bluuebunny/crossref_metadata_2025_split huggingface dataset:
Age‐associated decrease in histamine‐induced vasodilatation may be due to reduction of cyclic GMP formation
Authors: Moritoki Hideki , Tanioka Asao , Maeshiba Yoshihiro , Iwamoto Takeshi , Ishida Yukio , Araki Hiromasa 
Published: July 2012

The effects of aging on histamine‐induced vasodilatation and cyclic GMP production in rat thoracic aorta were investigated.
This histamine‐induced dilatation of the aorta was mediated by H1‐receptors and was dependent on the endothelium.
Histamine induced the greatest dilatation of arteries of 3–4 week old rats, progressively less of those of rats of 8 to 56 weeks old, and scarcely detectable dilatation of those of 100 week old rats.
Histamine induced cyclic GMP production in aorta from rats of 4 weeks old, with no change in the cyclic AMP level. This increase in the cyclic GMP level induced by histamine also decreased with age, being about 70% as great at 8 weeks, 50% as great at 50–60 weeks, and 10% as great at 130 weeks of age.
Removal of the endothelium completely abolished the histamine‐induced increase in cyclic GMP.
The dilator effect of nitroprusside, which enhances cyclic GMP production by stimulating guanylate cyclase directly (not indirectly via the endothelium derived relaxing factor, EDRF), also snowed age‐related attenuation.
The dilator effect of 8‐bromo cyclic GMP, which stimulates cyclic GMP‐dependent protein kinase, also decreased during aging.
These results suggest that aging reduces the ability of the endothelium to produce EDRF, which stimulates guanylate cyclase, and so decreases cyclic GMP production. Thus the decreased dilator response of the arteries to histamine during aging is probably due to both loss of endothelial function and reduction of guanylate cyclase activity. Alteration of cyclic GMP‐dependent protein kinase activity may also participate in the age‐related changes.
Noradrenaline release evoked by a physiological irregular sympathetic discharge pattern is modulated by prejunctional α‐ and β‐adrenoceptors in vivo
Authors: Kahan Thomas , Pernow John , Schwieler Jonas , Wallin B. Gunnar , Lundberg Jan M. , Hjemdahl Paul 
Published: July 2012

Sympathetic nerve stimulation‐evoked overflow of endogenous noradrenaline (NA) and vasoconstriction were studied in canine blood‐perfused gracilis muscle in situ. Nerves were stimulated at an average frequency of 2 Hz (240 pulses, 120 s) with impulses derived from a recording of the normal irregular sympathetic discharge to human skeletal muscle, with regular bursts of impulses, or with the conventional continuous stimulus mode.
Variations in impulse activity were closely paralleled by changes in vascular tone. However, all stimulation patterns evoked the same integrated NA overflow and the same degree of vasoconstriction.
Blockade of β‐adrenoceptors by propranolol (0.5mgkg−1 i.v.) significantly reduced NA overflow and vasoconstriction evoked both by continuous and irregular nerve stimulation, by approximately 15–20%.
The enhancement of NA overflow following α‐adrenoceptor blockade by phenoxybenzamine (0.5mgkg−1 local i.a.) was significantly greater when evoked by continuous than by irregular nerve discharge (24 vs 14 fold). Effects were similar with irregular and regular burst activity. Half of this enhancement has been shown to be due to blockade of neuronal uptake of NA by phenoxybenzamine. Vasoconstrictor responses to all stimulation patterns were similarly reduced, but not abolished, by phenoxybenzamine.
The normal irregular sympathetic discharge seems to evoke a similar integrated NA release and equally pronounced vasoconstriction as stimulation with regular bursts or at constant frequency. We provide additional evidence for a physiological prejunctional α‐adrenoceptor‐mediated inhibition of NA release. This mechanism may be influenced by the discharge pattern. Also prejunctional β‐adrenoceptors seem to modulate NA release under physiological conditions. However, the α‐adrenoceptor‐mediated mechanism is quantitatively more important.
Effects and interactions of sensory neuropeptides on airway microvascular leakage in guinea‐pigs
Authors: Rogers Duncan F. , Belvisi Maria G. , Aursudkij Boonrut , Evans Timothy W. , Barnes Peter J. 
Published: July 2012

We have studied the effect of the sensory neuropeptides substance P (SP), neurokinin A (NKA), neurokinin B (NKB) and calcitonin gene‐related peptide (CGRP) on microvascular permeability in guinea‐pig airways in vivo and investigated whether CGRP would potentiate the effect of SP. We used the extravasation of intravenously‐injected Evans blue dye as an index of permeability.
The tachykinins SP, NKA and NKB (0.025–5.0 nmol kg−1, i.v.) significantly (P < 0.05) increased extravasation of dye in a dose‐related manner and with a similar pattern of distribution; they were most potent in the trachea and main bronchi, less potent in the larynx and intrapulmonary airways, and had little significant effect in the bladder.
SP was significantly more potent in causing extravasation of dye than NKA or NKB with ED50 values (nmol kg−1) in the range 0.04–0.1, depending on the airway level, compared with values in the range 0.3–0.7 for the neurokinins.
CGRP (0.0025–2.5 nmol kg−1, i.v.) had no significant effect on microvascular permeability and did not potentiate SP‐induced extravasation of dye.
Each neuropeptide decreased mean arterial blood pressure, indicating vasodilatation, in a dose‐related manner. Co‐injection of CGRP and SP produced additive decreases in arterial pressure.
We conclude that, in guinea‐pig airways, tachykinins increase microvascular permeability via tachykinin receptors of the NK‐1 sub‐type (indicated by an order of potency of SP > NKA = NKB) on endothelial cells. The response appears to be related to mechanisms in addition to vasodilatation. The relevance of the responses to the tachykinins in asthma is discussed.
The effects of nitroglycerin on regional myocardial contractile dysfunction produced by treadmill exercise or isoprenaline stimulation in dogs
Authors: Schneider W. , Grohs J.G. , Krumpl G. , Mayer N. , Raberger G. 
Published: July 2012

To compare different methods of cardiac stress testing that are clinically applied in the management of coronary heart disease, 2 groups of dogs each were chronically instrumented and subjected to treadmill exercise or isoprenaline infusion in the presence of coronary stenosis.
It was of interest to determine differences in haemodynamic and regional myocardial contractile parameters, the response to antianginal therapy (nitroglycerin 15μgkg−1 15min−1, i.v.), and, in particular, whether this response differed according to the mode of cardiac stimulation, i.e. treadmill exercise or isoprenaline infusion.
After stenosis of the circumflex branch of the left coronary artery which affected resting myocardial function only minimally, treadmill exercise or isoprenaline infusion induced transient regional contractile dysfunction. Heart rate, arterial blood pressure, left ventricular end‐diastolic pressure and left ventricular dp/dtmax were registered and myocardial oxygen demand was calculated. Regional contractile performance was assessed by ultrasonic distance measurement in the underperfused and in a normally perfused area.
Treadmill exercise led to an increase in systolic arterial and left ventricular end‐diastolic pressure. In contrast, isoprenaline‐induced stimulation led to a decrease in diastolic arterial and left ventricular end‐diastolic pressure. Regional contractile function in the critically underperfused area showed a deterioration during both modes of stress. Nitroglycerin completely abolished stress‐induced contractile dysfunction only in the group where treadmill exercise was employed for stimulation.
The inability of nitroglycerin to prevent myocardial dysfunction in the isoprenaline group may be due to exhaustion of the arterial and/or venous vasodilator potency of nitroglycerin in the presence of adrenoceptor vasodilatation induced by isoprenaline.
These findings indicate that clinical antianginal drug testing and the evaluation of the course of disease in patients with coronary heart disease may be highly dependent on the test method chosen.
Dietary ω3 polyunsaturated fatty acids augment endothelium‐dependent relaxation to bradykinin in coronary micro vessels of the pig
Authors: Shimokawa Hiroaki , Aarhus Lawrence L. , Vanhoutte Paul M. 
Published: July 2012

The effects of chronic dietary supplementation with ω3 polyunsaturated fatty acids on endothelium‐dependent relaxations were examined in isolated coronary microvessels of the pig.
Animals were maintained for four weeks with or without dietary supplementation of purified eicosapentaenoic acid (3.5 g daily) and docosahexaenoic acid (1.5 g daily). Fatty acid profiles of plasma lipids showed that only the fraction of eicosapentaenoic acid increased by the treatment, together with a decrease of that of arachidonic acid.
In the treated group, endothelium‐dependent relaxations to bradykinin were significantly augmented, while contractions to acetylcholine or relaxations to nitroprusside were unaltered.
These results indicate that dietary ω3 polyunsaturated fatty acids (mainly eicosapentaenoic acid) augment endothelium‐dependent relaxations in coronary microvessels of the pig, without changing the ability of vascular smooth muscle to contract or relax.
Interactions between angiotensin II, sympathetic nerve‐mediated pressor response and cyclo‐oxygenase products in the pithed rat
Authors: Grant T.L. , McGrath J.C. 
Published: July 2012

The influence of angiotensin II (AII) on resting blood pressure and on sympathetic nerve‐mediated pressor responses in the pithed rat was investigated either by inhibiting the renin‐angiotensin system or by infusing AII.
Plasma AII levels in the pithed rat were approximately 20 fold higher than in normotensive rats.
Infusion of a subpressor dose of AII (50ngkg−1 min−1) had no effect on sympathetic nerve mediated pressor responses but a pressor dose of AII, (200ngkg−1min−1) facilitated nerve‐mediated pressor responses.
The angiotensin converting enzyme inhibitor, teprotide, and the AII‐receptor antagonist, saralasin, lowered the diastolic blood pressure and attenuated sympathetic nerve‐mediated pressor responses. There was no difference in the effects of teprotide at 1 mgkg1‐ and 10mgkg−1. Infusion of sodium nitroprusside at concentrations producing a fall in diastolic blood pressure of similar magnitude to that produced by teprotide and saralasin significantly attenuated nerve‐mediated pressor responses.
After teprotide, AII 50 mg kg−1 min −1 increased diastolic blood pressure. The inhibitory effect of teprotide on nerve‐mediated pressor responses was antagonized by this infusion of AII only if the rats were pretreated with the cyclo‐oxygenase inhibitor, flurbiprofen.
It is concluded that AII is a major determinant of vascular tone in the pithed rat and that inhibition of the renin‐angiotensin system attenuates sympathetic nerve‐mediated pressor responses at least in part through the fall in blood pressure per se. The demonstration of this is complicated by an excessive release of vasodilator prostaglandins possibly due to the infused AII. Since plasma AII levels are high, the effects of blockade of the renin‐angiotensin system will be exaggerated and so the importance of AII as a modulator of sympathetic responses will be overestimated in this model.
Microinfusion of clonidine and yohimbine into locus coeruleus alters EEG power spectrum: effects of aging and reversal by phosphatidylserine
Authors: de Sarro G.B. , Bagetta G. , Ascioti C. , Libri V. , Nisticò G. 
Published: July 2012

The behavioural and electrocortical (ECoG) power spectrum effects of clonidine, and yohimbine, an agonist and an antagonist at α2‐adrenoceptors, after their unilateral microinfusion into the rat locus coeruleus (LC) in young (50–70 days old) and old (13–15 months old) rats were studied.
Clonidine (0.09, 0.19, 0.28 and 0.56 nmol) microinfused into the LC of young rats induced dose‐dependent behavioural and ECoG slow wave sleep (SWS) with a significant increase in total voltage power and power in the lower frequency bands. In contrast, yohimbine (1.3 and 2.6 nmol) infused into the LC of young rats produced ECoG desynchronization and a significant decrease in total voltage power.
In contrast to young rats, clonidine (0.19 and 0.28 nmol) given into the LC did not affect behaviour and the ECoG power spectrum in old rats. However, after higher doses of clonidine (0.56 and 1.2 nmol) a small and short‐lasting period of behavioural and ECoG SWS was still evident. Similarly, in old rats yohimbine, at a dose (1.3 nmol) which was stimulative in young animals, did not significantly affect behaviour and ECoG power spectrum. Higher doses of yohimbine (2.6 and 5.2 nmol) were required to induce behavioural and ECoG changes similar to those observed with lower doses of yohimbine in young rats.
Chronic treatment with phosphatidylserine (30mgkg−1, orally, daily for 21 and 30 days), was able gradually to restore in old rats, in comparison with a vehicle‐treated group, the responsiveness of α2‐adrenoceptors to clonidine and yohimbine given into the LC.
Biphasic effects of intra‐accumbens histamine administration on spontaneous motor activity in the rat; a role for central histamine receptors
Authors: Bristow L.J. , Bennett G.W. 
Published: July 2012

The effect of intra‐accumbens injection of histamine and related compounds on the spontaneous motor activity of the rat has been investigated.
Microinjections of histamine (1–200μg) induced dose‐dependent, biphasic changes in rat activity consisting of an initial brief hypoactivity response followed by a marked hyperactivity phase. The histamine metabolite, n‐tele‐methylhistamine was without effect.
Pretreatment with the H1‐receptor antagonist mepyramine (10 μg) blocked the hypoactivity response and markedly attenuated histamine‐induced hyperactivity. In contrast, pretreatment with the H2‐receptor antagonist SKF93479 had no effect on histamine‐induced behaviour.
Microinjection of the H1‐receptor agonist 2‐thiazolylethylamine induced a marked hyperactivity response, but unlike the response to histamine, there was no initial hypoactivity. The H2‐receptor agonist dimaprit had no apparent behavioural effects following intra‐accumbens injection.
Intra‐accumbens injection of the non‐selective histamine agonists nα‐methylhistamine or nα, nα‐dimethylhistamine induced both marked hypoactivity and hyperactivity responses which were comparable with the effects of histamine.
The present results demonstrate a histamine, H1‐receptor‐mediated arousal in the nucleus accumbens which follows transitory hypoactivity, possibly due to activation of presynaptic H3‐receptors.
Nifedipine kinetics in the rat and relationship between its serum concentrations and uterine and cardiovascular effects
Authors: Downing Sandra J. , Hollingsworth M. 
Published: July 2012

The kinetics of nifedipine and the relationship between its serum concentration and uterine and cardiovascular effects were investigated in 3 groups of animals. These were ovariectomized (ovx) anaesthetized non‐pregnant rats following bolus i.v. injection (400 μg kg−1) and during 300 min infusion (10 μg kg−1 min−1) and ovx, progesterone‐treated late pregnant rats during infusion. Also, the kinetics were determined in ovary‐intact late pregnant rats following bolus i.v. injection (400 μg kg−1).
Measurement of serum nifedipine concentrations after bolus i.v. injection in ovx non‐pregnant rats showed a biexponential decay with time from which the following parameters were calculated: Vβ= 300 ± 30 ml kg−1; rate constants k12 = 0.51 ± 0.18 min−1; k21 = 0.07 ± 0.02 min−1; kel = 0.10 ± 0.05 min−1; elimination clearance = 2.4 ± 0.2 (ml min−1)kg−1; t1/2α = 2.5 ± 1.0 min; t1/2β = 102 ± 15 min. In intact pregnant rats, a biexponential decay of serum nifedipine concentrations with time was also observed after bolus i.v. administration with similar parameters to non‐pregnant animals. These kinetic parameters, used to calculate serum nifedipine concentrations obtained during infusion, predicted values similar to experimental values for 180 min, but thereafter slightly underestimated experimental values.
Immediate reductions in uterine contractions, mean blood pressure and heart rate were observed following bolus i.v. injection of nifedipine to ovx non‐pregnant rats, with returns towards control values as serum nifedipine concentrations declined. IC15 values (15% change from baseline), calculated from log10 serum concentration‐response curves, of 0.3 ± 0.05 μg ml−1 for inhibition of uterine contractions, 0.8 ± 0.3 μg ml−1 for depression of blood pressure and 3.8 ± 1.0 μg ml−1 for reduction in heart rate were obtained.
In ovx non‐pregnant rats, nifedipine infusion produced a maximum reduction in integral of uterine contractions of 70% by 120 min and a maximum reduction of 15% in heart rate. Mean blood pressure was not significantly different from vehicle‐treated rats. IC15 values were 0.7 ± 0.1 μg ml−1 and 2.8 ± 0.6 μg ml−1 for inhibition of uterine contractions and heart rate respectively.
In ovx, progesterone‐treated late pregnant rats, nifedipine infusion produced similar serum concentrations to those of non‐pregnant rats but completely abolished uterine contractions by 70 min. Maximum reductions of 30% in heart rate and blood pressure were observed. IC15 values were 0.5 ± 0.1 μg ml−1 for uterine contractions, 0.9 ± 0.3 μg ml−1 for blood pressure and 1.2 ± 0.3 μg ml−1 for heart rate.
The findings suggest that the kinetics of nifedipine are similar in pregnant and non‐pregnant rats and support the idea that the drug exerts a slight selectivity for uterine inhibition relative to cardiovascular effects. The uterus of the late pregnant rat appears to be more sensitive to nifedipine than that of the non‐pregnant animal.
Tricyclic antidepressants block N‐methyl‐D‐aspartate receptors: similarities to the action of zinc
Authors: Reynolds Ian J. , Miller Richard J. 
Published: July 2012

Using the radioligand [3 H]‐MK801, we have examined drug interactions with the phencyclidine recognition site of the N‐methyl‐D‐aspartate receptor.
The trycyclic antidepressants desmethylimipramine and imipramine inhibited [3 H]‐MK801 binding with IC50 values of 7.4 and 22.5 μM, respectively. Other related tricyclic antidepressants and neuroleptics were also effective but less potent.
Desmethylimipramine, imipramine and chlorimipramine slowed the dissociation rate of [3 H]‐MK801 in a similar manner to Zn2+. Phencyclidine and related compounds had no effect on the dissociation rate of [3 H]‐MK801.
Desmethylimipramine, imipramine and ketamine also prevented the Ca2+ influx into cultured cortical neurones of the rat produced by N‐methyl‐D‐aspartate.
As the actions of tricyclic antidepressants in this system are not competitive with respect to N‐methyl‐D‐aspartate, glycine or MK‐801, and as they slow the dissociation of [3 H]‐MK801, we conclude that tricyclic antidepressants may be acting at the Zn2+ recognition site on the N‐methyl‐D‐aspartate receptor.
Stimulatory and inhibitory actions of excitatory amino acids on inositol phospholipid metabolism in rat cerebral cortex
Authors: Godfrey Philip P. , Wilkins C. Jason , Tyler Wendy , Watson Stephen P. 
Published: July 2012

The effects of excitatory amino acids on [3 H]‐inositol phosphate levels have been examined in rat cortical slices under basal conditions or following agonist stimulation.
Ibotenate and quisqualate provoked a substantial dose‐dependent (EC50, 30 μM and 20 μM respectively) increase in inositol phosphates; these responses were not additive suggesting a common site of action for the two amino acids. The responses to maximally effective concentrations of ibotenate and quisqualate were not blocked by verapamil, tetrodotoxin or Cd2+, indicating that these effects are not indirect. Small, but significant, increases in inositol phosphates were also seen with glutamate and N‐methyl‐DL‐aspartate (NMDLA); kainate and aspartate were ineffective.
Each excitatory amino acid tested reduced carbachol (1 mM) stimulated inositol phosphate formation. Kainate (IC50, 20 μM) and NMDLA (IC50, 20 μM) were the most effective inhibitors. Kainate also reduced the responses to noradrenaline, 5‐hydroxytryptamine and 20 mM K+.
The inhibitory action of NMDLA, but not kainate, could be reversed with the NMDA antagonists, DL‐2‐amino‐5‐phosphonovalerate (APV) and MK‐801; DL‐2‐amino‐4‐phosphonobutyrate (APB) was without effect. Since MK‐801 blocks the ion channels associated with the NMDA receptor, it appears that inhibition requires the entry of ions into the cell.
APV and MK‐801 potentiated the stimulatory response to ibotenate but had no effect on the response to quisqualate. Potentiation was presumably the result of blocking the inhibition by ibotenate mediated through NMDA receptors.
In conclusion, excitatory amino acids appear to reduce agonist‐mediated inositol phosphate formation in rat cerebral cortex by a non‐specific action, possibly including the influx of Na+ ions. In addition ibotenate and quisqualate substantially enhance inositol phosphate production: the pharmacology of the response suggests that it is mediated by a receptor distinct from previously defined excitatory amino acid receptor subtypes.
Evidence for dopaminergic co‐transmission in dog mesenteric arterial vessels
Authors: Soares‐da‐Silva P. 
Published: July 2012

The overflow of dopamine and noradrenaline (NA) from the main trunk of the dog mesenteric artery and its proximal branches during prolonged depolarization (120 min) by K+ (52 mM) was quantified by high performance liquid chromatography with electrochemical detection.
K+‐induced depolarization resulted in release of both dopamine and NA. The amount of NA released from both blood vessels declined progressively throughout the experiment. In the main trunk the same pattern of release was observed for dopamine, whereas in the proximal branches the overflow of dopamine increased throughout the experiment.
The addition of phentolamine (0.2 μM) to the perifusion fluid increased the overflow of both amines. In the presence of sulpiride (1 μM) the overflow of dopamine and NA was found to be increased in the proximal branches, but not in the main trunk. The addition of phentolamine to sulpiride caused a further increase in amine overflow in proximal branches, but not in the main trunk.
The addition of α‐methyl‐p‐tyrosine (50 μM) to the perifusion fluid caused a decrease in the amounts of dopamine and NA released from both preparations. In α‐methyl‐p‐tyrosine‐treated preparations phentolamine increased amine overflow to the same extent as in experiments without tyrosine hydroxylase inhibition. The increasing effect of sulpiride on the overflow of dopamine and NA from the proximal branches was completely abolished after α‐methyl‐p‐tyrosine.
The results presented suggest that in the proximal branches of the dog mesenteric artery, dopamine β‐hydroxylase represents a rate limiting step in the synthesis of NA; dopamine, through activation of prejunctional dopamine receptors acts like a prejunctional co‐transmitter in the control of transmitter release, but only newly‐synthesized dopamine appears to be responsible for this effect.