Changes in psychosocial health during a 7-week paediatric weight management program.

Youth with obesity are at increased risk of psychosocial symptoms; however, little is known regarding the impact of paediatric weight management (PWM) on psychosocial health. The aim of the study was to investigate changes in psychosocial health among children who completed a 7-week PWM program. Participants aged 5 to 16 years with a BMI ≥85th percentile completed a 7-week, family-centred PWM program focused on health behaviour education, exercise and mentored goal setting. The Paediatric Symptom Checklist (PSC) was assessed via parent report to evaluate psychosocial symptoms before and after the program, and subscales were calculated for internalizing (PSC-IS), externalizing (PSC-ES) and attention symptoms (PSC-AS). At baseline, positive screen rates for psychosocial symptoms among the 317 patients included 16.1% for PSC, 14.1% for PSC-ES, 18.6% for PSC-IS and 12.3% for PSC-AS. Among program completers, total PSC scores improved in those with normal (p = 0.010) and elevated p < .001 psychosocial symptoms at baseline. Youth with positive screens for elevated PSC subscales improved their subscale scores, on average, and the majority reduced scores to below elevated levels for PSC (54.2%), PSC-ES (64.7%), PSC-IS (78.3%) and PSC-AS (64.7%). Improvements in PSC remained significant after adjusting for BMI changes during treatment, but BMI differed across PSC-change groups, including BMI increases among participants with PSC deterioration (0.33 ± 0.64 kg m-2 ) (P = 0.035) and BMI decreases among patients with no reliable PSC change (-0.26 ± 1.04 kg m-2 ) (P = 0.038) or reliable PSC improvement (-0.22 ± 0.74 kg m-2 ) (P = 0.025). Youth with positive screens for psychosocial symptoms can improve emotional and behavioural functioning during short-term PWM. Future research is needed to elucidate mechanisms and long-term outcome durability.

Psychiatric diagnoses and medication treatment among patients presenting for paediatric weight management: associations with adiposity, aerobic fitness and cardiometabolic health.

We compared anthropometry, cardiometabolic risk and aerobic fitness among obese youth in weight management who were diagnosed with one or more psychiatric disorders (PD), with (PD+M) or without (PD-M) a prescribed psychotropic medication with those with no PD (NPD). Physical measures were evaluated at baseline, and psychiatric diagnoses and related medications were identified from medical records. Of 99 patients 64 (65%) had a diagnosed PD, and of those, 23 (36%) had a related medication (PD+M). Compared to NPD, PD-M had a higher body mass index (BMI) (P = 0.003), BMI z-score (P = 0.015), percent body fat (P = 0.005) and waist circumference (P < 0.001), after adjusting for age, but PD+M did not. Cardiometabolic risk did not differ between groups, but aerobic fitness was lower among PD-M (P = 0.001) and PD+M (P = 0.008) compared to NPD. Obese youth in weight management exhibit high rates of psychiatric diagnoses that are associated with lower fitness and higher adiposity and may impact treatment efficacy.

Effect of aging on cholecystokinin-induced panic.

OBJECTIVE: Epidemiologic surveys have found that the incidence and prevalence of panic disorder decline in later life. The goal of this study was to determine whether aging has an effect on healthy subjects' responses to the panicogenic agent cholecystokinin tetrapeptide (CCK-4). METHOD: The study used a double-blind, placebo-controlled design: 40 subjects 20-35 years old and 40 subjects 65 years old or older were randomly assigned to receive an intravenous bolus of either 50 micrograms of CCK-4 or normal saline. RESULTS: When given CCK-4, older subjects had significantly fewer and less intense symptoms of panic, shorter duration of symptoms, and less of an increase in heart rate than did younger subjects. CONCLUSIONS: This study found an age-related change in responsiveness to CCK-4. Further research to delineate the mechanism of this change is warranted.

Elevated plasma levels of neuropeptide Y in patients with panic disorder.

OBJECTIVE: Neuropeptide Y is a pancreatic polypeptide closely associated with noradrenergic activity both in the central and peripheral nervous systems. The objective of this study was to assess plasma neuropeptide Y-like immunoreactivity in panic disorder. METHOD: Radioimmunoassays were performed in 12 patients with DSM-III-R panic disorder and two groups of normal comparison subjects (N = 22 and N = 16). RESULTS: Markedly higher plasma neuropeptide Y-like immunoreactivity was found in patients with panic disorder. CONCLUSIONS: Higher plasma neuropeptide Y-like immunoreactivity suggests that this peptide may be implicated in the etiology or expression of symptoms of panic disorder.

Acute and chronic role of 5-HT3 neuronal system on behavioral and neuroendocrine changes induced by intravenous cholecystokinin tetrapeptide administration in humans.

The influence of single and multiple oral doses of ondansetron, a selective 5-HT3 receptor antagonist, was evaluated against placebo on cholecystokinin tetrapeptide (CCK-4)-induced behavioral and neuroendocrine changes in humans. As compared to placebo, subjects receiving acute ondansetron treatment showed a significant decrease in the sum intensity of CCK-4-induced-panic symptoms (iPSS). Pre-CCK-4 neuropeptide Y (NPY) plasma levels were significantly higher and maximal changes in cortisol, growth hormone, and prolactin secretion from baseline (delta max) were significantly lower in the ondansetron group. After ondansetron and placebo chronic administration, there were no statistical differences in the iPSS between groups. Pre-CCK-4 NPY plasma levels were significantly higher; whereas, delta max for NPY significantly lower in the ondansetron group as compared to placebo. These results suggest a role for the 5-HT3 receptor in the neurobiology of panic disorder through a possible interaction with CCK and NPY systems. Ondansetron chronic effect on CCK-4-induced behavioral changes needs further exploration.

Occurrence, distribution and ontogeny of CGRP immunoreactivity in the rat lower respiratory tract: effect of capsaicin treatment and surgical denervations.

The occurrence and distribution of calcitonin gene-related peptide (CGRP) immunoreactivity in the rat respiratory tract were investigated by means of immunocytochemistry and radioimmunoassay using antibodies raised in rabbits to synthetic rat CGRP. Substantial amounts of CGRP immunoreactivity (range 5-37 pmol/g) were detected in all parts of the respiratory tract, the highest being in the stem bronchus. Gel filtration chromatography of extractable CGRP immunoreactivity revealed one single peak, eluting at the position of synthetic rat CGRP. CGRP immunoreactivity was localized both in mucosal endocrine cells and nerve fibres from the larynx down to the peripheral lung. CGRP-immunoreactive endocrine cells were found singly in trachea and stem bronchi and in groups in intrapulmonary airways. They appeared at a late stage of gestation (17 days), reached a maximum number near term and decreased after birth to maintain a population similar to that of the adult animals by postnatal day 21. Similarly, CGRP-immunoreactive nerve fibres were first identified by day 18 of the gestation period and reached the adult distribution by postnatal day 21. CGRP-immunoreactive nerve fibres were localized among smooth muscle, seromucous glands, beneath and within the epithelium of the airways and around blood vessels. CGRP was also found in sensory ganglia and in motor end plates of the larynx musculature. Neonatal pretreatment with capsaicin caused a marked reduction in CGRP immunoreactivity of nerve fibres in the respiratory tracts as well as a less marked decrease in the population of CGRP-containing endocrine cells of the lung. No change was seen in motor end plates immunostaining. Vagal ligation experiments revealed that CGRP-immunoreactive nerve fibres travelling in the vagus originate mainly from neurons located in the jugular ganglion. Infranodosal right vagal ligation induced a marked loss in CGRP-immunoreactive nerves of the trachea, and of the ipsilateral stem bronchus, but no changes were observed in peripheral lung. By contrast infranodosal left side vagal ligation caused a decrease in CGRP-immunoreactive nerves of the ipsilateral lung and bronchus without affecting the peptide content in the trachea. Left vagal ligation also induced a marked increase in both the intensity of staining and number of CGRP-immunoreactive endocrine cells in the lung. We conclude that CGRP immunoreactivity is localized in both nerve fibres and endocrine cells and is associated principally with the afferent (sensory) innervation of the respiratory tract.(ABSTRACT TRUNCATED AT 400 WORDS)

Carbamylcholine- and 5-hydroxytryptamine-induced contraction in rat isolated airways: inhibition by calcitonin gene-related peptide.

1. The effects of rat and human alpha-calcitonin gene-related peptide (alpha-CGRP) were investigated in isolated smooth muscle preparations obtained from three levels of the rat respiratory tract. 2. Neither peptide (10(-10)-10(-6) M) had any effect on resting tension or on carbamylcholine (10(-6) M)-induced tone of trachea or main bronchus. In contrast, CGRP sometimes reduced spontaneous or carbamylcholine-induced tone of lung parenchymal strips. 3. CGRP produced a significant rightward shift of the log concentration-response curves to carbamylcholine and 5-hydroxytryptamine (5-HT) in the main bronchus. A rightward shift was also seen in trachea and parenchymal strips but this did not achieve the level of significance. The maximal response to 5-HT was reduced in the main bronchus and lung parenchyma whereas the maximal contraction to carbamylcholine was decreased in parenchymal strip only. 4. In all three airway preparations, CGRP caused concentration-dependent inhibition of responses elicited by challenges with 10(-7) M carbamylcholine or 5 x 10(-7) M 5-HT. The inhibitory effect of the peptide was inversely related to the size of the airways: the smaller the calibre, the greater the inhibition. 5. The inhibitory action of CGRP was not modified by pretreatment with tetrodotoxin (10(-6) M), propranolol (10(-6) M) or indomethacin (10(-6) M). 6. The results strongly suggest that (a) CGRP has a nonspecific inhibitory action on airway smooth muscle cells, (b) CGRP may act as a potent inhibitor of responses elicited by bronchoconstrictor substances and (c) its inhibitory activity may be most powerfully expressed in peripheral regions of the respiratory tract.

Antagonism of the inhibitory action of neuropeptide Y (NPY) in guinea-pig trachea by the C-terminal fragment NPY (2-36).

The C-terminal fragment of neuropeptide Y (NPY), NPY(2-36) was used as a means of discriminating between two differently located NPY receptor sites in guinea-pig trachea. Both NPY and NPY(2-36) reduced the maximal relaxation elicited by vasoactive intestinal peptide (VIP). In contrast, the C-terminal fragment did not mimic the inhibitory action of NPY on the noradrenaline-(NA) evoked response. However, pretreatment of the trachea with 30 nM NPY(2-36), 5 min before generating NA and VIP concentration-response curves in the presence of NPY, abolished the inhibitory effect of NPY on NA-elicited response but did not affect the modulatory action of NPY on VIP-induced relaxation. These results suggest that the two differently located NPY receptor sites in guinea-pig trachea are of two distinct subpopulations.

Vasoactive intestinal peptide in bovine pulmonary artery: localisation, function and receptor autoradiography.

The role of vasoactive intestinal peptide (VIP) in the control of pulmonary vascular tone was investigated by functional response, immunocytochemical localisation and receptor autoradiography in bovine pulmonary arteries. VIP-immunoreactive nerve fibres were present at the adventitial-medial junction and in the media of the vessels. Exposure of precontracted bovine pulmonary artery segments to VIP in vitro resulted in almost complete (86 +/- 3%; mean +/- s.e.mean) relaxation, the concentration needed for 50% relaxation being 4.47 +/- 0.37 X 10(-9)M. VIP effects did not depend on the presence of intact endothelial cells. The distribution of VIP receptors was studied by autoradiography using [125I]-VIP. A high density of VIP receptors was found in arterial vascular smooth muscle, with a gradient of density from adventitia to luminal surface. There were no receptors on endothelial cells. These data show that VIP is a potent vasodilator of bovine pulmonary arteries, via direct activation of VIP receptors in vascular smooth muscle. VIP-immunoreactive nerves may influence pulmonary vascular tone directly and could, therefore, be important in regulating pulmonary blood flow.

Nitric oxide limits the eicosanoid-dependent bronchoconstriction and hypotension induced by endothelin-1 in the guinea-pig.

1. This study attempts to investigate if endogenous nitric oxide (NO) can modulate the eicosanoid-releasing properties of intravenously administered endothelin-1 (ET-1) in the pulmonary and circulatory systems in the guinea-pig. 2. The nitric oxide synthase blocker N(omega)-nitro-L-arginine methyl ester (L-NAME; 300 microM; 30 min infusion) potentiated, in an L-arginine sensitive fashion, the release of thromboxane A2 (TxA2) stimulated by ET-1, the selective ET(B) receptor agonist IRL 1620 (Suc-[Glu9,Ala11,15]-ET-1(8-21)) or bradykinin (BK) (5, 50 and 50 nM, respectively, 3 min infusion) in guinea-pig isolated and perfused lungs. 3. In anaesthetized and ventilated guinea-pigs intravenous injection of ET-1 (0.1-1.0 nmol kg(-1)), IRL 1620 (0.2-1.6 nmol kg(-1)), BK (1.0-10.0 nmol kg(-1)) or U 46619 (0.2-5.7 nmol kg(-1)) each induced dose-dependent increases in pulmonary insufflation pressure (PIP). Pretreatment with L-NAME (5 mg kg(-1)) did not change basal PIP, but increased, in L-arginine sensitive manner, the magnitude of the PIP increases (in both amplitude and duration) triggered by each of the peptides (at 0.25, 0.4 and 1.0 nmol kg(-1), respectively), without modifying bronchoconstriction caused by U 46619 (0.57 nmol kg(-1)). 4. The increases in PIP induced by ET-1, IRL 1620 (0.25 and 0.4 nmol kg(-1), respectively) or U 46619 (0.57 nmol kg(-1)) were accompanied by rapid and transient increases of mean arterial blood pressure (MAP). Pretreatment with L-NAME (5 mg kg(-1); i.v. raised basal MAP persistently and, under this condition, subsequent administration of ET-1 or IRL 1620, but not of U-46619, induced hypotensive responses which were prevented by pretreatment with the cyclo-oxygenase inhibitor indomethacin. 5. Thus, endogenous NO appears to modulate ET-1-induced bronchoconstriction and pressor effects in the guinea-pig by limiting the peptide's ability to induce, possibly via ET(B) receptors, the release of TxA2 in the lungs and of vasodilatory prostanoids in the systemic circulation. Furthermore, it would seem that these eicosanoid-dependent actions of ET-1 in the pulmonary system and on systemic arterial resistance in this species are physiologically dissociated.

BIIE0246, a potent and highly selective non-peptide neuropeptide Y Y(2) receptor antagonist.

1. BIIE0246, a newly synthesized non-peptide neuropeptide Y (NPY) Y(2) receptor antagonist, was able to compete with high affinity (8 to 15 nM) for specific [(125)I]PYY(3 - 36) binding sites in HEK293 cells transfected with the rat Y(2) receptor cDNA, and in rat brain and human frontal cortex membrane homogenates. 2. Interestingly, in rat brain homogenates while NPY, C2-NPY and PYY(3 - 36) inhibited all specific [(125)I]PYY(3 - 36) labelling, BIIE0246 failed to compete for all specific binding suggesting that [(125)I]PYY(3 - 36) recognized, in addition to the Y(2) subtype, another population of specific NPY binding sites, most likely the Y(5) receptor. 3. Quantitative receptor autoradiographic data confirmed the presence of [(125)I]PYY(3 - 36)/BIIE0246-sensitive (Y(2)) and-insensitive (Y(5)) binding sites in the rat brain as well as in the marmoset monkey and human hippocampal formation. 4. In the rat vas deferens and dog saphenous vein (two prototypical Y(2) bioassays), BIIE0246 induced parallel shifts to the right of NPY concentration-response curves with pA(2) values of 8.1 and 8.6, respectively. In the rat colon (a Y(2)/Y(4) bioassay), BIIE0246 (1 microM) completely blocked the contraction induced by PYY(3 - 36), but not that of [Leu(31), Pro(34)]NPY (a Y(1), Y(4) and Y(5) agonist) and hPP (a Y(4) and Y(5) agonist). Additionally, BIIE0246 failed to alter the contractile effects of NPY in prototypical Y(1) in vitro bioassays. 5. Taken together, these results demonstrate that BIIE0246 is a highly potent, high affinity antagonist selective for the Y(2) receptor subtype. It should prove most useful to establish further the functional role of the Y(2) receptor in the organism.

Calcitonin gene-related peptide is localised to human airway nerves and potently constricts human airway smooth muscle.

In human airways synthetic human sequence calcitonin gene-related peptide (hCGRP), a novel peptide produced by alternative processing of mRNA from the calcitonin gene, caused concentration-dependent contraction of human bronchi (EC50 4.9 X 10(-9) M) and was significantly more potent than substance P or carbachol. The contractile response was unaffected by atropine (2 X 10(-6) M), propranolol (10(-6) M), indomethacin (10(-5) M), tetrodotoxin (3 X 10(-6) M), chlorpheniramine (10(-4) M), cimetidine (10(-5) M), or FPL55712 (10(-4) M) suggesting a direct effect of CGRP on airways smooth muscle. CGRP was detected in human airways by radioimmunoassay with highest concentrations in cartilaginous airways. CGRP was localised by immunocytochemistry to both nerves and ganglia in human airways. CGRP, is a potent constrictor of human airways and may have important effects on airway function and be implicated in the pathogenesis of bronchial hyper-responsiveness and asthma.

Effect of asbestos on the metabolism of vasoactive substances in isolated perfused guinea pig lungs.

The measurement of pulmonary metabolism of three vasoactive substances and quantitative assessment of changes in lung morphology were performed in a long-term study of asbestos-exposed guinea pigs. Animals received intratracheal injections of a single dose of a sterile suspension of Canadian chrysotile B (5 mg), while control animals received only saline. Six months after the treatment, the guinea pigs were sacrificed, the lungs removed, perfused via the pulmonary artery and the metabolism of vasoactive substances was assessed (in vitro) in a cascade superfusion system. At the end of the experiments, the lungs were fixed in a glutaraldehyde solution for microscopic examination. The tissue response consisted of both inflammatory reaction of terminal and respiratory bronchioles and diffuse alveolar septal infiltration with interstitial fibrosis. The reaction was characterized at six months by a progressive bronchiolitis obliterans with fibroblastic proliferation and collagen formation. The development of the disease did not cause significant changes in the metabolism of acetylcholine and bradykinin. However, the metabolism of prostaglandin E2 decreased with the appearance of the bronchiolitis obliterans. Our results showed that asbestos exposure may produce early biochemical changes resulting in altered lung metabolism of vasoactive substances; these modifications could contribute to the pathogenesis of asbestosis.

An adherent cell perifusion technique to study the overall and sequential response of rat alveolar macrophages to toxic substances.

Essentially pure (97%) alveolar macrophages were isolated by bronchoalveolar lavage of rats with warm (37 degrees C) PBS solution. These cells were allowed to adhere to the inside walls of open-ended glass cylinders which were closed off at each end by three-way stopcocks. The adhering cells were perifused with RPMI-1640 medium supplemented with 5% fetal bovine serum for 18 hr at the rate of 1 mL/hr, and the effluent medium was collected automatically in 2-mL aliquots. Cell recoveries and viabilities did not differ from those found for Petri cultures treated similarly, indicating that the perifusion method under study offered an adequate milieu for short-term primary cultures. The alveolar macrophages in culture were subjected to the presence of particulate (chrysotile asbestos) and soluble (phorbol myristate) toxicants, and their response was monitored in the effluent medium by measuring the release of prostaglandins (PGE) by radioimmunoassay. A significant increase in the sequential release of PGE was observed in the presence of asbestos (100 micrograms/mL) or phorbol myristate (200 ng/mL). Treatment of the cells with indomethacin (20 microM) completely abolished the release of PGE stimulated with phorbol myristate. A cumulative response to the toxicants was also observed when cells were harvested manually from the chambers: asbestos caused a 2-fold increase in cell mortality relative to control, while phorbol myristate brought about a 3-fold increase in the number of dead cells. This effect was not prevented by the presence of indomethacin. Cell aggregation was also observed when cells were perifused in the presence of phorbol myristate, whether indomethacin was present or absent. Our results indicate that the cell perifusion system combines the advantages of conventional adherent cell cultures (viability, aggregation) with those of perifusion techniques (sequential metabolism studies).

Peptide YY derivatives as selective neuropeptide Y/peptide YY Y1 and Y2 agonists devoided of activity for the Y3 receptor sub-type.

Peptide YY derivatives were evaluated for their respective ability to bind and activate the NPY/PYY receptor sub-types (Y1, Y2 and Y3) present in various preparations. The analogue [Leu31,Pro34]PYY demonstrated high (nM) affinity in rat frontoparietal cortical membrane preparations (Y1-enriched tissue) and the rabbit saphenous vein (Y1 in vitro bioassay) but only low affinity in a Y2-enriched preparation (rat hippocampus). In contrast, PYY C-terminal fragments such as PYY3-36 and PYY13-36 were more potent in Y2 than Y1 assays. Interestingly, and in contrast to [Leu31,Pro34]NPY and NPY13-36, the PYY derivatives [Leu31,Pro34]PYY and PYY3-36 were inactive in a purported Y3 bioassay (rat colon). These results suggest that [Leu31,Pro34]PYY and PYY3-36 respectively represent the first selective and potent Y1 and Y2 agonists, devoided of significant affinity/activity for the Y3 receptor class.

The rabbit saphenous vein: a tissue preparation specifically enriched in NPY-Y1 receptor subtype.

Neuropeptide Y (NPY), a co-transmitter in noradrenergic sympathetic nerves of the cardiovascular system, was tested on isolated segments of rabbit saphenous vein. NPY caused strong, long lasting and concentration dependent contraction resistant to adrenergic blockade. PYY, a NPY related peptide, shared this property. As pressor agents, both peptides were about 100-fold more potent than norepinephrine and at their highest concentrations caused a contraction of a similar magnitude as NE. Gradual shortening of N-terminal end of the NPY molecule caused major loss of potency and reduction of intrinsic activity; which suggests that the entire molecule is required to produce full biological activity in this vascular preparation. Addition of [Leu31,Pro34]pNPY, a NPY analog with specific agonist properties at Y1 receptors, mimicked the effect of NPY whereas NPY (13-36), a selective agonist at Y2 receptors, caused a 2 log unit shift to the right of the concentration response curve. These results suggest that the vasoconstrictor effect of NPY in rabbit saphenous vein results from a direct effect on smooth muscle cells and that the receptors involved are of the Y1 subtype.

Bronchoconstrictor action of neuropeptide Y (NPY) in isolated guinea pig airways.

Responses of various preparations of guinea pig and rat airways to synthetic porcine neuropeptide Y were analysed in vitro. NPY in doses up to 10(-6) M, induced a dose dependent contraction in trachea, bronchi and lung parenchymal strips of the guinea pig but did not have any effect in similar preparations obtained from the rat. In guinea pig airways the contractile responses to NPY were small in size and characterized by a slow onset and a long duration. This effect of the peptide was not dependent on pre-junctional nerve stimulation but rather mediated through the secondary generation of cyclooxygenase products. It is concluded that NPY may contribute per se to regulating the resting tone of guinea pig airways.

Apparent affinity and potency of BIBP3226, a non-peptide neuropeptide Y receptor antagonist, on purported neuropeptide Y Y1, Y2 and Y3 receptors.

The newly developed, purported non-peptide neuropeptide Y Y1 receptor antagonist BIBP3226 was evaluated for its potential effect on the recently characterized Y3 receptor subtype and for its apparent affinity in rat and human brain membrane binding assays using highly selective neuropeptide Y Y1 and Y2 radioligands. BIBP3226 potently blocked (pA2 = 7.36) the contractile effect of neuropeptide Y in the rabbit saphenous vein, a Y1 receptor bioassay and demonstrated nM affinity for Y1/[125I][Leu31,Pro34]peptide YY binding sites. In contrast, it failed to antagonize the biological effects of neuropeptide Y in the rat vas deferens (Y2) and rat colon (Y3) and did not significantly competed for Y2/[125I]peptide YY-(3-36) binding sites in rat and human brain homogenates. Taken together, the results demonstrate further the high potency and selectivity of BIBP3226 for the neuropeptide Y Y1 receptor by establishing its lack of antagonist activity on the Y3 subtype.

Inhibitory action of neuropeptide Y on agonist-induced responses in isolated guinea pig trachea.

The effect of neuropeptide Y (NPY) was tested on isolated guinea pig trachea. At 30 nM, NPY induced a weak but significant contractile response which was on average less than 6% of responses elicited by standard spasmogens. This myotropic action of NPY was blocked by indomethacin. In addition to its contractile activity, NPY greatly reduced the maximal response to vasoactive intestinal peptide (VIP), noradrenaline (NA), substance P (SP) and 5-hydroxytryptamine (5-HT), without affecting their pD2 values. However, NPY did not influence the response induced by histamine and carbamylcholine. Pretreatment of tracheal spirals with indomethacin (10(-6) M) abolished the NPY-evoked inhibition of VIP, SP and 5-HT responses but failed to reduce the action of NPY on NA-elicited relaxation. This latter effect was however blocked in the presence of tetrodotoxin. In conclusion, NPY inhibits responses elicited by various agonists in the guinea pig trachea. This effect seems to be mediated at both pre- and postjunctional levels. The postjunctionally mediated inhibitory action of NPY appears to be expressed especially with agents that generate prostaglandins concomitantly with inducing their response. In contrast, the NPY-evoked inhibition of NA-evoked relaxation seems to be mediated via a prejunctional mechanism.

Neuropeptide Y-induced contraction is mediated by neuropeptide Y Y2 and Y4 receptors in the rat colon.

Ascending and descending segments of the rat colon were studied to analyze their contractile responses to neuropeptide Y and related peptides. These responses are (a) completely eliminated by tetrodotoxin (1 microM), (b) reduced to a variable extent (20 to 60%) by atropine (1 microM) and (c) not modified by indomethacin, diphenhydramine or methysergide. The order of potency of agonists for peptides related to neuropeptide Y was as follows: human pancreatic polypeptide = rat pancreatic polypeptide > peptide YY = peptide YY-(3-36) = [Leu31,Pro34]neuropeptide Y > neuropeptide Y-(2-36) > C2-neuropeptide Y = neuropeptide Y > neuropeptide Y-(13-36), with minor differences observed between the two parts of the colon. This selectivity pattern does not correspond to the profile of any known cloned neuropeptide Y receptors. BIBP3226, a selective antagonist for the neuropeptide Y Y1 receptor sub-type, was found to be inactive, while a neuropeptide Y Y2 receptor antagonist, T4-[NPY-(33-36)]4, reduced the effects of neuropeptide Y, peptide YY, peptide YY-(3-36) and C2-neuropeptide Y without affecting those of human pancreatic polypeptide, rat pancreatic polypeptide and [Leu31,Pro34]neuropeptide Y. JCF 104 (compound 28), a putative neuropeptide Y Y5 receptor antagonist, showed no effect or a weak inhibition of human pancreatic polypeptide or [Leu31,Pro34]neuropeptide Y-induced contraction. Taken together, these data suggest that: (1) at least two neuropeptide Y receptor types are present in the rat colon autonomic nerve terminals and modulate the release of acetylcholine and possibly other transmitters; (2) a proportion of the receptors mediating the contractile response of the rat colon (especially descending part) to neuropeptide Y and related peptides appears to be of the Y2 type and (3) the significant portion of the response is mediated by a receptor which is insensitive to neuropeptide Y Y1, Y2 and to neuropeptide Y Y5 receptor antagonists. This receptor behaves as a neuropeptide Y Y4 receptor sub-type and appears to be located on enteric nerves.