bluuebunny/crossref_metadata_2025_split huggingface dataset:
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.
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.