Biomedical subjects

J S Lacroix

Publications and source records attributed to J S Lacroix.

At least 37 records · Page 2Linked to original sources

PubMed2000

[Effect of intranasal treatment with capsaicin on polyp recurrence after polypectomy and ethmoidectomy].

OBJECTIVE: To evaluate the influence of polypectomy and anterior ethmoidectomy associated with intranasal applications of capsaicin on the recurrence of nasal polyps. METHOD: Fifty one patients (19 females, 32 males, mean age 43) undergoing polypectomy and anterior ethmoidectomy were included in the study. In 29 patients, a cotton pellet soaked with capsaicin (3 x 10(-6) mol, dissolved in 70% ethanol) was left into the middle meatus for 20 min under local anaesthesia. As a control group, 22 patients were treated with the capsaicin vehicle alone (70% ethanol). All patients studied received the intranasal capsaicin or vehicle treatment once a week for 5 weeks. The clinical objective examination and the subjective evaluation of nasal obstruction, rhinorrhea were recorded by means of a visual analogic scale graded from 0 to 4 throughout the study. RESULT: Patients treated with intranasal capsaicin application reported 9 months later and 55 months later separately, a marked reduction of their subjective evaluation of nasal obstruction when compared to the pretreatment evaluation (P < 0.01). In contrast, patients treated with the capsaicin vehicle alone did not have any significant improvement of their subjective evaluation of nasal obstruction. Subjective rhinorrhea was not modified by either treatment. Of 29 patients with capsaicin treatment, 25 (86.2%) patients (9 months later) and 20 (69%) patients (55 months later) showed satisfactory result, compared to 10 (45.4%) patients and 8 (36.4%) patients separately in the control group, the difference was significant (P < 0.01). CONCLUSION: Intranasal capsaicin application can reduce polyp recurrence and nasal obstruction after polypectomy and ethmoidectomy.

Administration, Intranasal↗

PubMed1999

CGRP 27-37 analogues with high affinity to the CGRP1 receptor show antagonistic properties in a rat blood flow assay.

CGRP Y0-28-37 is known as a selective CGRP1 receptor antagonist. We succeeded in optimising the CGRP1 receptor affinity of this fragment by multiple amino acid replacement. The analogues [p34, F35]CGRP 27-37 and [D31, p34, F35]CGRP 27-37 exhibit a 100-fold increased affinity compared to the unmodified segment. Receptor binding studies were performed with human neuroblastoma cells SK-N-MC, which selectively express the hCGRP1 receptor. Blood flow, which is increased by exogenous CGRP, was measured in the right femoral artery. Preincubation of the rats with [p34, F35]CGRP 27-37 and [D31, p34, F35]CGRP 27-37 led to a significant decrease in CGRP induced increase in vascular conductance indicating the antagonistic properties of these compounds. Interestingly, an exchange of the amino acid Asn31 to Asp31 in [p34, F35]CGRP 27-37 shortened the period of the antagonistic effect significantly, suggestive of a different rate of metabolism for the two ligands. Secondary structure investigations obtained by circular dichroism measurements revealed that an increase in ordered structure correlates with high binding affinity.

Animals↗

PubMed1999

Influence of TASP-V, a novel neuropeptide Y (NPY) Y2 agonist, on nasal and bronchial responses evoked by histamine in anaesthetized pigs and in humans.

1. In nine anaesthetized pigs we have studied the influence of intranasal or intrabronchial pretreatment with TASP-V, a neuropeptide Y (NPY) Y2 agonist formed by the attachment of NPY 21-36 to a template-assembled synthetic peptide (TASP), on the functional responses to subsequent intranasal or intrabronchial histamine challenge. 2. In a parallel study, subjective and objective nasal airway resistance (NAR) increase following intranasal histamine challenge was evaluated in 11 healthy volunteers after TASP-V or placebo pretreatment. 3. In pigs, increase in sphenopalatine blood flow induced by histamine dihydrochloride nasal spray (0.25 mg kg(-1) in 3 ml of saline) was significantly reduced by 65% (P<0.05) following intranasal pretreatment with 10 microg kg(-1) of TASP-V. Bronchoconstriction induced by histamine dihydrochloride nebulization (0.5 mg kg(-1) in 3 ml of saline) was significantly attenuated by 25 and 55% following aerosolized pretreatment with TASP-V analogue at 10 and 20 microg kg(-1), respectively. 4. In healthy volunteers, objective increase in NAR and reduction in nasal minimal cross section area (MCSA) induced by intranasal spray of histamine dihydrochloride (15 microg kg(-1) in 200 microl of saline) were significantly attenuated by 50% following local pretreatment with 1.275 microg kg(-1) of TASP-V when compared with saline. 5. It is concluded that intranasal or intrabronchial pretreatment with TASP-V reduced nasal obstruction and bronchoconstriction evoked by histamine challenge in the pig. In healthy human volunteers, this agent attenuated NAR increase and MCSA reduction induced by intranasal application of histamine.

Adult↗

PubMed1999

Nasonasal reflex mechanisms in anaesthetized dogs.

In dogs anaesthetized with pentobarbitone, we recorded bilateral vascular and secretory responses to unilateral stimulation of intranasal afferent nerves. Nasonasal reflexes evoked by intranasal light mechanical stimulation, intranasal application of cold saline (2 ml at 3 degrees C), capsaicin (0.003-0.3 mmol) and antidromic electrical stimulation (15 V, 0.2 ms) of the trigeminal nerve at 10 Hz for 45 s were recorded. Vascular and secretory responses were studied before and after atropine pre-treatment, after ipsilateral section of the post-ganglionic parasympathetic fibres and the trigeminal nerve, and after administration of the ganglionic nicotinic receptor antagonist chlorisondamine. All stimuli studied induced bilateral increases in nasal arterial blood flow and secretion, although the contralateral responses were smaller under control conditions (p < 0.05). Bilateral vasodilatation evoked by mechanical stimulation, capsaicin and antidromic trigeminal nerve stimulation was resistant to atropine. The ipsilateral non-cholinergic vasodilatation evoked by mechanical stimulation or capsaicin was reduced by 50% (p < 0.05) after section of both trigeminal and post-ganglionic parasympathetic fibres. The remaining ipsilateral vasodilatation induced by these two stimuli was significantly reduced after chlorisondamine. The ipsilateral secretory responses to all stimuli studied were significantly reduced (p < 0.05), but not abolished by atropine. Contralateral secretory responses to all stimuli studied were not affected by atropine, the section of either the parasympathetic or trigeminal nerves, or chlorisondamine, suggesting the activation of local axon reflexes only. We conclude that unilateral intranasal stimulation of primary afferent neurons with light pressure, cold saline and capsaicin induces bilateral vascular and secretory responses via axon reflex mechanisms, as well as the activation of local and central sensory-parasympathetic reflex arcs.

Anesthesia, General↗

PubMed1999

Different ion channel control pH6-induced bronchoconstriction and calcitonin gene-related peptide release in the guinea-pig lung.

We have studied the bronchoconstriction and the release of calcitonin gene-related peptide-like immunoreactivity induced by perfusion of pH6 buffer in the isolated guinea-pig perfused lung. Both bronchoconstriction and peptide release were completely abolished after systemic capsaicin pretreatment. Ca(2+)-free pH6 buffer infusion also completely inhibited the bronchial response, whereas the calcitonin gene-related peptide-like immunoreactivity overflow was significantly reduced. omega-Conotoxine and omega-agatoxin IVA known as N-, L- and P-type Ca2+ channel blocker, respectively, and the Na+ channel blocker tetrodotoxin decreased significantly the pH6-induced bronchial response and calcitonin gene-related peptide like immunoreactivity overflow. Nifedipine was without influence suggesting the involvement of both P- and N-type Ca2+ channel as well as the activation of an axon reflex. Ruthenium red had a more pronounced reduction effect on the functional response than on the peptide release. Ryanodine and caffeine are both agents known to influence Ca2+ release from sarcoplasmic reticulum. Ryanodine significantly reduced both bronchoconstriction and calcitonin gene-related peptide-like immunoreactivity overflow. Caffeine as well as theophylline and the Na(+)-H+ blocker, dimethylamiloride, largely depressed the functional response while producing a significant increase of calcitonin gene-related peptide-like immuno-reactivity basal value. The pH6-induced peptide overflow was slightly inhibited after caffeine and dimethylamiloride pre-treatment whereas no significant change was observed after theophylline. It is concluded that multiple ion channels including different type of Ca2+ channels appear to participate in pH6-induced bronchoconstriction and calcitonin gene-related peptide-like immunoreactivity release in the guinea-pig lung.

Animals↗

PubMed1999

[Environment and nasal hyperreactivity].

The nasal mucosa is densely innervated by sensory nerve fibres which play an important part in the protection of the lower airways. Protective reflexes such as sneezing, secretion and nasal congestion can be elicited by exogenous noxious particles and numerous airborne irritants. The functions of the nasal mucosa is influenced at least in part, by biologically active neuropeptides that are released from sensory nerves endings. These sensory neuropeptides are involved in local vasodilatation, vascular permeability and mucus secretion. In addition, these neuropeptides are chemotactic for inflammatory cells such as eosinophiles and granulocytes. Therefore, neuropeptides of sensory origin are most likely involved in the pathophysiological mechanisms of specific (allergy) as well as non specific nasal hyperreactivity.

Capillary Permeability↗

PubMed1998

Inhibition of vagal vasodilatation by a selective neuropeptide Y Y2 receptor agonist in the bronchial circulation of anaesthetised dogs.

Neuropeptide Y (NPY) is both co-stored and co-released with noradrenaline from sympathetic nerve terminals. In the cardiovascular system, NPY acts on two main receptor subtypes. At postjunctional, or Y1 receptors, NPY can cause both direct vasoconstriction and the potentiation of various constrictor agents. NPY acting at the presynaptic, or Y2 receptor, inhibits the release of neurotransmitter from autonomic nerves. In the present paper, we have used both sympathetic stimulation and the selective NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31] NPY24-36, to examine the role of NPY in the inhibition of vagally mediated vasodilatation in the bronchial circulation of the anaesthetised dog. Stimulation of the cardiac end of the cervical vagus nerve at 1 Hz for 15 s (1 ms, 70 V) increased bronchial vascular conductance by 45%. This increase in flow was abolished by atropine. Sympathetic stimulation for 2.5 min at 16 Hz (1 ms, 20 V) produced a significant (P < 0.05) and prolonged (9 min) inhibition of the subsequent parasympathetically evoked vasodilatation. Similarly, the NPY Y2 receptor agonist, N-acetyl [Leu28,Leu31] NPY24-36, produced a significant (P < 0.05) and prolonged (15 min) inhibition of parasympathetically evoked vasodilatation. When vagus was stimulated at 2.5 Hz for 30 s (1 ms, 70 V), an atropine-resistant, but capsaicin-sensitive vasodilatation was observed. Neither sympathetic stimulation nor the NPY Y2 receptor agonist could be demonstrated to inhibit this vasodilatation. These results suggest that NPY can inhibit cholinergic parasympathetic vasodilatation in the bronchial circulation by an action on NPY Y2 receptors.

Anesthesia↗

PubMed1998

Nitric oxide and parasympathetic vascular and secretory control of the dog nasal mucosa.

Nasal vascular and secretory responses to local intra-arterial injection of acetylcholine (ACh) and vasoactive intestinal polypeptide (VIP) and to electrical stimulation of the nasal parasympathetic nerve fibres were recorded in dogs anaesthetized with pentobarbital. The influence of pretreatment with atropine and propranolol and the nitric oxide synthetase (NOS) inhibitor Nomega-nitro-L-arginine (L-NNA) was analysed. As a marker for NOS, NADPH-diaphorase (NADPH-d) histochemistry was studied in the sphenopalatine ganglion, trigeminal nerve and nasal mucosa. Local intra-arterial infusion of ACh and VIP evoked dose-dependent vasodilatation and nasal secretion which were not modified in the presence of L-NNA. The NO donor nitroprusside induced dose-dependent vasodilatation but no secretion. Atropine did not reduce the vasodilatation evoked by the parasympathetic nerve stimulation, but did reduce the secretory response by 55% (p < 0.05). During L-NNA infusion, the atropine-resistant vasodilatation evoked by parasympathetic nerve stimulation was reduced by a further 80% (p < 0.01) and the non-cholinergic secretory response was reduced by a further 30% (p < 0.05). Simultaneous infusion of the NO donor nitroprusside reversed the secretory response but not the vasodilator response to parasympathetic nerve stimulation. Histochemical studies revealed that NADPH-d activity was co-localized with VIP in parasympathetic axons. These observations suggest that NO could act as a non-cholinergic parasympathetic neurotransmitter in the vascular and secretory control of the dog nasal mucosa.

Acetylcholine↗

PubMed1998

Prejunctional control of pH 6-induced bronchoconstriction by NK1, NK2, mu-opioid, alpha2-adrenoceptor and glucocorticoid receptors in guinea-pig isolated perfused lung.

This study investigated the release of calcitonin-gene related peptide-like (CGRP) immunoreactivity and bronchoconstriction induced by pH 6 buffer in guinea-pig isolated perfused lung. Both pH 6-induced CGRP-like immunoreactivity and bronchoconstriction were completely abolished after systemic pretreatment with capsaicin. Pretreatment with the NK2 receptor antagonist SR 48968 (5 x 10(-7)M) completely inhibited bronchoconstriction and significantly reduced the immunoreactivity induced by the pH 6 buffer. The NK1 antagonist SR 140333 (5 x 10(-7)M) and, to a lesser extent the NK1 antagonist CP 96345, morphine (5 x 10(-6)M), the alpha2-adrenoceptor agonist UK 14304 (10(-7)M) and betamethasone (10(-6)M) significantly reduced both pH 6-induced bronchial response and CGRP-like immunoreactivity overflow. The effects of morphine and UK14304 were partially reversed by naloxone (5 x 10(-5)M) and idazoxan (5 x 10(-50M). Therefore, NK1, NK2, mu-opioid, alpha2-adrenoceptor and glucocorticoid receptors seemed to have a prejunctional action on pH 6 buffer-induced CGRP-like immunoreactivity and bronchoconstriction.

Adrenergic alpha-2 Receptor Agonists↗

PubMed1997

Sympathetic and parasympathetic interaction in vascular and secretory control of the nasal mucosa in anaesthetized dogs.

1. In dogs anaesthetized with pentobarbitone, electrical stimulation of the parasympathetic nerve fibres to the nasal mucosa evoked frequency dependent increases in both nasal arterial blood flow and nasal secretion. Blood flow was measured using a transonic flow probe placed around the artery. 2. Sympathetic nerve stimulation for 3 min at 10 Hz evoked significant and prolonged (> 30 min) attenuation of the vasodilator and secretory responses to subsequent parasympathetic stimulation. 3. Intravenous and intranasal administration of the neuropeptide Y (NPY) analogue N-acetyl [Leu28,Leu31] NPY 24-36, a selective NPY Y2 receptor agonist (20 nmol kg-1), significantly attenuated both vasodilator and secretory effects of subsequent parasympathetic nerve stimulation. When given intravenously, the inhibitory effect of this Y2 receptor agonist on vascular and secretory effects of parasympathetic nerve stimulation was rapid in onset (5 min) and lasted for more than 60 min. The modulatory effect of the Y2 receptor agonist was also seen with intranasal administration, but was slower in onset (15 min), and lasted less than 45 min. The effects of the intranasal pretreatment with the Y2 receptor agonist were significantly prolonged in the presence of the endopeptidase inhibitor phosphoramidon (10 nM). 4. Atropine pretreatment did not significantly reduce the change in vascular conductance evoked by parasympathetic nerve stimulation. Subsequent pretreatment with the NPY Y2 receptor agonist N-acetyl [Leu28,Leu31] NPY 24-36 reduced the stimulation induced increase in conductance by 30%. Nasal secretion was reduced by 70% following pretreatment with atropine and a further 30% by pretreatment with the NPY Y2 receptor agonist. Dose dependent vasodilator and secretory effects of local intra-arterial infusion of acetylcholine and vasoactive intestinal peptide were not modified by the NPY Y2 agonist. 5. Total protein and albumin concentration were measured in nasal lavage fluid collected after nerve stimulation. Atropine pretreatment increased the percentage of the total protein that was albumin in nasal lavage fluid. Neither sympathetic nerve stimulation nor Y2 receptor agonist pretreatment further modified the albumin exudation (a marker of vascular permeability) in nasal fluid lavage collected after parasympathetic nerve stimulation. 6. We propose that sympathetic nerve stimulation releases NPY, which acts on Y2 receptors, probably located on parasympathetic nerve endings, to attenuate both vasodilatation and nasal secretion evoked by subsequent parasympathetic nerve stimulation. This effect is also observed after pretreatment with the Y2-selective NPY analogue N-acetyl [Leu28,Leu31] NPY 24-36.

Administration, Intranasal↗

PubMed1997

A new device for in vivo measurement of nasal transepithelial potential difference in cystic fibrosis patients and normal subjects.

Measurement of transepithelial potential difference (PD) on the nasal mucosa has been proposed to test for defective ion transport in cystic fibrosis (CF), and its possible correction after gene therapy or other treatments. The "classical" method records nasal PD under the inferior turbinate, with the disadvantage that the tip of the electrode is not seen by the operator. We have developed a purpose-designed perfusion electrode for PD recording on the visible, medial/posterior aspect of the turbinate. We wanted to determine whether such PD recordings adequately discriminate between CF patients and normal subjects. Measurements of baseline PD and response to a standardized perfusion protocol were performed in 20 normal subjects and 12 CF patients. Solutions of amiloride, with or without low chloride buffer were applied for 3 min. Increased baseline PD and depolarization after amiloride discriminated CF patients from normal subjects. Only one CF patient overlapped with the normal range. Superfusion of low chloride buffer with amiloride and terbutaline caused repolarization in 18 out of 20 normal subjects (90%), consistent with physiological Cl- secretion process, but in none of the CF patients. We conclude that measurements of potential difference on the medial/posterior aspect of the turbinate can discriminate between cystic fibrosis patients and normal subjects. At this site, visual control of the measurement is possible, and the mucosa is easily accessible for subsequent cytological sampling or biopsy.

Adult↗

PubMed1997

Post-exercise nasal vasoconstriction and hyporeactivity: possible involvement of neuropeptide Y.

Neuropeptide Y (NPY) is co-localized with noradrenaline (NA) in perivascular sympathetic nerve and is a vasoconstrictor. Pre-treatment with exogenous NPY markedly reduced nasal airway obstruction and rhinorrhea induced by the irritant capsaicin in control subjects. The aim of the present experiments was to study the time course variations of plasma concentrations of NA and NPY during and after intense exercise in 17 healthy volunteers. In parallel, changes in nasal airway resistance (NAR) were recorded. Nasal obstruction and rhinorrhea induced by capsaicin were compared after 30 min of rest and after 30 min of exercise. Both subjective and objective NAR were significantly reduced (p < 0.05) for over 15 min after the end of exercise. Plasma levels of NPY remained increased for more than 15 min after exercise whereas NA returned to basal values within less than 10 min. The increases of NAR and mucus production evoked by capsaicin were markedly attenuated for 30 min after exercise (p < 0.05). Variations of plasma NPY concentrations over time correlated better with post-exercise nasal vasoconstriction and hyporeactivity to capsaicin than NA. These observations suggest that endogenous NPY could be involved in the prolonged post-exercise nasal vasoconstriction and acts as a modulator of nasal airways reactivity.

Adult↗

PubMed1996

Attenuation of allergen-evoked nasal responses by local pretreatment with exogenous neuropeptide Y in atopic patients.

BACKGROUND: Nasal obstruction and rhinorrhea present in allergic rhinitis are at least partly influenced by neuropeptides released from sensory, parasympathetic, and sympathetic nerves. Neuropeptide Y (NPY) is co-localized with norepinephrine in sympathetic perivascular nerves. NPY is released with norepinephrine on sympathetic nerve stimulation and produces long-lasting vasoconstriction of the nasal vascular bed. In addition to vasoconstriction, there is evidence to suggest that NPY modulates the release of transmitters originating from parasympathetic and sensory nerves by acting on prejunctional receptors. Putative therapeutic application of NPY in rhinitis has been recently suggested because intranasal administration of exogenous NPY in human beings reduces nasal airway resistance and vascular permeability without affecting submucosal gland secretion. OBJECTIVE: The aim of this study was to determine whether intranasal pretreatment with exogenous NPY could influence the functional responses to subsequent allergen challenge. METHODS: A randomized double-blind, three-way, crossover, placebo-controlled study was performed in 13 patients with allergic rhinitis. Pretreatments with NPY (20 nmol), oxymetazoline hydrochloride (20 nmol), or saline solution (NaCl 0.9%) were administered in one nostril 5 minutes before nasal challenge with grass pollen allergen (10,000 standardized quality units). The number of sneezes and the subjective evaluation of nasal itching obstruction, and rhinorrhea were recorded. Nasal airway resistance was measured by anterior rhinomanometry, and nasal secretions were weighed. Mean arterial pressure and heart rate were recorded by noninvasive methods. RESULTS: The number of sneezes, nasal itching, and subjective rhinorrhea evoked by the allergen were similar after the three pretreatments. Subjective and objective increases in nasal airway resistance and mucus production induced by the allergen were significantly (p < 0.01) reduced after NPY pretreatment when compared with saline solution or oxymetazoline pretreatment. Mean arterial pressure and heart rate were not changed. CONCLUSIONS: Local pretreatment with exogenous NPY reduces nasal obstruction and mucus secretion evoked by allergen challenge in allergic patients without modification of local itching and number of sneezes.

Administration, Intranasal↗

PubMed1996

Intranasal administration of neuropeptide Y in man: systemic absorption and functional effects.

1. Exogenous neuropeptide Y (NPY, 10 nmol, 50 nmol and 100 nmol) and its vehicle (NaCl 0.9%) were administered in a double blind, randomized and controlled manner by intranasal spray in 7 healthy volunteers. Variations of plasma NPY concentration over time were measured during 120 min. Forty min after the administration of 50 nmol and 100 nmol of exogenous NPY, plasma NPY increased from 5.5 +/- 1.1 pM to 9.8 +/- 2.3 pM (P < 0.05) and from 9.06 +/- 5.1 pM to 20.8 +/- 6.16 pM (P < 0.001), respectively. There was no significant modification of the mean arterial blood pressure and no subjective discomfort was reported. 2. Nasal airway resistance (NAR) was measured by anterior rhinomanometry and was reduced by 25 +/- 3% and 32 +/- 5% after the spray of 50 nmol and 100 nmol, respectively, for about 90 min. 3. Double-blind, randomized, placebo-controlled and 3-way crossover design experiments were performed in 8 healthy volunteers to evaluate the influence of intranasal pretreatment with NPY (20 nmol) and the mixed alpha 1/alpha 2-adrenoceptor agonist oxymetazoline (20 nmol) on the functional effects of subsequent local irritation evoked by capsaicin (3.3 x 10(-4) mol). Subjective evaluation of NAR and local intensity of discomfort were evaluated by means of a visual analogue scale. Nasal secretions were collected and objective NAR was recorded by rhinomanometry. 4. Subjective NAR, nasal secretions and rhinomanometry recordings were not modified by intranasal application of saline, NPY or oxymetazoline. Subjective nasal obstruction, local discomfort, nasal secretions and NAR increase evoked by capsaicin were markedly reduced by NPY pretreatment (P < 0.05) when compared to saline or oxymetazoline. 5. It is concluded that intranasal application of exogenous NPY has very low systemic absorption but induced long lasting nasal vasoconstriction without cardiovascular effects. Pretreatment of the nasal mucosa with exogenous NPY reduces both secretagogue and vasodilator responses to subsequent application of capsaicin.

Absorption↗

PubMed1996

Lung mechanics and pulmonary but not systemic vascular responses to ET-1 are Tx and infusion rate dependent.

The role of cyclooxygenase metabolites formation in the systemic and pulmonary vascular and airway responses to different intravenous infusion rates of endothelin-1 (ET-1) was investigated in eight barbiturate-anesthetized mechanically ventilated adult sheep. ET-1 (20, 200, and 400 pmol/kg) was infused into the femoral vein over either 1, 10, or 180 s before and after pretreatment with indomethacin (1.5 mg/kg i.v.). ET-1 infusion produced a dose-dependent systemic vasoconstriction that was similar with all three infusion rates. In contrast, the pulmonary vascular and airways responses to ET-1 were not only dose dependent but also infusion rate dependent so that consistent effects on the pulmonary vasculature and airways were observed only when the peptide was injected over 1 s. At the highest dosage and at the fastest rate of administration, ET-1 produced a fivefold rise in pulmonary vascular resistance, a twofold rise in airway resistance, and a 45% decrease in dynamic pulmonary compliance, whereas no changes were observed when the peptide was injected over 180 s. Plasma levels of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) increased 20-fold when ET-1 was administered over 1 s but only 5-fold when it was administered over 180 s. Thromboxane B2 (TxB2) increased 5-fold when ET-1 was administered over 1 s and did not increase when ET-1 was given over 180 s. Plasma TxB2 levels were linearly correlated with pulmonary vascular or airway resistance during the bolus ET-1 infusion. Pretreatment with indomethacin completely prevented the ET-1-induced rise in TxB2 and 6-keto-PGF1 alpha and blocked pulmonary vaso- and bronchoconstriction observed, whereas it enhanced systemic vasoconstriction. These results demonstrate that in adult sheep intravenous ET-1 produces pulmonary vaso- and bronchoconstriction that is infusion rate dependent and is associated with the rate-dependent production of thromboxane. In contrast, the increase in systemic vascular tone elicited by ET-1 is not affected by its rate of infusion and does not depend on the secondary generation of cyclooxygenase metabolites.

Animals↗

PubMed1995

Functional effects of phosphoramidon and captopril on exogenous neuropeptides in human nasal mucosa.

The functional effects of the intranasal application of exogenous vasoactive intestinal polypeptide (VIP), substance P (SP) and calcitonin gene-related peptide (CGRP) were evaluated in 12 healthy volunteers before and after neutral endopeptidase (NEP) inhibition with phosphoramidon (PA) and angiotensin-converting enzyme (ACE) inhibition with captopril. The three neuropeptides increased nasal airway resistance (NAR) measured by anterior rhinomanometry and superficial capillary blood flow measured by laser Doppler flowmetry (LDF). After pretreatment of the nasal mucosa with PA, the effects of VIP, SP and CGRP on the LDF signal, NAR and mucus production were potentiated, whereas local pretreatment with captopril did not modify these functional effects. These observations suggest that NEP, but not ACE, may participate in the catabolism of neuropeptides when applied directly to the human nasal mucosa. Furthermore, since these neuropeptides induced nasal obstruction, increased blood flow and rhinorrhea, a decreased activity of the enzymes involved in their degradation could be involved in the physiopathology of rhinitis symptoms.

Adult↗

PubMed1995

Beta-adrenergic mechanisms in the nasal mucosa vascular bed.

In thiopentone-anesthetized mature pigs (n = 7), local intra-arterial infusion of the beta 2-adrenoceptor agonists terbutaline and salbutamol and the beta 3-agonist BRL 37344 induced dose-dependent increases in nasal arterial blood flow (BF) and volume of the nasal mucosa (reflecting capacitance vessel function). Increases were also found in the laser Doppler flowmeter signal, reflecting superficial mucosal BF. In contrast to terbutaline and salbutamol, BRL 37344 showed marked effects on volume. Pretreatment with the beta-adrenoceptor blocker propranolol significantly reduced the vasodilatory effects of terbutaline and salbutamol, whereas the BF increase evoked by BRL 37344 was not affected. Exogenous noradrenaline (NA) induced in vitro dose-dependent contractions of human nasal mucosa biopsies obtained from patients with non-allergic chronic rhinitis (n = 21) or non-allergic nasal polyposis (NANP, n = 16). On a molar basis, the contractile effect of NA was significantly greater in nasal mucosa samples without histological abnormalities when compared to biopsies with abundant inflammatory cells and edema within the submucosa. In the presence of propranolol, the vasoconstrictor effect of NA was significantly enhanced in biopsies with abundant inflammatory cells obtained from patients with NANP (P < 0.01). This observation suggests the possible occurrence of a beta 2 hyper-reactivity in the nasal mucosa of patients with NANP. After precontraction in a Krebs-Ringer solution with 50 nM K+, all nasal biopsies studied showed dose-dependent relaxation to terbutaline, salbutamol and BRL 37344. This relaxant effect was markedly reduced after pretreatment with propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

PubMed1995

Neutral endopeptidase activity and concentration of sensory neuropeptide in the human nasal mucosa.

Human nasal mucosa biopsy samples were studied by biochemical and histological methods to determine whether the concentration of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) as a marker of sensory nerves was dependent on the activity of neutral endopeptidase-like enzyme (NEP-LE). Mucosal samples from the middle turbinate were obtained from 32 patients undergoing functional endoscopic nasal surgery for non-allergic chronic rhinosinusitis. The degree of symptoms related to nasal obstruction, rhinorrhea and headaches was recorded. The number of inflammatory cells in each biopsy sample was evaluated by conventional histopathological examination. CGRP-LI was measured by radioimmunoassay. The activity of NEP-LE was evaluated in vitro using [3H] Leu5-enkephalin as substrate. A good correlation was observed between increased concentrations of CGRP, abundant inflammatory cells and the intensity of symptoms (R2 = 0.80). A low activity of NEP-LE was associated with a high concentration of both inflammatory cells and CGRP, suggesting that NEP-LE activity was reduced during inflammation. These observations further support the hypothesis that reduced degradation of sensory neuropeptides could be involved in the pathophysiological mechanisms of non-specific chronic rhinosinusitis.

Calcitonin Gene-Related Peptide↗