bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of p‐chlorophenylalanine on release of 5‐hydroxytryptamine from the rat frontal cortex in vivo
Authors: O'Connell M.T. , Portas C.M. , Sarna G.S. , Curzon G. 
Published: July 2012

Rats were given p‐chlorophenylalanine (PCPA, 150 mg kg−1, i.p.) to inhibit partially 5‐hydroxytryptamine (5‐HT) synthesis so that its concentration in the frontal cortex fell by about half. The effects of this treatment on frontal cortex dialysate 5‐HT and 5‐hydroxyindoleacetic acid (5‐HIAA) concentrations were determined before and after stimulation by increasing K+ concentration in the perfusion fluid by 100 mm for 20 min. Rates of 5‐HT synthesis as indicated by the effects of 3‐hydroxybenzylhydrazine (NSD 1015, 150 mg kg−1, i.p.) on frontal cortex tissue and dialysate 5‐hydroxytryptophan (5‐HTP) and dialysate 5‐HIAA were also measured in rats that had not been stimulated with K+.
Dialysate 5‐HT and 5‐HIAA concentrations of both vehicle‐ and PCPA‐treated rats fell into major (group 1) and minor (group 2) populations statistically distinguishable from each other by the high 5‐HT and low 5‐HIAA values of the latter group.
In group 1 animals, PCPA decreased both the dialysate 5‐HT concentration and its rise following stimulation by K+ in proportion with the decrease of 5‐HT in frontal cortex tissue. 5‐HIAA fell more markedly than 5‐HT and in similar proportion in both tissue and dialysate. The fall of dialysate 5‐HIAA on stimulation by K+ was also attenuated to the same degree. The elevated 5‐HT/5‐HIAA ratios after PCPA treatment imply increased conservation of the depleted 5‐HT stores.
PCPA decreased the above 5‐HIAA values and the effects of NSD 1015 on tissue 5‐HTP or dialysate 5‐HIAA concentrations in similar proportion. However, PCPA had little effect on corresponding dialysate 5‐HTP values.
The results are discussed with respect to relationships between synthesis, storage and release of 5‐HT. They indicate that (under the conditions of the present study) the availability of 5‐HT to receptors is directly proportional to total vesicular stores under both basal conditions and during neuronal firing.
Flosequinan, a vasodilator with a novel mechanism of action
Authors: Resnick Moira S. , Maitland L.A. , Morgan Kathleen G. 
Published: July 2012

The mechanism of action of flosequinan was investigated in ferret aortic smooth muscle by the simultaneous measurement of aequorin luminescence and isometric force.
The control calcium‐force curve was obtained by plotting the calibrated aequorin luminescence against the force from potassium‐depolarized muscles. Flosequinan relaxed potassium‐depolarized muscles by causing parallel changes in [Ca2+]i and force with no shift in the control [Ca2+]i‐force relationship.
The [Ca2+]i‐force relationship in the presence of a maximally effective concentration of phenylephrine was significantly shifted to the left of that for the control, potassium‐depolarized muscle. Flosequinan relaxed the phenylephrine‐contracted muscle by causing a large decrease in force with only a minimal decrease in [Ca2+]i, resulting in an apparent rightward shift of the [Ca2+]i‐force relationship, toward the control curve.
In comparison, sodium nitroprusside caused relaxation of either the potassium‐ or phenylephrine‐induced contraction solely by a decrease in [Ca2+]i with no shift in either calcium‐force relationship.
Milrinone caused no significant rightward shift of the calcium‐force relationship during phenylephrine‐ or potassium‐induced contractions, but when milrinone was added in the absence of vasoconstrictors, relaxation was obtained with no significant decrease in [Ca2+]i.
Flosequinan appears to differ in mechanism of action from both nitroprusside and milrinone. It relaxes depolarization‐mediated contractions solely by decreasing [Ca2+]i but also appears to be capable of reversing the apparent calcium sensitizing action of phenylephrine.
P2 purinoceptor regulation of mucin release by airway goblet cells in primary culture
Authors: Kim K. Chul , Lee Bong C. 
Published: July 2012

The effects of adenine analogues on mucin release by airway goblet cells have been examined in a hamster primary tracheal epithelial cell culture.
Adenosine, a P1 receptor agonist, had no effect on mucin release even at 2 mm, while ATP, a P2 receptor agonist, stimulated mucin release in a dose‐dependent fashion with an apparent EC50 of 20μm. The relative potency order among adenine nucleotides was ATP > ADP > AMP = adenosine.
ATPγS, a non‐hydrolyzable analogue of ATP, was equipotent with ATP in stimulating mucin release. The potency order among some ATP analogues was ATP > 2‐methylthio ATP > α,β‐methylene ATP > β,γ‐methylene ATP. Reactive blue 2, a putative P2y‐purinoceptor antagonist, did not block the ATP‐induced mucin release.
The present results indicate that mucin release by airway goblet cells is stimulated by extracellular ATP via P2 receptor‐mediated mechanism. We suggest that this mechanism may be important in the physiological regulation of airway goblet cell mucin release in vivo.
Pulse exposure to protein synthesis inhibitors enhances vascular responses to des‐Arg9‐bradykinin: possible role of interleukin‐1
Authors: deBlois Denis , Bouthillier Johanne , Marceau François 
Published: July 2012

The modulation of the spontaneous increase in contractile responses to des‐Arg9‐bradykinin (des‐Arg9‐BK) of rabbit aortic strips incubated in vitro was studied. Rapid hypotensive responses to exogenous kinins were also measured in rabbits anaesthetized 5 h following pretreatment.
Continuous exposure to the protein synthesis inhibitors cycloheximide (71 μm) or anisomycin (3.8 μm) profoundly inhibited the sensitization to des‐Arg9‐BK in incubated aortic strips. However, temporary (3 h) inhibition of protein synthesis in vitro followed by further incubation (3 h) of tissues without inhibitor, paradoxically enhanced both the maximal contractile responses to des‐Arg9‐BK (1.7 μm) and the apparent affinity of the kinin without affecting contractions to noradrenaline (NA, 100 nm) at 6.5 h.
The stimulatory activity of the short treatment (pulse) with cycloheximide was abolished in the presence of dexamethasone sodium phosphate (100 μm throughout the incubation). The function of receptors for kinins did not appear to be altered directly by the steroid treatment.
Interleukin‐1β (IL‐1β), applied at low concentrations (100–250 pg ml−1) on aortic strips between 3 h and 6.5 h of incubation time, mimicked the selective stimulatory effect of the cycloheximide pulse on responses to des‐Arg9‐BK. Higher concentrations of IL‐1β (0.5–5 ng ml−1) did not further amplify the responses to des‐Arg9‐BK but decreased the contractile responses to NA.
The modulation by IL‐1β of vascular sensitivity to des‐Arg9‐BK and to NA was prevented by blockade of protein synthesis.
The induction in vivo by IL‐1β (5 μg kg−1) or by cycloheximide (10 mg kg−1) of cardiovascular responsiveness to des‐Arg9‐BK was demonstrated with a blood pressure assay of exogenous kinins or with tissues isolated ex vivo 5 h after pretreatment of animals. Evidence of active disposition of cycloheximide in vivo was also obtained.
We propose the production of endogenous IL‐1 as a possible mechanism for the enhancement of responsiveness to des‐Arg9‐BK observed in tissues pulsed with a protein synthesis inhibitor and for the inducing effect of cycloheximide or E. coli lipopolysaccharide in vivo. These results suggest that effects mediated by the BK1 receptor for kinins are potentially present in pathological conditions associated with IL‐1 production.
Comparison of the effects of the K+‐channel openers cromakalim and minoxidil sulphate on vascular smooth muscle
Authors: Wickenden A.D. , Grimwood S. , Grant T.L. , Todd M.H. 
Published: July 2012

The actions of the potassium channel openers, cromakalim and minoxidil sulphate, were compared in a range of isolated blood vessel preparations.
Cromakalim and minoxidil sulphate inhibited spontaneous mechanical activity of the guinea‐pig portal vein and relaxed the noradrenaline precontracted rat aorta with similar potency. In contrast, minoxidil sulphate was less potent than cromakalim in inhibiting spontaneous activity in the rat portal vein and was essentially inactive in the noradrenaline precontracted rat mesenteric artery and rabbit aorta.
Minoxidil sulphate did not antagonize the effects of cromakalim in the rabbit aorta indicating it was not acting as a partial ‘agonist’.
Charybdotoxin, noxiustoxin and rubidium failed to discriminate between cromakalim and minoxidil sulphate indicating that the apparently selective effects of minoxidil sulphate were not mediated by either Ca2+‐activated potassium channels, delayed rectifiers or rubidium impermeable potassium channels.
Glibenclamide antagonized the effects of cromakalim in an apparently competitive manner whereas the effects of minoxidil sulphate were antagonized in a non‐competitive manner. The involvement of subtypes of ATP‐sensitive potassium channels is discussed.
Cardioprotective and endothelial protective effects of [Ala‐IL8]77 in a rabbit model of myocardial ischaemia and reperfusion
Authors: Lefer Allan M. , III Gerald Johnson , Ma Xin‐liang , Tsao Phillip S. , Thomas G. Roger 
Published: July 2012

We studied the effects of a form of interleukin‐8 (i.e., [Ala‐IL8]77) on endothelial dysfunction and myocardial injury in rabbits. Pentobarbitone‐anaesthetized rabbits were subjected to 1.5 h occlusion of the marginal coronary artery and 3.5 h reperfusion. [Ala‐IL8]77 (50 μg or its vehicle) was given i.v. as a bolus 10 min prior to reperfusion. [Ala‐IL8]77 was also studied in isolated perfused hearts of rabbits.
Myocardial ischaemia plus reperfusion in untreated rabbits produced severe endothelial dysfunction and myocardial injury, including marked myocardial necrosis, elevated cardiac myeloperoxidase (MPO) activity in ischaemic cardiac tissue, and loss of response of marginal coronary rings to the endothelium‐dependent vasodilators, acetylchloline (ACh) and A23187.
Administration of [Ala‐IL8]77 10 min prior to reperfusion resulted in significant protective effects in post‐ischaemic reperfusion. Compared with untreated rabbits, [Ala‐IL8]77 caused a reduced necrotic zone (P < 0.01), lower MPO activity in the necrotic zone (P < 0.05), and significantly preserved vasorelaxant responses of marginal coronary artery rings to endothelium‐dependent vasodilators, ACh (P < 0.001) and A23187(P < 0.001).
These results indicate that myocardial ischaemia and reperfusion result in a severe endothelial dysfunction and myocardial injury which involved the interaction of neutrophils and endothelial cells. However, [Ala‐IL8]77 did not appear to exert a direct endothelial protective effect in the absence of neutrophils in rabbit isolated perfused hearts.
Inhibition of neutrophil accumulation in the myocardium, perhaps by prevention of endothelial dysfunction resulting from [Ala‐IL8]77, leads to significant protective effects in ischaemia and reperfusion in rabbits.
Short‐term effects of administration of anticonvulsant drugs on free carnitine and acylcarnitine in mouse serum and tissues
Authors: Camiña M.F. , Rozas I. , Gómez M. , Paz J.M. , Alonso C. , Rodriguez‐Segade S. 
Published: July 2012

The short‐term evolution of concentrations of free carnitine and acylcarnitine was studied in the serum, liver, kidney, heart and skeletal muscle of mice after administration of single therapeutic doses of the anticonvulsant drugs, valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT) and phenobarbitone (PHB).
The effects of the drugs were immediate but transitory, control levels of free carnitine and acylcarnitine having been recovered or almost recovered in serum and in all tissues 8 h post administration (p.a.).
VPA was the only drug that significantly reduced free carnitine concentration in serum, which recovered control levels by 4 h p.a.
All the drugs studied brought about marked deficits of serum acylcarnitine, which had disappeared 2 h p.a. in the case of VPA and not until 8 h p.a. for CBZ, PHT or PHB.
The minimum concentrations of free carnitine and acylcarnitine in serum were invariably associated with the maximum concentration of drug in serum.
Free carnitine concentration was not affected by VPA in any tissue, PHT and PHB brought about significant deficits in heart and kidney, and CBZ a significant deficit in muscle.
Acylcarnitine concentration was significantly reduced in heart, kidney and muscle by CBZ, PHT and PHB, but in liver the effects of all drugs were very small.
These results are compatible with the hypothesis that the primary cause of anticonvulsant‐induced alteration of carnitine metabolism is interference with renal reabsorption of carnitine.
An electrophysiological study of the actions of angiotensin II at the sympathetic neuroeffector junction in the guinea‐pig vas deferens
Authors: Ziogas James , Cunnane Thomas C. 
Published: July 2012

The effects of angiotensin II on sympathetic neuroeffector transmission in the guinea‐pig vas deferens have been investigated by the use of intracellular and focal extracellular recording techniques to measure indirectly, the release of adenosine 5′‐triphosphate (ATP).
Angiotensin II (10–100 nm) did not alter the amplitude of the first excitatory junction potential (e.j.p.) in a train but increased the amplitude of subsequent e.j.ps. There was a corresponding increase in the probability of occurrence of extracellularly recorded evoked excitatory junction currents (e.j.cs). Spontaneous quantal transmitter release was unaffected by angiotensin II.
The enhancement of transmitter release produced by angiotensin II was prevented by the angiotensin receptor antagonist, saralasin.
The increase in transmitter release produced by angiotensin II was due to an increase in the probability of transmitter release from individual varicosities and not due to any detectable change in the configuration of the nerve terminal impulse or to the induction of repetitive firing.
There was no overall enhancement of e.j.ps or e.j.cs by angiotensin II in reserpinized tissues. Surprisingly, the predominant effect of angiotensin II in reserpinized vasa deferentia was to inhibit evoked transmitter release, an effect reversed by indomethacin (3 μm).
The results show that angiotensin II increases the release of sympathetic transmitter by activating prejunctional angiotensin II receptors. However, when the co‐transmitter noradrenaline was depleted, angiotensin II now inhibited transmitter release indirectly, presumably by stimulating prostaglandin formation in the smooth muscle cells which then inhibited release transjunctionally.
Nedocromil sodium inhibits airway hyperresponsiveness and eosinophilic infiltration induced by repeated antigen challenge in guinea‐pigs
Authors: Schellenberg R. Robert , Ishida Kiyoshi , Thomson Randall J. 
Published: July 2012

Repeated exposure to ovalbumin aerosol produced significant increases in epithelial eosinophils of airways of all sizes and produced increased pulmonary resistance (RL) to inhaled acetylcholine (ACh) in guinea‐pigs.
Nedocromil sodium 10 mg ml−1, by nebulization prior to each ovalbumin (OA) challenge inhibited both the airway eosinophilia and hyperresponsiveness to ACh.
Nedocromil sodium pretreatment (10 mg ml−1 by nebulization) 10 min prior to OA completely inhibited the acute bronchoconstrictor response to OA.
Our findings suggest that nedocromil sodium inhibits airway hyperresponsiveness by inhibiting eosinophilic infiltration, or by simultaneously inhibiting mechanisms involved in both processes.
Direct evidence for an important species difference in the mechanism of 8‐OH‐DPAT‐induced hypothermia
Authors: Bill D.J. , Knight M. , Forster E.A. , Fletche A. 
Published: July 2012

Parallel series of experiments were carried out in the rat and mouse in order to investigate the mechanism(s) underlying the hypothermia induced in rodents by the selective 5‐HT1A receptor agonist, 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT).
In the mouse, lesioning of central 5‐hydroxytryptaminergic neurones (by use of the neurotoxin, 5,7‐dihydroxytryptamine; 5,7‐DHT) abolished the hypothermic response to 8‐OH‐DPAT, and depletion of brain 5‐hydroxytryptamine (5‐HT) levels (with the 5‐HT synthesis inhibitor, p‐chlorophenylalanine) markedly attenuated the response in this species. These pretreatments did not significantly attenuate 8‐OH‐DPAT‐induced hypothermia in the rat, except for a significant attenuation of the response in 5,7‐DHT‐lesioned rats at the top dose of 8‐OH‐DPAT (1.0 mg kg−1, s.c.).
Pharmacological pretreatments which facilitate 5‐HT release (selective 5‐HT uptake inhibitors, precursor (5‐hydroxytryptophan) loading, or fenfluramine), markedly attenuated or abolished 8‐OH‐DPAT‐induced hypothermia in the mouse. These pretreatments generally had no significant effect on 8‐OH‐DPAT‐induced hypothermia in the rat.
The selective noradrenaline uptake inhibitor, desipramine, had no effect on the hypothermic response to 8‐OH‐DPAT in either species. The selective dopamine uptake inhibitor, nomifensin, significantly increased the hypothermic response to 8‐OH‐DPAT in the mouse, but did not affect the response in the rat except at high, motor stimulant doses, when the response was attenuated.
These data are consistent with the hypothesis that 8‐OH‐DPAT‐induced hypothermia is mediated by presynaptic autoreceptors in the mouse and by postsynaptic 5‐HT1A receptors in the rat. Preliminary data also indicate an involvement of dopamine release in the mouse but not in the rat.
Haemodynamic changes and acetylcholine‐induced hypotensive responses after NG‐nitro‐l‐arginine methyl ester in rats and cats
Authors: van Gelderen E. Marcel , Heiligers Jan P.C. , Saxena Pramod R. 
Published: July 2012

The haemodynamic effects of NG‐nitro‐l‐arginine methylester (l‐NAME; 1, 3,10 and 30 mg kg−1) and its potential ability to attenuate the hypotensive responses to acetylcholine (0.03, 0.1, 1.0 and 3.0 μg kg−1) have been investigated in anaesthetized rats and cats.
In the rat, l‐NAME elicited a dose‐dependent pressor effect increasing mean arterial blood pressure from the baseline value of 116 ± 4 mmHg to a maximum of 156 ± 6 mmHg with 30 mg kg−1. This increase in blood pressure could be only partly reversed by l‐arginine (300 mg kg−1). However, the increase in blood pressure by lower doses (up to 10 mg kg−1) of l‐NAME was effectively reversed by l‐arginine (1000 mg kg−1).
In the cat, l‐NAME did not significantly modify systemic haemodynamic variables (heart rate, mean arterial blood pressure, cardiac output, stroke volume or total peripheral resistance), when compared to the changes in saline‐treated animals. Administration of l‐arginine did not cause any significant effect in cats treated with l‐NAME, but some decrease in heart rate and increases in cardiac output and stroke volume were observed in the saline‐treated group.
With the lowest dose (1 mg kg−1), l‐NAME did not affect tissue blood flows in the cat, but higher doses (3 and 30 mg kg−1) significantly reduced blood flows to the mesentery, stomach, spleen, intestines, lungs and the total liver. l‐Arginine (300 mg kg−1) injected into the control (saline‐treated) animals resulted in a significant increase in blood flow to the heart, mesentery, lungs as well as the total liver, particularly its portal fraction. l‐Arginine‐induced increases in tissue blood flows (mesentery, kidneys, spleen, lungs, total liver and portal blood flow) in saline‐treated animals were attenuated in animals treated with l‐NAME.
The acetylcholine‐induced peak hypotensive response was not reduced in rats or cats by l‐NAME. The duration of acetylcholine response was, however, attenuated in both species by l‐NAME. Treatment with l‐arginine (10–100 mg kg−1) did not change the acetylcholine‐induced hypotension.
The above results reveal a marked difference between the haemodynamic effects of l‐NAME in rats and cats and suggest that in cats, unlike rats, the role of the l‐arginine‐NO pathway in the regulation of blood pressure is rather limited, although such a pathway may exist in several tissues. Furthermore, the hypotensive response to acetylcholine in both species seems to be mediated largely by NO‐independent pathways.
Blockade of intracellular actions of calcium may protect against ischaemic damage to the gerbil brain
Authors: Asano T. , Ikegaki I. , Satoh S. , Mochizuki D. , Hidaka H. , Suzuki Y. , Shibuya M. , Sugita K. 
Published: July 2012

The brain cytoprotective effects of a putative calcium‐associated protein kinase inhibitor, HA1077, as well as a calcium entry blocker nicardipine were evaluated in models of cerebral ischaemia in Mongolian gerbils. Morphological changes characterizing delayed neuronal death of selectively vulnerable CA1 pyramidal neurones in the hippocampus of the Mongolian gerbil brain occurred 7 days after transient bilateral occlusion of the common carotid arteries.
A single injection of HA1077 (1 and 3 mg kg−1, i.p.) 5 min after the occlusion led to a dose‐dependent protection of the CA1 neurones. Repeated administrations of HA1077 (1 and 3 mg kg−1, i.p., twice daily for 7 days post‐ischaemia) revealed an increase in the number of normal cells, compared to findings with a single administration.
In contrast to HA1077, nicardipine (0.3 and 1 mg kg−1, i.p.) did not reduce neuronal degeneration.
HA1077 did not interact with the ion channel within which MK‐801 binds, as determined by receptor binding.
The calcium ionophore, A23187, caused a tonic contraction in canine cerebral arterial strips. HA1077, but not nicardipine, relaxed the A23187‐induced contraction, concentration‐dependently.
These results suggest that blockade of the intracellular actions of calcium may provide protection against ischaemic damage in the brain.
Effects of zaprinast and rolipram on platelet aggregation and arrhythmias following myocardial ischaemia and reperfusion in anaesthetized rabbits
Authors: Holbrook Mark , Coker Susan J. 
Published: July 2012

This study was designed to compare the effects of two selective inhibitors of certain phosphodiesterase (PDE) isoenzymes on arrhythmias induced by coronary artery occlusion and reperfusion. The drugs used were zaprinast which inhibits guanosine 3′: 5′‐cyclic monophosphate (cyclic GMP)‐specific PDE (PDE V) and rolipram which inhibits cyclic GMP‐insensitive, adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP)‐specific PDE (PDE IV).
Pretreatment of anaesthetized rabbits with zaprinast (300 μg kg−1 plus 30 μg kg−1 min−1) had no significant effect on ischaemia‐ or reperfusion‐induced ST‐segment changes, or arrhythmias. In contrast, rolipram (30 μg kg−1 plus 3μg kg−1 min−1) and (100 μg kg−1 plus 10μg kg−1min−1) increased the severity of arrhythmias. With the higher dose of rolipram, ST‐segment changes were increased in magnitude and mortality due to ventricular fibrillation during ischaemia or reperfusion was increased to 80% compared with 30% in controls (n = 10 per group).
Zaprinast caused small but significant increases in heart rate and arterial blood pressure whereas rolipram decreased diastolic arterial pressure, increased left ventricular (LV) dP/dtmax and substantially increased heart rate.
At the end of each experiment platelet aggregation was measured ex vivo. Pretreatment of rabbits with either dose of rolipram had no significant effect on platelet aggregation induced by adenosine diphosphate (ADP), collagen, arachidonic acid or thrombin or on isoprenaline‐ or prostacyclin‐induced inhibition of aggregation. Aggregatory responses to ADP and collagen were increased in platelets obtained from rabbits which had received zaprinast.
These results indicate that in the dose used here, the PDE V inhibitor zaprinast had no significant effect on arrhythmias. The effects of the PDE IV inhibitor rolipram on haemodynamics, combined with its lack of antiplatelet activity, may have contributed to the exacerbation of arrhythmias observed during myocardial ischaemia and reperfusion.