bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of NG‐nitro‐l‐arginine methyl ester on the cardiovascular system of the anaesthetized rabbit and on the cardiovascular response to thyrotropin‐releasing hormone
Authors: Seligsohn Eva E. , Bill Anders 
Published: July 2012

The effects of 300 mg kg−1 of the nitric oxide (NO) inhibitor NG‐nitro‐l‐arginine methyl ester (l‐NAME) on the regional blood flow, on the flow response to 1 mg kg−1 of thyrotropin‐releasing hormone (TRH) and on cerebral blood flow autoregulation were studied in urethane anaesthetized rabbits subjected to unilateral sectioning of the cervical sympathetic chain. The blood flow measurements were performed by the tracer microspheres method.
The cerebral arteriovenous difference in oxygen saturation (CAVOD) was measured before and after the administration of l‐NAME and TRH in order to ascertain whether the effects on cerebral blood flow that were observed were secondary to changes in cerebral metabolism.
l‐NAME caused a significant decrease in blood flow in several cerebral regions; CBFtot decreased to 72 ± 4% of control (P < 0.001). An increase in blood pressure and a concurrent decrease in heart rate and cardiac output were noted.
In the eye, l‐NAME caused a reduction in uveal blood flow which was more pronounced on the sympathetically intact side; in the retina the blood flow decreased to 50% of control on both sides.
The administration of TRH in animals pretreated with l‐NAME caused a significant increase in blood pressure and cerebral blood flow.
In l‐NAME‐treated animals the CBF was not affected when the mean arterial blood pressure was increased by ligation of the abdominal aorta.
The CAVOD increased from 56.0 ± 5.2 to 73.6 ± 3.5%, 20 min after the administration of l‐NAME. In animals given 1 mg kg−1 TRH after l‐NAME the CAVOD decreased to 54.6 ± 4.6%, 5 min after the injection of TRH.
The results of the present study indicate that endogenous NO is involved in the regulation of regional blood flow and blood pressure in the anaesthetized rabbit. The reduction in cerebral blood flow that was caused by l‐NAME was not due to a reduction in cerebral metabolism. An interaction between the NO synthesis/release/effect and the sympathetic nervous system was found in the uvea. There was no evidence for a major involvement of NO in the cardiovascular responses to TRH and autoregulation of cerebral blood flow was not abolished by l‐NAME.
Effects of heparin on the vasodilator action of protamine in the rabbit mesenteric artery
Authors: Akata Takashi , Kodama Kenji , Takahashi Shosuke 
Published: July 2012

The effects of protamine on the rabbit isolated small mesenteric artery were investigated both in the presence and in the absence of heparin, by the isometric tension‐recording method.
The dissociation constant for the binding of heparin to protamine has never been previously reported, so in order to minimize the effects of protamine, known to have a vasodilator action, and to examine only the effects of a heparin‐protamine complex, the experiments with heparin were performed in the presence of high concentrations of heparin (21–700 u ml−1), concentrations at which heparin itself does not affect the vascular tone.
Protamine (15–500 μg ml−1), in the absence of heparin, was found to inhibit (P < 0.05) noradrenaline (1 μm)‐induced contractions both in endothelium‐intact and in endothelium‐denuded tissues.
Such vasodilator action of protamine in either endothelium‐intact or ‐denuded tissues continued, even in the presence of excess heparin at a heparin/protamine (H/P) ratio of 1.4 uμg−1, but was almost completely blocked in the presence of a much greater excess of heparin (H/P ratio ≥ 4.7 u μg−1): heparin was present both before and during the application of protamine.
The vasodilator action of protamine in the absence of heparin was prolonged both in the endothelium‐intact and ‐denuded tissues after protamine had been washed out from the bath with Krebs solution. Although this washing out with a Krebs solution containing excess heparin (4.7 u ml−1) readily reversed such prolonged vasodilator action of protamine both in the endothelium‐denuded strips and in the endothelium‐intact strips which had been pretreated with inhibitors of the endothelium‐derived relaxing factor (EDRF) pathway, it did not affect the prolonged vasodilator action of protamine in the endothelium‐intact strips which received no pharmacological intervention.
These results suggest that: (1) only protamine, not a heparin‐protamine complex, exerts vasodilator action in vitro; (2) the vasodilator action of protamine presumably has an EDRF‐mediated component; and (3) protamine probably exerts its direct vasodilator action without entering the smooth muscle cell.
Vascular mode of action of kinin B1 receptors and development of a cellular model for the investigation of these receptors
Authors: Levesque Luc , Drapeau Guy , Grose John H. , Rioux Francis , Marceau François 
Published: July 2012

Kinins exert a contractile effect on rabbit aortic rings via the stimulation of B1 receptors. Des‐Arg9‐bradykinin (BK) is more potent than BK on this receptor type. The mode of action of des‐Arg9‐BK on rabbit aortic tissue has been studied by both the aortic ring contractility assay and a cellular model using cultured aortic smooth muscle cells (SMCs).
The des‐Arg9‐BK‐induced contractions in rabbit aortic rings were unaffected by pretreatments with nifedipine, indomethacin, REV‐5901 (a 5‐lipoxygenase blocker) and LY‐83583 (a guanylyl cyclase inhibitor); however, the protein kinase inhibitors H‐7 and H‐9 significantly reduced the maximal effect of des‐Arg9‐BK.
The contractile responses to des‐Arg9‐BK in calcium‐free Krebs solution were slightly but not significantly attenuated in amplitude, as compared to paired control tissues bathed in Krebs solution, and sustained plateaus of contraction were observed in the absence of Ca2+. However, Ca2+ replenishment further increased the kinin‐induced contraction measured in Ca2+‐free bathing fluid.
Despite the lack of evidence of a mediating role for prostaglandin in the mechanical response to des‐Arg9‐BK, the kinin stimulated the release of prostacyclin from rabbit aorta rings measured as immunoreactive 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α).
Smooth muscle cells (SMCs) derived from the rabbit aorta exhibit functional responses to des‐Arg9‐BK in acute release of 6‐keto‐PGF1α and of inositol phosphate turnover which were inhibited by pretreatment with the B1 receptor antagonist, Lys[Leu8]des‐Arg9‐BK, but not by the B2 receptor antagonist, Hoe‐140. Preincubation of the cells with interleukin‐1 (IL‐1) 20 h before stimulation with the kinin had no effect on basal inositol phosphate turnover, but potentiated the acute effect of des‐Arg9‐BK.
These results suggest that second mesengers derived from the action of phospholipase C are produced by SMCs when B1 receptors are activated in rabbit aortic tissue. Intracellular calcium stores are primarily mobilized by des‐Arg9‐BK, although receptor‐controlled calcium influx has not been ruled out, and may contribute to initiate the contractile responses. The maintenance of the contractile state involves protein kinase C activity and is consistent with a current model of SMC function. The cell model retains some of the cardinal properties of B1 receptor‐mediated vascular responses: endothelium‐independent PGI2 release and up‐regulation by the cytokine IL‐1. PGI2 is not involved in the mechanical response, possible because the rabbit aorta is refractory to this prostaglandin.
The effects of α‐adrenoceptor agonists on intracellular Ca2+ levels in freshly dispersed single smooth muscle cells from rat tail artery
Authors: Li Xiao‐Fang , Kargacin Margaret E. , Triggle Christopher R. 
Published: July 2012

The presence of functional α‐adrenoceptors in freshly dispersed single smooth muscle cells from rat tail arteries was investigated by use of selective α‐adrenoceptor agonists and antagonists.
Cirazoline, a selective α1‐adrenoceptor agonist, caused a prazosin‐sensitive, rapid but transient increase in intracellular Ca2+, which was partially inhibited by the voltage‐dependent Ca2+ channel blocker, nifedipine.
TL99, an α2‐adrenoceptor agonist, in the presence of prazosin, initiated a slow and sustained increase in intracellular Ca2+ which was partially inhibited by yohimbine and almost completely blocked by nifedipine.
In rat tail artery, the effects (dose‐response and time‐response curves) of cirazoline and TL99 on intracellular Ca2+ levels in freshly dispersed single smooth muscle cells were comparable with those obtained with organ bath studies of ring preparations of artery.
In freshly dispersed single smooth muscle cells, the time‐course response curves induced by the selective α1‐adrenoceptor agonist, phenylephrine and the selective α2‐adrenoceptor agonist, UK14304, were similar to those observed with cirazoline and TL99, respectively.
These results indicate that: (a) functional α1‐ and α2‐adrenoceptors are present in freshly dispersed single smooth muscle cells from rat tail artery and (b) α1‐ and α2‐adrenoceptors are coupled to different cellular processes that lead to an increase in intracellular Ca2+.
Lack of effect of L‐687,414 ((+)‐cis‐4‐methyl‐HA‐966)5 an NMDA receptor antagonist acting at the glycine site, on cerebral glucose metabolism and cortical neuronal morphology
Authors: Hargreaves R.J. , Rigby M. , Smith D. , Hill R.G. 
Published: July 2012

N‐methyl‐d‐aspartate (NMDA) receptor ion channel antagonists have been reported to cause pronounced increases in cerebral glucose metabolism (CMRglc) and transient reversible vacuolation within pyramidal cortical neurones. The present studies examined in rats the effects of the NMDA receptor antagonist, L‐687,414 (R‐(+)‐cis‐4‐methyl‐3‐amino‐l‐hydroxypyrolid‐2‐one; (+)‐cis‐4‐methyl‐HA‐966) on regional CMRglc and cortical neuronal morphology.
L‐687,414 was given as a steady state intravenous infusion for 4 h in a neuroprotective dose regime of 17.5 mg free base kg−1 bolus followed by 225 μg kg−1 min−1 (n = 8) or at the higher dose rate of 35 mg kg−1 bolus followed by 440 μg kg−1 min−1 (n = 10). Data were compared to a parallel series of experiments in rats given the NMDA receptor ion channel antagonist, dizocilpine for 4 h in the optimum intravenous neuroprotective dose‐regime of 0.12 mg kg−1 bolus followed by 1.8 μg kg−1 min−1 (n = 8) or at the higher dose rate of 0.4 mg kg−1 bolus followed by 6 μg kg−1 min−1 (n = 4; morphology only studied). A saline‐infused group of rats (n = 8) were used as controls.
CMRglc was studied by use of [14C]‐2‐deoxyglucose and autoradiography (n = 4 each group) whilst plasma drug levels were in a steady state during the final 45 min of the 4 h drug infusion. Effects on cortical neuronal morphology were assessed at the end of the 4 h infusion period using light microscopic techniques (n = 4–6 each group).
The results showed a selective activation of limbic CMRglc by dizocilpine at optimal neuroprotective dose levels and showed that this dose was at the threshold for the neuronal vacuolation response as 1 of 4 rats showed morphological changes in the pyramidal neurones in the posterior cingulate and retrosplenial cortices. At the higher dose rate of dizocilpine, all 4 animals showed extensive morphological changes in these cortical neurones. In contrast, L‐687,414 did not increase limbic CMRglc nor evoke vacuolation when given in the neuroprotective dose‐regime or at the higher dosage rate.
The findings of the present study suggest that neuroprotection mediated through the NMDA receptor complex can be achieved without changes in CMRglc or cortical neuronal morphology by antagonism at the glycine modulatory site.
Effect of heparin and a low‐molecular weight heparinoid on PAF‐induced airway responses in neonatally immunized rabbits
Authors: Sasaki Masahiro , Herd Caroline M. , Page Clive P. 
Published: July 2012

We have investigated the effect of an unfractionated heparin preparation, a low‐molecular weight heparinoid (Org 10172) and the polyanionic molecule polyglutamic acid against PAF‐induced airway hyperresponsiveness and pulmonary cell infiltration in neonatally immunized rabbits in vivo.
Exposure of neonatally immunized rabbits to aerosolized platelet activating factor (PAF) (80 μg ml−1 for 60 min) elicited an increase in airway responsiveness to inhaled histamine 24 h and 72 h following challenge which was associated with an infiltration of inflammatory cells into the airways, as assessed by bronchoalveolar lavage (BAL).
A significant increase in the total numbers of cells recovered from BAL fluid was associated with significantly increased cell numbers of neutrophils, eosinophils and mononuclear cells 24 h following PAF exposure. The numbers of eosinophils and neutrophils in the airways remained elevated 72 h after challenge.
The intravenous administation of an unfractionated preparation of heparin (100 units kg−1) or Org 10172 (100 μg kg−1) 30 min prior to PAF exposure significantly inhibited the airway hyperresponsiveness induced by PAF, 24 h and 72 h following challenge. PAF‐induced hyperresponsiveness was not significantly affected by prior intravenous administration of polyglutamic acid (100 μg kg−1).
The intravenous administration of unfractionated heparin (100 units kg−1), Org 10172 (100 μg kg−1) or polyglutamic acid (100 μg kg−1) 30 min prior to PAF exposure significantly inhibited the expected increase in total cell infiltration.
This study shows that unfractionated heparin and a low‐molecular weight heparinoid, Org 10172, are capable of inhibiting both the airway hyperresponsiveness and pulmonary cell infiltration induced by PAF in the rabbit.
The effect of platelet‐activating factor on the responsiveness of the human nasal airway
Authors: Austin C.E. , Foreman J.C. 
Published: July 2012

The effects of inhaled platelet‐activating factor (PAF) on responsiveness of the human nasal airway were examined in normal subjects by measuring nasal airway resistance in response to histamine and bradykinin at 2, 6, 24, 48 h and 7 d after PAF administration. Eosinophil cationic protein (ECP) in nasal secretions was also measured.
Intranasal aerosol administration of PAF, 30 or 60 μg per nostril to normal human subjects induced an increased responsiveness to inhaled histamine, 50 to 400 μg and bradykinin, 100 μg per nostril at 2, 6 and 24 h following PAF treatment. However the effect was not apparent at 48 h or 7 days after PAF administration.
Intranasal administration of lyso‐PAF, 60 μg by aerosol did not increase the reactivity of the nasal airway in response to histamine, 200 μg.
There was no difference in the time course of the PAF‐induced hyperresponsiveness to histamine or bradykinin.
PAF‐induced nasal hyperresponsiveness at 2 and 6 h was associated with increases in the ECP concentration of the nasal lavage fluid.
Vitamin E pretreatment of subjects resulted in the attenuation of the PAF‐induced hyperresponsiveness to histamine, and a decrease in ECP levels of the nasal lavage fluid.
The results suggest that in the human nasal airway, PAF induces a non‐specific hyperresponsiveness which is accompanied by eosinophil activation in the nasal cavity. Free radical production induced by PAF may contribute to the hyperresponsiveness and the activation of eosinophils.
Relation between α1‐adrenoceptor subtypes and noradrenaline‐induced contraction in rat portal vein smooth muscle
Authors: Sayet Irène , Neuilly Ghislaine , Rakotoarisoa Lala , Mironneau Chantal , Mironneau Jean 
Published: July 2012

In vascular smooth muscle, α1‐adrenoceptors have been classified recently into two or three subtypes. We examined which α1‐adrenoceptor subtypes are involved in the noradrenaline‐induced contraction of rat portal vein smooth muscle.
Binding studies with [3H]‐prazosin in membranes from equine portal vein smooth muscle revealed the presence of two distinct affinity binding sites. The high‐affinity site for [3H]‐prazosin was also identified in intact strips of rat portal vein. Prazosin, HV723 (α‐ethyl‐3,4,5‐trimethoxy‐α‐(3‐((2‐(2‐methoxyphenoxy)ethyl)‐amino)‐propyl) benzene‐acetonitrile fumarate), WB4101 (2‐(2,6‐dimethoxyphenoxyethyl)aminomethyl‐1,4‐benzodioxane), 5‐methylurapidil, phentolamine and yohimbine antagonized [3H]‐prazosin binding at both types of sites. Pretreatment with 50 μm chloroethylclonidine (CEC) eliminated the high‐affinity sites for prazosin but had no effect on the low‐affinity sites.
Noradrenaline produced a concentration‐dependent contraction in the rat portal vein. Pretreatment with 50 μm CEC induced a slight rightward displacement of the concentration‐response curve but the maximal contraction was not significantly affected suggesting that the CEC‐sensitive α1‐adrenoceptors played a minor role in the noradrenaline‐induced contraction. Prazosin, WB4101 and HV723 produced a concentration‐dependent inhibition of noradrenaline‐induced contractions. The inhibition curves were little affected by CEC‐pretreatment and yielded a relative order of potency of WB4101 > prazosin > HV723.
In the presence of 0.1 μm isradipine to block voltage‐dependent Ca2+ channels, the noradrenaline‐induced contraction is due to release of Ca2+ ions from agonist‐sensitive intracellular Ca2+ stores. Under these conditions, the noradrenaline‐induced contraction was not significantly affected by pretreatment with 50 μm CEC but was inhibited by the antagonists mentioned above with affinities different from those in the absence of isradipine. The rank order of potency became HV723 ≥ WB4101 > prazosin.
The present results indicate the existence of two distinct α1‐adrenoceptor subtypes in rat portal vein smooth muscle, which show high‐ and low‐affinities respectively for each of prazosin, WB4101 and HV723 and correspond to α1H‐ and α1L‐adrenoceptor subtypes. According to recent α1‐adrenoceptor subclassifications, the α1H‐adrenoceptor subtype which is sensitive to inactivation by CEC may correspond to the α1B‐adrenoceptor subtype. The contraction induced by noradrenaline seems to be predominantly mediated through the α1L‐adrenoceptor subtypes which may include the α1N‐adrenoceptor subtype, as recently proposed.
Effect of adrenoceptor agonists on striated muscle strips of the canine oesophagus
Authors: Tokuhara Taigo , Meulemans Ann L. , De Ridder Walter J.E. , Higashino Masayuki , Kinoshita Hiroaki , Schuurkes Jan A.J. 
Published: July 2012

Acute psychological stress, which could be related to the release of a large amount of catecholamines, may cause oesophageal motility disorders. Therefore, the aim of our study was to elucidate the influence of adrenoceptor agonists on the striated muscle portion of the oesophagus by use of isolated strips from dogs.
Contractions were evoked in isolated striated muscle strips by electrical field stimulation (1 pulse min−1, 1 ms/pulse, submaximal voltage). The effects induced by administration of adrenoceptor agonists alone or in the presence of antagonists were tested to determine the nature of the adrenoceptors on this muscle preparation.
The administration of both the natural adrenoceptor agonists, adrenaline and noradrenaline, and the synthetic β‐adrenenoceptor agonists, isoprenaline (β1 + β2), dobutamine (β1) or ritodrine (β2), enhanced the amplitude of the contractions induced by electrical stimulation in a concentration‐dependent manner. The maximum responses were 82.6 (adrenaline), 66.2 (noradrenaline), 86.2 (isoprenaline), 34.6 (dobutamine) and 80.8% (ritodrine). The EC20 values obtained were respectively 2 nm, 0.2 μm, 0.91 nm, 3 μm and 80 nm. The administration of the α1‐adrenoceptor agonist, phenylephrine, also enhanced the contractile response in a concentration‐dependent manner (EC20 value = 0.3 μm) and the maximum response was 64.6%, but the administration of the α2‐adrenoceptor agonist, clonidine, did not influence the contractile response. These data suggest the involvement of β2‐ and possibly α1‐adrenoceptors in the responses of these adrenoceptor agonists.
The selective β2‐adrenoceptor antagonist ICI 118551 (3–100 nm) shifted the concentration‐effect curves for noradrenaline, phenylephrine and ritodrine to the right in a concentration‐dependent manner. ICI 118551 (3 nm) also shifted the concentration‐effect curves for adrenaline and isoprenaline to the right, but increasing the concentration of ICI 118551 did not cause any further antagonist activity until a concentration of 100 nm, when a further rightward shift was obtained.
The selective α1‐adrenoceptor antagonist, prazosin (30–300 nm), did not affect the increased contractile responses induced by adrenaline, noradrenaline, phenylephrine, isoprenaline or ritodrine.
In conclusion, it appears that β2‐adrenoceptors are present in the striated muscle portion of the canine oesophagus, where they mediate an enhancement of contractile responses evoked by electrical stimulation. The α1‐agonist, phenylephrine, appears to interact with β2‐adrenoceptors on this preparation. β3‐Adrenoceptors have already been demonstrated in smooth muscle from various parts of the gastrointestinal tract, and our study does not exclude the possibility that there is an additional population of β3‐receptors in the canine striated muscle part of the oesophagus.
Effects of excitatory neurotransmitters on Ca2+ channel current in smooth muscle cells isolated from guinea‐pig urinary bladder
Authors: Nakayama S. 
Published: July 2012

A whole‐cell voltage clamp technique was used to examine the effects of purinoceptor and muscarinic receptor agonists on voltage‐sensitive Ca2+ channels in guinea‐pig isolated urinary bladder cells.
When the cell membrane was clamped at the holding potential, rapid application of ATP elicited a large inward current in normal solution containing 2.5 mm Ca2+, and reduced the subsequent Ca2+ channel current evoked by a depolarizing pulse (0 mV). Carbachol (CCh) elicited little membrane current, but similarly reduced the Ca2+ current.
When purinoceptor agonists were rapidly applied during conditioning depolarizations at +80 mV, an outward current was elicited, and the Ca2+ channel current evoked by the subsequent test potential of 0 mV was not affected. Application of CCh at +80 mV also elicited an outward current, but it reduced the subsequently evoked Ca2+ current.
The inhibitory effect of muscarinic agonists on the Ca2+ channel current was attenuated by caffeine (10 mm).
In Ca2+‐free, low‐Mg2+ solution, a Na+ current flowing through voltage‐dependent Ca2+ channels was evoked by depolarization. This current was not reduced by bath application of purinoceptor agonists (ATP and α,β‐methylene ATP).
These results suggest that the main effect of purinoceptor stimulation is opening of non‐selective cation channels, and that muscarinic stimulation triggers Ca2+ release from intracellular stores. Voltage‐sensitive Ca2+ channels are inactivated through an increase in intracellular Ca2+ induced by either activation of purinoceptor or muscarinic receptors.