action of isoprenaline in rat atria
Authors: Hughes P.R. , Stone T.W.
Published: July 2012

The effects of a series of adenosine derivatives were examined on the catecholamine‐stimulated electrically‐driven rat left atrium in vitro.

All the purines tested reduced the positive inotropic action of isoprenaline, 0.1 μM, with the potency order: L‐N6‐phenlylisopropyladenosine (L‐PIA) > 5′‐N‐ethylcarboxamide adenosine (NECA) > D‐PIA > 2‐chloroadenosine > adenosine. Dipyridamole did not change the IC50 of adenosine. The adenosine deaminase inhibitor, 2′deoxycoformycin, produced a small but nonsignificant shift to the left of the adenosine concentration‐response curve.

The cardiac depressant effects of these purines were reversed by theophylline and the IC50 values were unchanged in the presence of atropine or in atria taken from reserpine‐treated rats.

It is concluded that the purine receptor mediating these effects should not be classified on the A1/A2 system. The relationship between functionally characterized purine receptors and those originally defined as modulating adenylate cyclase is discussed.
Nicotine self‐administration in rats
Authors: Cox Brian M. , Goldstein Avram , Nelson William T.
Published: July 2012

Female Wistar rats were allowed to self‐administer nicotine solutions through indwelling jugular vein cannulae for 23 h per day for periods from three to five weeks.

Two response levers were available to the rats; responding on one lever, designated the active lever, produced an immediate infusion of nicotine solution or saline. A second lever for which responding had no programmed consequences was introduced as a control for the locomotor stimulant action of low doses of nicotine.

Baseline lever response rates were determined over a period of one week, in which active lever responding produced an infusion of saline. Rats were then allowed access to varying doses of nicotine or saline for a further two or three weeks. Response rates on the active lever increased significantly in rats with access to nicotine at a dose of 30 μg kg−1 per response. However, control lever response rates were also significantly elevated.

The role of nicotine‐induced locomotor stimulation in the self‐administration behaviour was further evaluated in a dose‐reduction experiment, in which the dose of nicotine available to rats responding for 30 μg kg−1 per response was reduced to 3 μg kg−1 per response. This resulted in a significant differential increase in active lever responding relative to control lever responding.

The results suggest that nicotine is positively reinforcing in rats which had not previously been deprived of food or water or received prior drug treatment, but also indicate that nicotine induced locomotor stimulation may contribute to the observed increases in lever response rates when rats self‐administer nicotine.
Calcium‐dependence and antagonism of responses to α1‐ and α2‐adrenoceptor agonists in vascular tissues from hypertensive and normotensive rats
Authors: Rutledge A. , Swamy V.C. , Triggle D.J.
Published: July 2012

Inhibition by D600 (methoxyverapamil) of responses to an α2‐adrenoceptor selective agonist, B‐HT 920, (6‐allyl‐2‐amino‐5, 6, 7, 8‐tetrahydro‐4H‐thiazolo [4, 5‐d] azepin dihydrochloride), an α1‐adrenoceptor selective agonist, phenylephrine (PE), and a nonselective agonist, noradrenaline (NA), was studied in isolated preparations of the aortae and carotid arteries obtained from young (5–7 weeks) and old (15–17 weeks) hypertensive (SHR) and normotensive (WKY) rats.

Maximum responses of WKY tissues to B‐HT 920 were the most sensitive, PE‐induced responses the least sensitive and maximum responses to NA were intermediate in their sensitivity to inhibition by D600.

Sub‐maximal responses to NA and PE were not different in their sensitivity to inhibition by D600, but were less sensitive than the responses to B‐HT 20. Sub‐maximal responses to PE were significantly more sensitive to D600 inhibition than were the maximal responses to this agonist.

NA‐induced responses of tissues from older SHR were less sensitive to inhibition by D600 when compared to responses in WKY rats.

Responses to B‐HT 920, in tissues suspended in calcium‐free solutions, showed the largest decline compared to NA‐ and PE‐induced responses.

We conclude that responses to B‐HT 920 largely utilize extracellular calcium. PE‐ and NA‐induced responses mobilize extracellular calcium to varying degrees depending upon the concentration of the agonist employed to elicit the response.
Comparison of s‐ and κ‐ opiate receptor ligands as excitatory amino acid antagonists
Authors: Berry S.C. , Dawkins S.L. , Lodge D.
Published: July 2012

Using the technique of microelectrophoresis in pentobarbitone‐anaesthetized cats and rats, the effects of benzomorphans, with known actions at s‐ and κ‐ opioid receptors, were tested on responses of spinal neurones to amino acids and acetylcholine.

The racemic mixture and both enantiomers of the sigma opiate receptor agonist, N‐allylnormetazocine (SKF 10,*** 047), and the dissociative anaesthetic, ketamine, reduced or abolished excitation evoked by N‐methyl‐aspartate (NMA) with only small and variable effects on responses to quisqualate or kainate. (+)‐SKF 10,***047 was 1.2 ± 0.7 times more potent than the (—) enantiomer in antagonizing NMA.

On Renshaw cells, (+)‐SKF 10,***047 enhanced responses to acetylcholine whereas the (—) enantiomer produced only a small reduction.

The κ‐ opiate receptor agonist, ethylketocyclazocine, had no selective effects on responses to amino acids or to acetylcholine.

We conclude that actions at s‐ but not κ‐, opiate receptors are responsible for the NMA antagonism observed with benzomorphans.
5‐HT2 receptor characteristics in frontal cortex and 5‐HT2 receptor‐mediated head‐twitch behaviour following antidepressant treatment to mice
Authors: Goodwin Guy M. , Green A. Richard , Johnson Pauline
Published: July 2012

The effects of repeated administration of antidepressant drugs or electroconvulsive shock on the binding of [3H]‐spiperone to the 5‐hydroxytryptamine2 (5‐HT2) receptor in mouse frontal cortex and the 5‐HT‐mediated head‐twitch response have been examined.

Repeated electroconvulsive shock increased both the head‐twitch response and the number of 5‐HT2 binding sites (Bmax).

After 35 d but not 24 h or 14 d oral tranylcypromine (5.6 mg kg−1 per day) there was a marked decrease in both the behavioural response and the number of 5‐HT2 receptors.

Repeated oral doses of zimeldine (20 mg kg−1 per day, 14 days) also decreased the head‐twitch response and the number of 5‐HT2 binding sites and these effects persisted after 48 h withdrawal.

Oral mianserin (2.1 mg kg−1 per day, 14 days) decreased both the behaviour and the number of 5‐HT2 binding sites, but this change was also seen after acute (1 day) administration. After 48 h withdrawal from chronic treatment the head‐twitch response was still decreased but the Bmax had returned to control values.

Desipramine given orally (27 mg kg−1 per day, 14 days) decreased both the behaviour and number of 5‐HT2 binding sites. After 48 h withdrawal, binding was still decreased but the head‐twitch response was enhanced above control values.

In contrast to repeated electroconvulsive shock (ECS), all drugs decreased both 5‐HT2 binding and the head‐twitch response, while the mice were still on treatment. Binding and behaviour did not correlate after withdrawal. It is concluded that antidepressant treatments do not produce a common alteration in 5‐HT2 receptor number and function.
Nisoldipine‐induced relaxation in intact and skinned smooth muscles of rabbit coronary arteries
Authors: Itoh T. , Kanmura Y. , Kuriyama H. , Suzuki H.
Published: July 2012

In smooth muscles of the rabbit coronary artery, nisoldipine inhibited the phasic and tonic responses of the contraction induced by 128 mm K (the IC50 values were 4 × 10−8 m and 1 × 10−13 m, respectively). This agent also inhibited the tonic response of the acetylcholine (ACh) (10−5 m)‐induced contraction (the IC50 value was 3 × 10−10 m), but only slightly inhibited the phasic response (in 10−7m, 0.86 times the control).

Nisoldipine (<10−7 m) had no effect on the K‐induced depolarization of the membrane at any given concentration. This drug (5 × 10−8 m) did inhibit the oscillatory potential changes and spike potential evoked on the ACh‐induced slow depolarization.

After depletion of stored Ca from the polarized muscles (5.9 mm K), muscle cells accumulated Ca by application of 2.6 mm Ca without generation of contraction, i.e. a subsequently applied 20 mm caffeine produced the contraction in Ca‐free solution. Nisoldipine (<10−7 m) had little effect on this accumulation of Ca.

The rate of rise and time to reach the maximum amplitude of the 128 mm K‐ or ACh‐induced contraction (in 2.6 mm Ca) depended on the amount of stored Ca in cells. Nisoldipine (10−8 m) consistently inhibited the Ca‐induced contraction evoked in depolarized muscles (128 mm K), regardless of the amount of stored Ca. However, this agent (10−8 m) did not inhibit the Ca release from storage sites evoked by activation of the muscarinic receptor.

After prolonged superfusion (over 120 min) with Na‐ and Ca‐free solution (guanethidine and atropine were present), application of 2.6 mm Ca produced contraction which was inhibited by 10−8 m nisoldipine, while the depolarization induced by application of these solutions was not inhibited by nisoldipine.

In saponin‐skinned muscles, nisoldipine had no effect on the contractile proteins, as estimated from the pCa‐tension relationship, or on the Ca accumulation into and Ca release from the Ca storage sites, as estimated from the caffeine‐induced contraction.

It is concluded that nisoldipine possesses a selective inhibitory action on voltage‐dependent Ca influx, when the Ca channel is activated by depolarization.
Selectivities of opioid peptide analogues as agonists and antagonists at the δ‐receptor
Authors: Corbett A.D. , Gillan M.G.C. , Kosterlitz H.W. , McKnight A.T. , Paterson S.J. , Robson L.E.
Published: July 2012

The endogenous opioid ligands interact with more than one of the μ‐, δ‐ and κ‐binding sites. By the use of binding assays and bioassays, enkephalin analogues have been assessed for their selectivity for binding at the (5‐binding site and for their agonist and antagonist activities at the δ‐receptor. The electrically‐induced contractions of myenteric plexus‐longitudinal muscle preparations of the guinea‐pig ileum were inhibited by μ‐ and κ‐receptor ligands. Inhibitions were seen with μ‐, δ‐ and κ‐receptor ligands in the mouse vas deferens, mainly with μ‐receptor ligands in the rat vas deferens and only with κ‐receptor ligands in the rabbit vas deferens.

From observations on a considerable number of [Leu5] enkephalin analogues, it has been concluded that [d‐Pen2, d‐Pen5] enkephalin and [d‐Pen2, l‐Pen5] enkephalin are the most selective δ‐agonists and that N,N‐diallyl‐Tyr‐Aib‐Aib‐Phe‐Leu‐OH is the most selective antagonist (Aib = α‐aminoisobutyric acid). The binding of these peptides at the δ‐site is 99% of the total binding. As to potency, the agonists are superior to the antagonists.
Wash‐out of noradrenaline and its metabolites by calcium‐free reperfusion after ischaemia: support for the concept of ischaemia‐induced noradrenaline release
Authors: Abrahamsson T. , Almgren O. , Carlsson L.
Published: July 2012

The outflow of noradrenaline (NA) and its metabolites on reperfusion after 60 min of regional ischaemia in the isolated heart of the rat was not diminished when calcium was omitted from the reperfusion medium. The findings suggest a release of NA during ischaemia, washed‐out at reperfusion.
Temperature‐dependence of the action of nerve blocking agents and its relationship to membrane‐buffer partition coefficients: thermodynamic implications for the site of action of local anaesthetics
Authors: Bradley D.J. , Richards C.D.
Published: July 2012

The local anaesthetic action of a series of nerve blocking agents was examined at temperatures between 4°C and 20°C in isolated sciatic nerves from cold‐adapted frogs. Cooling alone had little effect on the amplitude of the action potential but the conduction velocity was decreased and the duration increased. Cooling had little effect on the local anaesthetic action of the short chain alkanols but that of the long chain alkanols, benzyl alcohol, benzocaine and pentobarbitone was markedly enhanced.

The partition of both short and long chain alkanols and of pentobarbitone into a liposome suspension of similar composition to axonal membrane lipids was reduced by cooling from 40°C to 4°C.

The results are not compatible with the lipid hypotheses of anaesthetic action. The implications for the nature of the site of action are discussed.
Role of auto‐inhibitory feed‐back in cardiac sympathetic transmission assessed by simultaneous measurements of changes in 3H‐efflux and atrial rate in guinea‐pig atrium
Authors: Angus J.A. , Bobik A. , Jackman G.P. , Kopin I.J. , Korner P.I.
Published: July 2012

Guinea‐pig right atria were labelled with [3H]‐noradrenaline or [3H]‐dopamine before superfusion in a flow‐cell. Choice of label did not significantly alter either the relationship between 3H‐efflux and number of electrical field pulses or the inhomogeneity of labelling.

The relationship between 3H‐efflux and frequency of 4 field pulses (0.125–2 Hz) was hyperbolic and similar to the tachycardia‐frequency relationship measured simultaneously. No evidence was found for a U shaped 3H‐efflux‐frequency relationship (Story, McCulloch, Rand & Standford‐Starr, 1981).

Phentolamine (1 μM) did not alter the 3H‐efflux or atrial rate responses to 4 field pulses at stimulus levels that gave 50–60% of the maximum rate response.

In the presence of neuronal uptake inhibition (desipramine, DMI 0.1 μm), rate and 3H‐efflux responses to 4 field pulses were enhanced at all frequencies and were further increased by phentolamine.

In the absence of DMI, prolonged trains of field pulses (8 and 12 pulses) at low frequency (0.25 Hz) were not sufficient to activate auto‐inhibitory feed‐back. At 2 Hz phentolamine enhanced both 3H‐efflux and rate responses at 12 field pulses.

We conclude that in guinea‐pig right atrium auto‐inhibitory feed‐back plays little role in the modulation of transmitter release at levels of stimulation that cause 50–60% of maximum tissue response. This is because neuronal uptake normally prevents synaptic concentrations of noradrenaline from activating prejunctional α2‐adrenoceptors. Stimulation sufficient to induce a near‐maximal response or the presence of neuronal uptake inhibition are necessary to evoke auto‐inhibitory feed‐back.
Effect of glucocorticoids on vascular reactivity to vasoactive hormones in rat isolated kidney: lack of relationship to prostaglandins
Authors: Cooper Christy L. , Malik Kafait U.
Published: July 2012

The relationship between the effects of glucocorticoids on renal vascular reactivity and prostaglandin synthesis elicited by noradrenaline (NA), angiotensin II (AII), arginine vasopressin (AVP) and bradykinin (Bk) was investigated in the isolated kidney of the rat perfused with Tyrode solution.

Administration of NA 0.3–3.0 nmol, AII 0.028–0.28 nmol, AVP 0.027–0.27 nmol and Bk 0.28–2.8 nmol enhanced in a dose‐dependent manner the renal output of immunoreactive prostaglandin E2 (PGE2) and 6‐keto‐PGF1a. NA, AII and AVP, but not Bk, produced renal vasoconstriction and increased perfusion pressure.

In the presence of dexamethasone (2.6 × 10−5m) or corticosterone (2.9 × 10−5m), the effects of NA and AII, in enhancing prostaglandin synthesis and producing renal vasconstriction, were reduced. In contrast, stimulation of prostaglandin synthesis by Bk and AVP and the renal vasoconstriction produced by AVP were not altered by the glucocorticoids. Dexamethasone or corticosterone did not alter the output of prostaglandins elicited by A‐23187 or arachidonic acid (AA).

Addition of mepacrine (2.1 × 10−5m) to the perfusion fluid reduced the renal output of prostaglandins elicited by the vasoactive hormones and by A‐23187, but not by AA; the vasoconstrictor response to NA and AII, but not to AVP was reduced.

In kidneys in which prostaglandin synthesis was inhibited by indomethacin (2.8 × 10−6m), administration of dexamethasone also reduced the renal vasoconstrictor effect of NA and AII.

These data indicate that in Tyrode‐perfused rat kidney the glucocorticoids dexamethasone and corticosterone exert a differential effect on the renal vascular reactivity to vasoactive hormones, and that their inhibitory effect on NA and AII‐induced renal vasoconstriction appears to be unrelated to prostaglandin synthesis.
Recovery of β‐adrenoceptors and cyclic AMP response after long term treatment of intact heart cells with β‐blockers
Authors: Becker Charlotte , Porzig Hartmut
Published: July 2012

We have studied the recovery of receptor binding and of isoprenaline‐stimulated cyclic AMP responses after chronic (2–5 days) exposure of tissue‐cultured living rat heart cells to several β‐adrenoceptor antagonists. Most experiments were performed with [3H]‐ (±)‐carazolol and [3H]‐(±)‐CGP 12177, as prototypes of high affinity lipophilic and hydrophilic ligands respectively.

Chronic antagonist treatment did not alter the total number of receptors nor did it cause intracellular accumulation of the ligands.

At the end of the treatment, radiolabeled antagonists were displaced either by ‘infinite’ dilution of the incubation medium or by competitive displacement with the non‐labelled ligand (‐)‐timolol. In dilution assays dissociation of Carazolol from specific sites was biphasic with t1/2 values of 41 ± 14 and 219 ± 15 min. Dissociation of CGP 12177 was monophasic with t1/2 of 102 ± 2 min.

Timolol enhanced the dissociation rates of both radioligands and suppressed the slow phase of Carazolol dissociation.

Isoprenaline‐stimulated cyclic AMP formation did not recover in parallel with the release of the two antagonists from receptor binding sites. To reach about 80% of control values for receptor availability or cyclic AMP response required 3 h and 24 h washout periods, respectively, after Carazolol (0.2 nm) treatment, or 1.5 and 12 h washout periods after CGP 12177 (4 nm) treatment. Such a ‘decoupling’ effect was not observed during recovery from chronic exposure to the antagonists, timolol and propranolol.

We conclude that some antagonists cause a novel form of desensitization that is not linked to their partial agonistic potency. Moreover, Carazolol‐type drugs seem to induce an additional isomeric form of the β‐receptor that is not recognized by other antagonists. These observations could explain the well known discrepancy between long duration of action and rapid removal from the circulation of several antagonists in current therapeutic use.
Stereoselectivity of extraneuronal uptake of catecholamines in guinea‐pig trachealis smooth muscle cells
Authors: Bryan Lesley J. , O'Donnell Stella R.
Published: July 2012

The extraneuronal uptake of the (‐)‐ and (+)‐isomers of three catecholamines, isoprenaline, adrenaline and noradrenaline, were compared in guinea‐pig trachealis smooth muscle cells, by a fluorescence microphotometric method.

Preliminary experiments showed that the initial rates of uptake of the (‐)‐isomers were greater than those of the (+)‐isomers in tissues incubated in 25 μm adrenaline or noradrenaline or 50 μm isoprenaline.

More detailed experiments showed that the Km values of the (+)‐isomers of the amines for extraneuronal uptake were not significantly different from each other, but the Km value of (‐)‐isoprenaline < (‐)‐adrenaline < (‐)‐noradrenaline. Thus, the order of the ratios of the Km values for the (+):(‐)‐isomers was isoprenaline > adrenaline > noradrenaline.

The results showed that there is stereoselectivity of the extraneuronal uptake of catecholamines, but it is greatest for isoprenaline (4.9 fold), less for adrenaline (2.5 fold) and almost negligible (1·6 fold) for noradrenaline.
Cardioprotective actions of pentoxifylline in an animal model of acute myocardial ischaemia
Authors: Gallenkämper W. , Rücker W. , Schrör K.
Published: July 2012

The action of pentoxifylline on some of the consequences of acute myocardial ischaemia was studied in cats in vivo.

Occlusion of the left anterior descending coronary artery (LAD) for 5 h resulted in a significant elevation in the ST‐segment of the ECG, a reduction in free platelet count in right atrial blood and a loss of creatine Phosphokinase (CK) and cathepsin D activities in homogenates of the severely ischaemic myocardium as compared to non‐ischaemic myocardium.

Intravenous infusions of pentoxifylline (0.30 mg kg−1 min−1 for 1 h and 0.15 mg kg−1 min−1 for the remainder of the 5 h observation period, starting 0.5 h after LAD occlusion) significantly reduced the loss of enzymes from the ischaemic myocardium, prevented any further increase in the ST‐segment and restored the platelet count to its control level.

There were no significant changes in plasma immunoreactive 6‐oxo‐prostaglandin F1α (6‐oxo‐PGF1α) and thromboxane B2 (TXB2), although a tendency for a reduction in TXB2 levels was observed.

Pentoxifylline seems to affect, beneficially, the myocardium in this animal model of acute myocardial ischaemia. The reason for this cardioprotective action remains to be elucidated. It is, however, noteworthy that the overall profile of action of pentoxifylline resembles that of PGI2 administration in this model.
Vascular reactivity in diabetes mellitus: possible role of insulin on the endothelial cell
Authors: Fortes Zuleica B. , Leme J. Garcia , Scivoletto Regina
Published: July 2012

The response to vasoactive agents of microvessels of the rat was tested in vivo by direct microscopic observation of the exteriorized mesentery and assessment of cutaneous vascular permeability changes with Evans blue.

The constrictor response to a standard amount of noradrenaline in mesenteric microvessels was fully antagonized by acetylcholine in normal, diabetic, adrenalectomized and diabetic‐adrenalectomized rats. In contrast, the minimum doses of histamine or bradykinin, effective in normal or adrenalectomized animals, had to be increased about 20 fold to be active in diabetic or diabetic‐adrenalectomized animals.

Topical application of insulin to mesenteric microvessels of diabetic animals, in amounts not causing any increase in serum insulin levels, improved or restored the capacity of the animals to respond to histamine or bradykinin, acting as antagonists of the vasoconstrictor response to noradrenaline. Topical insulin, however, was ineffective in normal animals given 2‐deoxyglucose, the acute effects of which result from cellular glucopaenia unrelated to insulin deficiency.

Vascular permeability responses to intracutaneous histamine or bradykinin were decreased in animals pretreated with 2‐deoxyglucose as much as in diabetic animals.

Pretreatment of normal animals with indomethacin produced no effect on the responses of these animals to histamine or bradykinin, tested as antagonists of noradrenaline on mesenteric microvessels, or as vascular permeability‐increasing factors in the skin.

Pretreatment of normal animals with chloroquine, mepacrine or dexamethasone had no effect on the reactivity of mesenteric microvessels to histamine and bradykinin, acting as antagonists to noradrenaline.

It is suggested that vasoactive substances, endowed with permeability‐increasing properties, evoke relaxation of microvessels through an insulin‐dependent action on endothelial cells, unrelated to the release of arachidonic acid metabolites. This action would lead to increased vascular permeability, with opening of interendothelial junctions, and temporary changes in composition of extravascular fluid, which in turn, would provide the basis for vasodilatation. Diabetes mellitus apparently impairs such responses as a result of the accompanying cellular glucopaenia. Adrenal corticosteroids are not involved in the impaired responses.
ICI 118,551: an effective ocular hypotensive agent with selectivity for the ciliary process β2‐adrenoceptor and with minimal cardiac side effects
Authors: Nathanson James A.
Published: July 2012

Prior biochemical studies have shown that the ciliary process epithelium, which is involved in the secretion of aqueous humour, is rich in β‐adrenoceptors with pharmacological characteristics similar to those of the β2 subclass.

The present experiments demonstrate that the β‐adrenoceptor antagonist, ICI 118,551, is a potent inhibitor of isoprenaline‐stimulated adenylate cyclase activity measured in broken cell preparations of rabbit ciliary process.

In rabbit cardiac muscle, however, ICI 118,551 is a relatively weak antagonist of isoprenaline‐stimulated adenylate cyclase, being approximately 100 fold less potent than the non‐selective β‐adrenoceptor antagonist, timolol.

ICI 118,551 is also less potent than timolol in inhibiting isoprenaline‐sensitive adenylate cyclase of rabbit lung.

ICI 118,551 applied topically to eyes of unanaesthetized rabbits causes a dose‐dependent decrease in intraocular pressure. Furthermore, in a blind crossover study in rabbits, topically applied ICI 118,551 decreased intraocular pressure for more than 6 h and was more effective than an identical dose of the clinically effective anti‐glaucoma agent, timolol.

Systemic absorption from topically‐applied timolol, but not ICI 118,551, is sufficient to alter cardiac response to subcutaneous administration of isoprenaline. Furthermore, dose‐response studies, using direct systemic administration of the two β‐adrenoceptor antagonists, revealed that ICI 118,551 is about 60 times less potent than timolol in blocking isoprenaline‐induced cardio‐acceleration.

ICI 118,551, applied to one eye, causes a decrease in intraocular pressure in the contralateral eye, and systemic administration of ICI 118,551 results in decreased intraocular pressure in both eyes, data indicating that at least part of the ocular hypotensive effect of topical ICI 118,551 is mediated through systemic absorption.

These findings provide biochemical and physiological evidence that selective β2‐adrenoceptor blockers such as ICI 118,551, used topically or systemically, may be useful as ocular hypotensive agents with decreased cardiac side‐effects.
The mechanism of steroid anaesthetic (alphaxalone) block of acetylcholine‐induced ionic currents
Authors: Gillo Boaz , Lass Yoram
Published: July 2012

The effects of the steroid anaesthetic alphaxalone on acetylcholine (ACh)‐induced ionic channels were studied in voltage clamped ‘myoballs’ in culture.

Alphaxalone produced a reversible blockade of the ACh‐evoked inward current, ED50 = 6.0 μM.

The ACh reversal potential (−5.0 mV), the single channel conductance (13.5 pS) and mean open time (3.6 ms) were unchanged by the drug. Thus, alphaxalone produced an ‘all or none’ block of the ionic channel.

In double pulse conditioning experiments, alphaxalone produced an additional inhibition with a time constant of recovery (550 ms) much longer than the time constant of recovery of the normal desensitization (250 ms).

It was concluded that alphaxalone blocks active (open) ionic channels.
Effects of methysergide and 5‐hydroxytryptamine on carotid blood flow distribution in pigs: further evidence for the presence of atypical 5‐HT receptors
Authors: Saxena Pramod R. , Verdouw Pieter D.
Published: July 2012

The effects of acute (50–350 μg kg−1, i.v.) and subacute (350 μg kg−1 orally per day for six days) administration of methysergide, and of intra‐arterial infusions of 0.5 and 2.0 μg kg−1 min−1 5‐hydroxytryptamine (5‐HT) on the distribution of carotid blood flow into the capillary (nutrient) and arterio‐venous anastomotic (AVA) fractions were studied in anaesthetized pigs.

The acute, but not the subacute, administration of methysergide caused a moderate reduction of carotid blood flow. This reduction, noticed only in the AVA fraction, was due to a constriction of the arterio‐venous anastomoses (AVAs).

Both doses of 5‐HT reduced total carotid blood flow but its nutrient fraction — particularly that distributed to the skin and ears — increased substantially. The AVA fraction was greatly diminished.

After treatment with methysergide, 5‐HT no longer reduced the total carotid blood flow, but increased it. Despite this reversal the constriction of AVAs by the amine was only slightly diminished. On the other hand, the vasodilatation of the nutrient channels was enhanced.

The results of the interaction between methysergide and 5‐HT provide further evidence for the presence of ‘atypical’ 5‐HT receptors (probably corresponding to 5‐HT1 binding sites) mediating AVA contraction and nutrient vasodilatation. The 5‐HT2 receptors mediate vasoconstriction and are located in the large conducting arteries and possibly, in smaller numbers, in the AVAs and arterioles.
Characterization of the adenosine receptor responsible for the inhibition of histamine and SRS‐A release from human lung fragments
Authors: Hillyard P.A. , Nials A.T. , Skidmore I.F. , Vardey C.J.
Published: July 2012

The inhibitory effects of a range of natural and synthetic derivatives of adenosine on the antigen‐induced release of histamine and slow reacting substance of anaphylaxis (SRS‐A) from human lung has been studied.

The nucleotides ATP, ADP and AMP appear to act by being converted to adenosine.

The rank order of inhibitory potency of the synthetic analogues indicates that these compounds act at an extracellular A2/Ra purinoceptor.

The xanthines, 1, 3‐diethyl‐8‐phenylxanthine, 8‐phenyltheophylline and theophylline antagonized the inhibitory action of N‐ethyl‐carboxamideadenosine competitively. Theobromine was inactive. This supports the view that the inhibitory receptor is of the A/R type.

Hexobendine and dipyridamole, reported to antagonize the uptake of adenosine, failed to modify the response of human lung fragments to adenosine.

The P site agonist 2′, 5′ dideoxyadenosine inhibited the release of histamine and SRS‐A. This effect was not prevented by the inhibitors of uptake, hexobendine and dipyridamole, nor was it antagonized by 8‐phenyltheophylline.
The effects of nicotine on spontaneous contractions of cat urinary bladder in situ
Authors: Koley Biswanath , Koley Juthika , Saha Joy Krishna
Published: July 2012

Nicotine and dimethyl‐phenylpiperazinium (DMPP) increased intravesicular pressure and then transiently depressed the spontaneous activity of the urinary bladder in chloralose anaesthetized cats.

Adrenaline (5–10 μg kg−1), noradrenaline (5–20 μg kg−1) and isoprenaline (40–50 μg kg−1) which depressed spontaneous urinary bladder activity, were antagonized by the β‐receptor blocking agent propranolol (1 mg kg−1). Phenylephrine (10–30 μg kg−1) was ineffective on the urinary bladder though it increased the systemic blood pressure. This latter effect was blocked by the α‐receptor blocking agent phentolamine (2 mg kg−1).

Acetylcholine (2–8 μg kg−1) caused a marked fall in systemic blood pressure, which was potentiated by physostigmine, but failed to produce any response on the intravesicular pressure even after physostigmine (50–100 μg kg−1) treatment.

ATP (2 mg kg−1) produced an increase in intravesicular pressure accompanied by a fall in systemic blood pressure. The increased intravesicular pressure was antagonized by quinidine (20 mg kg−1); however, the fall in blood pressure remained unaltered.

The increased intravesicular pressure induced by nicotine (20–40 μg kg−1) or DMPP (50–100 μg kg−1) was not affected by phentolamine (2 mg kg−1), propranolol (1 mg kg−1) or guanethidine (15–20 mg kg−1). Physostigmine (50–100 μg kg−1), hemicholinium 3 (2 mg kg−1) or atropine (1 mg kg−1) were also unable to affect the response to nicotine.

Hexamethonium (1 mg kg−1), reduced the amplitude of spontaneous bladder contractions and quinidine (20 mg kg−1) abolished the effect of nicotine.

Bilateral sectioning of the cervical sympathetic or hypogastric nerves did not alter the effect of nicotine or DMPP. Higher spinal cord transection (C1–C2) blocked the spontaneous, as well as the nicotine‐ and DMPP‐induced, contractions of the bladder.

It is concluded that the increase in intravesicular pressure induced by nicotine is atropine‐resistant and is not mediated either through adrenergic or cholinergic mechanisms. It is probable that a purinergic mechanism is involved, via the activation of P2‐receptors present in the urinary bladder.
Prostanoid synthesis by aortic rings in human blood: selective increase of prostacyclin mediated by a serum factor
Authors: Ritter J.M.
Published: July 2012

Synthesis of vascular epoprostenol (PGI2) and platelet thromboxane (TX) A2 is influenced by the coagulation cascade in incompletely understood ways. To elucidate this, prostanoids were determined in human blood anticoagulated by different drugs and incubated with and without rat aortic rings. Control incubations were performed in Hanks balanced salt solution. PGI2 and TXA2 synthesis were assessed by radioimmunoassay of their stable hydrolysis products 6‐oxo‐prostaglandin (PG) F1α and TXB2.

Fresh aortic rings incubated in Hanks solution with a thrombin inhibitor (TCK) synthesized similar quantities of 6‐oxo‐PGF1α in the presence or absence of sodium citrate. In contrast, the intracellular calcium antagonist TMB‐8 inhibited 6‐oxo‐PGF1α synthesis.

In contrast to the finding in Hanks solution, sodium citrate inhibited 6‐oxo‐PGF1α synthesis by fresh aortic rings incubated in blood anticoagulated with TCK. However, TXB2 synthesis was not affected by citrate.

Blood incubated alone at 37°C in plain glass tubes generated a small amount of immunoreactive 6‐oxo‐PGF1α. A thromboxane synthase inhibitor, OKY1581, increased immunoreactive 6‐oxo‐PGF1α. However, blood anticoagulated with TCK and incubated similarly, generated no detectable 6‐oxo‐PGF1α either in the presence or absence of OKY1581, showing that 6‐oxo‐PGF1α synthesis in the previous experiments was dependent on the vascular rings.

OKY1581 had little or no effect on 6‐oxo‐PGF1α synthesis in incubations of fresh aortic rings with blood anticoagulated with TCK, despite inhibition of TXB2 synthesis. However, OKY1581 increased 6‐oxo‐PGF1α synthesis by rings pretreated with acetylsalicylic acid (ASA) when incubated in blood, presumably by diversion of platelet endoperoxide to vascular PGI2 synthase.

Sodium citrate did not influence the increase in 6‐oxo‐PGF1α synthesis by ASA pretreated aortic rings caused by OKY1581 in whole blood. This implies that the PGI2 stimulating activity of whole blood in the absence of citrate exerts its effect proximal to PGI2 synthase.

It is concluded that a low molecular weight serum factor formed during activation of the intrinsic coagulation pathway in blood, modulates PGI2/TXA2 balance by an action on vascular cyclooxygenase, possibly by an effect on intracellular calcium.
Neuropeptide Y potentiates the effect of various vasoconstrictor agents on rabbit blood vessels
Authors: Edvinsson Lars , Ekblad Eva , Håkanson Rolf , Wahlestedt Claes
Published: July 2012

The contractile effect of neuropeptide Y (NPY) was tested on isolated segments of basilar artery, central ear artery, gastro‐epiploic artery and vein, and femoral artery and vein from the rabbit. At 30 nM NPY did not evoke vasoconstriction; at 300 nM NPY evoked a weak and variable response.

NPY greatly potentiated the response of the gastro‐epiploic and femoral arteries to noradrenaline without affecting the maximum response. As tested on the gastro‐epiploic artery NPY was effective at concentrations of 1 nM and higher. As tested on the femoral artery the potentiating effect of 30 nM NPY on noradrenaline‐evoked contractions was apparent immediately and 30 min after the application of NPY, but not after one hour.

NPY (30 nM) potentiated the contractile response to noradrenaline and histamine but not to 5‐hydroxytryptamine or high K+. The response to histamine was augmented in both arteries and veins, whereas the response to noadrenaline was enhanced in arteries but not in veins. NPY failed to potentiate the prostaglandin F2α‐evoked contraction except in the gastro‐epiploic vein.
An analysis of the purinergic component of active muscle vasodilatation obtained by electrical stimulation of the hypothalamus in rabbits
Authors: Shimada Steven G. , Stitt John T.
Published: July 2012

In anaesthetized rabbits, electrical stimulation of the hypothalamus in areas analogous to the defence area in cats produces the ‘defence reaction.’ This response includes signs of arousal and a large increase in blood flow to skeletal muscle in the hind limb caused by a vasodilatation in the skeletal muscle vasculature.

The vasodilatation is a sympathetic response, and it is not dependent upon muscle activity in the hind limb.

The muscle vasodilatation is insensitive to α‐adrenoceptor, β‐adrenoceptor, cholinoceptor and histamine receptor antagonists.

Intra‐arterial injections of the purinoceptor agonists, adenosine triphosphate (ATP) and adenosine, mimic the vasodilatation produced by electrical stimulation.

The P1‐purinoceptor blocker, aminophylline, attenuates adenosine‐induced vasodilatation, but it does not affect the vasodilatation produced by ATP or hypothalamic stimulation.

The P2‐purinoceptor blocker, antazoline, attenuates the vasodilatation produced by both ATP and hypothalamic stimulation.

Our results suggest that the muscle vasodilatation produced by hypothalamic stimulation is mediated by purinergic nerves which release ATP and act on P2‐purinoceptors.
Prevention of dopaminergic toxicity of MPTP in mice by phenylethylamine, a specific substrate of type B monoamine oxidase
Authors: Melamed E. , Youdim M.B.H.
Published: July 2012

N‐methyl‐4‐phenyl‐1, 2, 5, 6‐tetrahydropyridine (MPTP) is toxic to dopaminergic neurones in several mammalian species including mice. Combined treatment with phenylethylamine prevented in mice the long‐term (30 days post‐treatment) dopamine depletions in striatum induced by MPTP. Phenylethylamine, a naturally‐occuring specific substrate of monoamine oxidase (MAO) type B, probably protects against effects of MPTP by competitively inhibiting the oxidative conversion of MPTP to its toxic metabolite N‐methyl‐4‐phenylpyridinium ion catalysed by MAO‐B.
Sex and hormonal influences on platelet sensitivity and coagulation in the rat
Authors: Emms H. , Lewis G.P.
Published: July 2012

Platelet sensitivity to adenosine di‐phosphate (ADP), thrombin, collagen, arachidonic acid and prostaglandin I2 (PGI2) and the activity of the coagulation system as measured by the activated partial thromboplastin time, prothrombin time, Russell's viper venom time and plasma fibrinogen have been examined in male and female rats, female rats during the oestrous cycle and female rats treated with oestrogen and a progestogen.

Male rat platelets were less sensitive to thrombin and more sensitive to inhibition by PGI2 than those from females and fibrinogen levels in male rat plasma were approximately twice those seen in females.

During the oestrous cycle, platelets were more sensitive to ADP and less sensitive to thrombin at dioestrus.

Following 6 weeks treatment with 17 β‐oestradiol or ethynyl oestradiol, both platelet aggregation and release of granular ATP induced by collagen were significantly reduced. Platelet sensitivity to other agents, ADP, arachidonic acid, thrombin and PGI2 was, however, unchanged following oestrogen treatment. Activation of factor X by Russell's viper venom was accelerated in rats treated with ethynyl oestradiol, although this enhancement was not reflected in the overall clotting times.
The isolated stomach preparation of the mouse: a physiological unit for pharmacological analysis
Authors: Black J.W. , Shankley N.P.
Published: July 2012

Although oxyntic cell secretion can be studied at many organisation levels between isolated cell suspensions and non‐invasive techniques in animals, the isolated, lumen‐perfused, stomach preparation of the mouse represents a hierarchical level which eliminates extrinsic regulatory influences but retains all the cellular architecture known to be necessary for physiological responses and so can be defined as the physiological unit of acid secretion.

The feeding pattern before and the distending pressure during an experiment have been identified as the main determinants of basal secretion: the combination of an intragastric pressure of 12 cmH2O and the fasted state generated a stable basal secretion over 2 h providing a satisfactory basis for bioassays.

Basal acid secretion was lowered by treatment with omeprazole and sodium thiocyanate but not with tetrodotoxin, N‐methylatropine or tiotidine, suggesting that basal secretion does not involve nervous stimulation or the local release of histamine under these experimental conditions.

The improved assay permitted the full characterization of cumulative agonist concentration‐effect curves in single stomach preparations to histamine, 5‐methylfurmethide, pentagastrin and isobutylmethylxanthine.

Interestingly, pentagastrin produced sustained stimulation of gastric acid secretion under conditions when there was no pharmacological evidence that histamine secretion was taking place. This finding is discussed in relation to the role of histamine in the control of gastric acid secretion.