Complications to acute bacterial rhinosinusitis in children - a prospective study; bacterial cultures, virus detection, allergy sensitization and immunoglobulins.

BACKGROUND: Prospective studies of complications due to acute rhinosinusitis are lacking, bacterial cultures are hard to obtain and the role of airborne allergies, viruses and immunoglobulin levels are unclear. The aim was to investigate the role of bacteria, viruses, allergy and immunoglobulins in children hospitalized due to rhinosinusitis. METHODOLOGY: A prospective cohort study in Stockholm, Sweden, of children up to 18 years of age, hospitalized due to acute bacterial rhinosinusitis, from April 1st, 2017 to April 1st, 2020. RESULTS: Of 55 children included, 51% had a positive viral nasopharyngeal PCR and 29% had a positive allergy sensitization test. A higher percentage of middle meatus cultures were positive for bacterial growth compared to nasopharyngeal and displayed a wider array of bacteria. Dominating bacteria were S. milleri in surgical (7/12 cases), S. pyogenes in middle meatus (13/52 cases), and S. pyogenes and H. influenza in nasopharyngeal cultures (8/50 cases respectively). Nasal cultures were negative in 50% of surgical cases. An association was found between S. pyogenes and peak CRP; H. influenzae and peak CRP; S. pneumoniae and peak CRP; and possibly between M. catarrhalis and days of IV antibiotics. Further, an association between influenza A/B and S. pyogenes; a positive viral PCR and lower grade of complication and peak CRP; and a possible association between influenza virus and lower grade of complication. Allergy sensitization was possibly associated with a higher number of days with IV antibiotics. No immunoglobulin deficiencies were found. CONCLUSIONS: There seem to be differences in the patterns of bacterial growth in nasopharyngeal, middle meatus and surgical cultures in children with complications to acute bacterial rhinosinusitis. Presence of certain viruses and sensitization to airborne allergies seem to play a role in complications to acute bacterial rhinosinusitis in children.

Position paper on olfactory dysfunction: 2023

BACKGROUND: Since publication of the original Position Paper on Olfactory Dysfunction in 2017 (PPOD-17), the personal and societal burden of olfactory disorders has come sharply into focus through the lens of the COVID-19 pandemic. Clinicians, scientists and the public are now more aware of the importance of olfaction, and the impact of its dysfunction on quality of life, nutrition, social relationships and mental health. Accordingly, new basic, translational and clinical research has resulted in significant progress since the PPOD-17. In this updated document, we present and discuss currently available evidence for the diagnosis and management of olfactory dysfunction. Major updates to the current version include, amongst others: new recommendations on olfactory related terminology; new imaging recommendations; new sections on qualitative OD and COVID-19 OD; updated management section. Recommendations were agreed by all co-authors using a modified Delphi process. CONCLUSIONS: We have provided an overview of current evidence and expert-agreed recommendations for the definition, investigation, and management of OD. As for our original Position Paper, we hope that this updated document will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency, and generalisability of work in this field.

Stathmin and EGFR correlates to HPV status and clinical outcome in sinonasal inverted papilloma.

BACKGROUND: Inverted papilloma (IP) is a locally destructive benign tumour of the sinonasal mucosa with a tendency for malignant transformation. Stathmin and epidermal growth factor receptor (EGFR) are important markers in cancer prognosis. Here we investigate if expression of stathmin and EGFR correlate to dysplasia, recurrence and HPV in IP. METHODS: 98 patients with IP diagnosed 2000-2010 were analyzed for stathmin and EGFR by immunohistochemistry (IHC) and HPV by polymerase chain reaction assay (PCR). RESULTS: All IPs expressed stathmin while its expression was absent or weak in normal mucosa. Dysplasia was present in 26,7% of IPs with high stathmin expression while only 7.4% of IPs with low stathmin expression showed dysplasia. Stathmin positive IPs showed a trend towards earlier recurrences. 57.1% of IP expressed EGFR but no significant association was seen between EGFR-positivity and recurrence or dysplasia. EGFR was expressed by 91.7% of the HPV-positive IPs compared to 52,3% of the HPV negative IPs. CONCLUSIONS: EGFR expression is significantly higher in HPV positive IP. Stathmin is expressed by all IP tumour cells. Stathmin was also associated with dysplasia and a trend towards a correlation between stathmin positivity and recurrence was found. Stathmin and EGFR might therefore be considered therapeutic targets.

Control of allergic rhinitis with MP-AzeFlu: a noninterventional study of a Swedish cohort.

BACKGROUND: The European Union has prioritised allergic rhinitis (AR) control. A visual analogue scale (VAS) has been endorsed as the AR control language and embedded into the most recent MACVIA-ARIA guideline. This study assessed the effectiveness and safety of MP-AzeFlu using a VAS in a real-life study in Sweden. METHODS: 431 patients aged 12 years or over with ARIA-defined moderate to severe AR were included in this multicentre, prospective, non-interventional study and prescribed MP-AzeFlu. Patients assessed symptom severity using a VAS from 0 (not at all bothersome) to 100 mm (very bothersome) on Days 0, 1, 3 and 7, and after approximately 14 days in the morning before using MP-AzeFlu. Patients' perceived level of disease control was assessed on Day 3. The proportion of patients who achieved a defined VAS score cutoff for well- and partly controlled AR was also calculated. RESULTS: MP-AzeFlu reduced mean (SD) VAS score from 67.9 (16.1) mm at baseline to 32.1 (22.8) mm on the last day. Results were consistent irrespective of severity, phenotype, patient age class or previous treatment. By Day 3, 84.0% of patients reported well- or partly controlled symptoms. Overall, 17.7%, 32.2%, 53.8% and 64.2% of patients achieved a 38 mm or greater "well-controlled" VAS score cutoff on Day 1, 3 and 7 and last day, respectively. CONCLUSIONS: MP-AzeFlu provided rapid, effective and sustained symptom control in patients with AR from Sweden in a realworld setting, aligning with EU and MACVIA-ARIA initiatives and supporting the effectiveness of MP-AzeFlu for AR treatment in real life.

Most preschool children hospitalised for acute rhinosinusitis had orbital complications, more common in the youngest and among boys.

AIM: This study established the incidence of acute rhinosinusitis and related orbital complications in tertiary care in Stockholm County and surveyed the clinical outcomes. METHODS: This was a population-based, retrospective, observational study, from July 1, 2003 to June 30, 2007, of the hospital admissions records of 213 children up to five years old, with a diagnosis of sinusitis and related complications. RESULTS: Preseptal cellulitis was present in 171 of the 213 admissions, which equated to an incidence of orbital complications due to acute rhinosinusitis of 36 per 100 000 people per year (95% confidence interval 26-49). Postseptal complications occurred in seven cases. The incidence rate ratio for hospitalisation of children less than two years old with rhinosinusitis compared with children aged 2-5 years was 2.8 (95% confidence interval 1.8-4.4). The incidence among boys was 53 per 100 000 people per year and 36 per 100 000 people per year for girls, and the incidence rate ratio was 1.5 (95% confidence interval 1.0-2.3). The most common bacterial finding was Streptococcus pneumoniae. CONCLUSION: Most children hospitalised for acute rhinosinusitis had an orbital complication, and this was more common in children under the age of two years and boys. Severe postseptal complications were rare.

Position paper on olfactory dysfunction.

BACKGROUND: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: - Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. - Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. - Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. - Comprehensive chemosensory assessment should include gustatory screening. - Smell training can be helpful in patients with olfactory loss of several aetiologies. CONCLUSIONS: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

The link between parental allergy and offspring allergic and nonallergic rhinitis.

BACKGROUND: Parental allergy-related disease increases the risk for rhinitis, but it remains unknown how different phenotypes of parental allergy affect this risk. The aim of this study was to investigate how parental hay fever, asthma, and eczema affect the risk of allergic rhinitis (AR) and nonallergic rhinitis (NAR) at 8 years of age. METHODS: Information on 2413 children from a population-based birth cohort was used combining questionnaire data and IgE to inhalant allergens. Logistic regression was used to estimate the association between parental allergy-related disease and AR and NAR. In addition, cluster analysis was used to search for latent phenotypes of heredity likely to be associated with AR and NAR. RESULTS: At age 8 years, 13.8% of the children had AR, while 6.4% had NAR. Parental isolated hay fever increased the odds of AR (OR 2.2, 95% CI 1.6-3.2), whereas isolated asthma or eczema did not. The odds of NAR increased when one parent had two or more allergy-related diseases. In the cluster analysis, the highest proportion of AR, 37.5%, was seen in a cluster where both parents had hay fever and pollen allergy and that of NAR, 11.0%, in a cluster where one parent had hay fever, pollen allergy, and eczema. CONCLUSIONS: Parental allergy-related disease may be an important risk factor for NAR as well as AR, and the risk is comparable for maternal and paternal allergy. Parental hay fever seems to be the dominating hereditary risk factor for AR.

Chronic rhinosinusitis in asthma is a negative predictor of quality of life: results from the Swedish GA(2)LEN survey.

BACKGROUND: Asthma and chronic rhinosinusitis (CRS) both impair quality of life, but the quality-of-life impact of comorbid asthma and CRS is poorly known. The aim of this study was to evaluate the impact of CRS and other relevant factors on quality of life in asthmatic subjects. METHODS: This Swedish cohort (age 17-76 years) consists of 605 well-characterized asthmatics with and without CRS, 110 individuals with CRS only, and 226 controls and is part of the Global Allergy and Asthma European Network (GA(2) LEN) survey. The Mini Asthma Quality of Life Questionnaire (mAQLQ), the Euro Quality of Life (EQ-5D) health questionnaire, spirometry, skin prick test (SPT), exhaled nitric oxide (FeNO), smell test, and peak nasal inspiratory flow were used. RESULTS: Subjects having both asthma and CRS have lower mAQLQ scores in all domains (P < 0.001) and a lower EQ-5D index value and EQ-5D VAS value (P < 0.001) compared to those with asthma only. Asthmatics with CRS have significantly lower FEV1%pred and FVC%pred (88.4 [85.1-91.7] and 99.9 [96.7-103.0], respectively) compared with asthma only (91.9 [90.3-93.4] and 104.0 [102.5-105.5], respectively P < 0.05). Multiple regression analysis shows that low asthma quality of life is associated with having CRS (P < 0.0001), lower lung function (P = 0.008), current smoking (P = 0.01), BMI > 30 kg/m2 (P = 0.04), high age (P = 0.03), and a negative SPT (P = 0.04). CONCLUSIONS: Comorbid CRS was a significant and independent negative predictor of quality of life in asthmatics. Other negative factors were lower lung function, current smoking, obesity, advanced age, and having nonatopic asthma.

Quality of life is improved by endoscopic surgery and fluticasone in nasal polyposis with asthma.

BACKGROUND: The aim was to investigate the health impact of nasal polyposis with asthma and to study effects of endoscopic sinus surgery (ESS), and addition of fluticasone propionate nasal drops (FPND), on health related quality of life (HRQoL). METHODS: Prospective study of 68 patients with nasal polyposis and asthma. Effects were measured with Study 36-Item Short Form (SF-36). A randomized, double-blind, placebo-controlled 14-weeks phase measuring additive effects of FPND 400 µg twice daily (b.i.d.) was included. RESULTS: HRQoL was significantly decreased in both Physical Component Summary, PCS, (45 vs 48, p=0.049) and Mental Component Summary, MCS, (43 vs 51, p<0.001) vs reference population. ESS significantly improved PCS, (p=0.027) and MCS (p=0.021) after five weeks. We found significant additional benefit of FPND on three domains (RP, p=0.002; VT, p=0.007; SF, p=0.002). The increase in HRQoL with FPND reached reference population levels in all domains, as well as in both PCS (50, p=0.003) and MCS (52, p=0.002), five weeks after ESS. CONCLUSIONS: FPND 400 µg b.i.d. can be added to ESS in order to improve, and to reach population levels of, HRQoL already five weeks post-ESS. Physicians should evaluate HRQoL and consider ESS with nasal steroids early in their treatment of these patients.

Evaluation of nasal mucosal swelling and microcirculation throughout nasal and bronchial provocation tests with lysine-aspirin in asthmatics with nasal polyposis.

According to the GA2LEN recommendations, nasal challenge test with lysine-aspirin should be performed only in patients with severe asthma, because the sensitivity of this test has been lower than in bronchial and oral challenge tests. The AIA patient group often have severe asthma with impaired lung function, and therefore improvement of the nasal challenge is warranted. The outcomes of this study clearly indicate that a prolonged detection time from two to three hours might improve the sensitivity of the nasal challenge as a method for diagnosing aspirin intolerance. Moreover, we found a different vascular response in the nasal mucosa in the subjects with AIA after local challenge with lysine-aspirin as compared to an ATA patient group. This puts RSM-LDF as a possible new method in addition to those previously recommended for this particular test.

Functional endoscopic sinus surgery improved asthma symptoms as well as PEFR and olfaction in patients with nasal polyposis.

BACKGROUND: Nasal polyposis is a disease known to be associated with asthma. The management is anti-inflammatory, with topical and oral corticosteroids as the first-line treatment. The effect of surgical treatment on lower airway inflammation has not been sufficiently studied. AIM: The aim of this study is to investigate the effects of functional endoscopic sinus surgery (FESS) as well as fluticasone proprionate nasal drops (FPND) 400 microg b.i.d. on nasal and lower airway parameters in asthmatics with nasal polyposis. METHODS: This was a prospective 21-week study of 68 patients with asthma and nasal polyposis, on the benefits of FESS on nasal '(butanol test, subjective olfaction, peak nasal inspiratory flow, congestion, rhinorrhoea, and polyp score)', and on the lower airway parameters (dyspnea, cough, mean daily peak expiratory flow rate (PEFR), and lung function tests). It also included a randomized, double-blind, placebo-controlled 14 weeks phase on FPND. RESULTS: Functional endoscopic sinus surgery significantly improved mean asthma symptom scores and daily PEFR and all nasal parameters including subjective and objective olfaction tests. This is the first study that shows the benefits of FESS on butanol tests in patients with nasal polyposis. We found no significant difference between topical treatment with FPND or placebo in the nasal or lower airway variables. CONCLUSION: Functional endoscopic sinus surgery improved nasal and asthma symptoms in patients with nasal polyposis. Functional endoscopic sinus surgery could be considered early in the natural course of nasal polyposis with concomitant asthma, as well as a second-line treatment in nasal polyposis patients with a reduced sense of smell. The potential benefits of FPND 400 microg b.i.d. were probably overshadowed by FESS.

Genes regulating molecular and cellular functions in noninfectious nonallergic rhinitis.

BACKGROUND: Chronic noninfectious, nonallergic rhinitis (NINAR) is a complex syndrome with a principally unknown pathophysiology. New technology has made it possible to examine differentially expressed genes and according to network theory, genes connected by their function that might have key roles in the disease. METHODS: Connectivity analysis was used to identify NINAR key genes. mRNA was extracted from nasal biopsies from 12 NINAR patients and 12 healthy volunteers. Microarrays were performed using Affymetrix chips with 54 613 genes. Data were analysed with the Ingenuity Pathway System for organization of genes into annotated biological functions and, thereafter, linking genes into networks due to their connectivity. The regulation of key genes was confirmed with reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In all, 43 genes were differentially expressed. The functional analysis showed that these genes were primarily involved in cellular movement, haematological system development and immune response. Merging these functions, 10 genes were found to be shared. Network analysis generated three networks and two of these 'shared genes' in key positions, c-fos and cell division cycle 42 (Cdc42). These genes were upregulated in both the array and the RT-PCR analysis. CONCLUSION: Ten genes were found to be of pathophysiological interest for NINAR and of these, c-fos and Cdc42 seemed to be of specific interest due to their ability to interact with other genes of interest within this context. Although the role of c-fos and Cdc42 in upper airway inflammation remains unknown, they might be used as potential disease markers.

Serious complications due to acute rhinosinusitis in children up to five years old in Stockholm, Sweden - Still a challenge in the pneumococcal conjugate vaccine era.

OBJECTIVES: The aim of this study was to analyze the rate of admissions, the rate of serious complications (postseptal orbital complications and surgery) and the bacterial etiology of acute rhinosinusitis in hospitalized children under five years old in Stockholm County, eight years after the introduction of the pneumococcal conjugate vaccine (PCV). The secondary aim was to compare this period with the period four years prior to the vaccine's introduction. METHODS: This was a population-based, descriptive observational study with retrospectively collected data from 1 July 2008 to 30 June 2016 in Stockholm County. Hospital admissions of children with a discharge diagnosis of rhinosinusitis and related complications were reviewed and compared to the pre-PCV period of 2003-2007. RESULTS: A total of 215 children were admitted, for a yearly incidence of 18.8 per 100 000 children (22.8 for boys, 14.6 for girls). Computer tomography-verified postseptal orbital complications occurred in 29 cases (13.5%) and surgery was necessary in nine (4.2%). Pathogens other than Streptococcus pneumoniae were found in the cases with postseptal complication or surgery (Streptococcus pyogenes in four, Haemophilus influenzae in three and Staphylococcus aureus in one case). In comparison to the four years pre-PCV, the incidence of admission decreased from 43.81 to 20.31 and 17.45 per 100 000/year for the two four-year periods after vaccine introduction. The incidence of CT-verified postseptal complication increased slightly from 1.51 to 2.34 and 2.74 per 100 000/year. The incidence of surgeries increased marginally but continued to be very low, from 0.22 to 0.54 and 1.03 per 100 000/year. CONCLUSIONS: Complications due to acute rhinosinusitis in children living in Stockholm County continues to be very rare after the introduction of pneumococcal vaccine. Hospitalization has decreased for children under five years old after PCV introduction, but the incidence or postseptal complications and surgery in the same population increased slightly. Predominantly bacteria other than Streptococcus pneumoniae was found. There is a need of larger studies to determine trends, and a need of prospective studies to elucidate the bacterial etiology, of serious complications due to acute rhinosinusitis in children.

Position paper on olfactory dysfunction.

Background: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: • Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. • Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. • Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. • Comprehensive chemosensory assessment should include gustatory screening. • Smell training can be helpful in patients with olfactory loss of several aetiologies. Conclusions: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Capsaicin and nicotine-sensitive afferent neurones and nasal secretion in healthy human volunteers and in patients with vasomotor rhinitis.

1. Applications of capsaicin, nicotine and methacholine were made locally onto the nasal mucosa in human controls and patients suffering from hyperreactive nasal disorders. Perception of sensation was registered as a sympton score and secretion quantified. The sensory reaction (irritation - pain) to capsaicin was similar in the three groups studied, i.e. controls, a group of patients with the diagnosis of vasomotor rhinitis and a group of patients with increased nasal secretion as the main symptom of the hyperreactive disorder. Nicotine induced only a mild itching sensation in the three groups. However, capsaicin and nicotine challenge caused a significantly larger secretory response in the last group than in the unselected vasomotor rhinitis group and in the control group. 2. Pretreatment with muscarinic receptor antagonists almost completely abolished the secretory response to both capsaicin and nicotine, and blocked methacholine-induced secretion. Furthermore, pretreatment with a combination of local anaesthetic and vasoconstrictor agent abolished the capsaicin-induced irritation, as well as the capsaicin- and nicotine-induced secretion on both the ipsilateral and the contralateral side. Therefore, no clearcut contribution seems to be exerted by locally released peptides from sensory neurones as direct trigger substances for the secretory response to capsaicin. 3. In conclusion, the nasal secretory response, in man, to both capsaicin and nicotine, seems to be mediated via cholinergic parasympathetic reflexes. In patients with hyperreactive non-allergic disorders of the nasal mucosa with rhinorrhea as the main complaint, the enhanced secretion may be due to a hyperreactive efferent cholinergic mechanism rather than hypersensitive irritant receptors on capsaicin- and nicotine-sensitive sensory neurones. Challenge with irritant agents seems a useful test for the evaluation of both afferent and efferent reflexogenic responses in hyperreactive disorders of the nasal mucosa.

Bronchodilatation in vivo by carbon monoxide, a cyclic GMP related messenger.

1. Recent studies suggest that gaseous carbon monoxide (CO) is involved in neurotransmission and that this molecule also is an important vasodilator in vivo. In the present study we evaluated the effect of inhaled CO on guinea-pig airway smooth muscle tone. The mechanisms involved were characterized by use of a cyclic GMP antagonist, Rp-8Br-cyclic GMPS, and a nitric oxide synthase inhibitor, L-NAME. 2. Anaesthetized, ventilated guinea-pigs were given a bolus injection of histamine (0.12 mg kg(-1), i.v.), followed by a continuous infusion of histamine (0.30 microg kg(-1) min(-1)) to increase total pulmonary resistance (RL). Subsequent exposure to 7, 15 or 30 breaths of CO (100%), resulted in a dose-dependent inhibition of the bronchoconstriction. In the highest dose tested (30 breaths), CO inhibited 80% of the histamine-induced increase in RL. 3. In separate experiments, animals receiving histamine infusions followed by 30 breaths of CO, were pretreated with Rp-8Br-cyclic GMPS (0.05 mg kg(-1)). This pretreatment abolished >60% of the CO-induced reduction in RL, but it had no effect on the bronchodilator response induced by salbutamol. In another set of experiments animals were pretreated with L-NAME (1.60 mg kg(-1)). In contrast to the Rp-8Br-cyclic GMPS pretreatment, the pretreatment with L-NAME did not affect the CO-induced reduction in RL. 4. The present findings indicate that CO causes bronchodilatation in vivo via cyclic GMP.

PACAP 1-38 as an inhaled bronchodilator in guinea pigs in vivo.

The effect on total pulmonary resistance (R1) was examined for inhaled PACAP 1-38, PACAP 1-27 and VIP in anesthetized, ventilated guinea pigs. Two minutes after inhalation, PACAP 1-38 (36 +/- 6%), PACAP 1-27 (42 +/- 9%) and VIP (48 +/- 19%) inhibited the increase in R1 (% inhibition of histamine-induced R1 prior to inhalation) caused by histamine i.v., whereas the vehicle (-1 +/- 10%) did not. This inhibitory effect lasted five times longer for PACAP 1-38 (> 50 min) than for PACAP 1-27 and VIP (< 10 min). The inhaled peptides caused no sustained effects on heart rate or blood pressure. Infusion of PACAP 1-38 i.v. dose-dependently inhibited the increase in R1 caused by inhaled histamine and by carbachol i.v..

Functional type II VIP-PACAP receptors in human airway epithelial-like cells.

VIP-PACAP receptors were characterized in a human airway epithelial-like cell line (Calu-3), Pituitary adenylate cyclase activating polypeptide (PACAP) 1-27, PACAP 1-38, vasoactive intestinal polypeptide (VIP) and the beta 1- and beta 2-adrenoceptor agonist isoproterenol (3 nM-1 microM) increased cAMP concentration dependently. The peptides and isoproterenol displayed similar potencies (range of means pEC50[M]: 6.5-7.1). The maximum increase in cAMP (Emax in % of basal cAMP level) was similar for the peptides (range of means Emax: 2500-5100%). Pretreatment with the peptidase inhibitors captopril (10 microM) and phosphoramidon (1 microM) significantly increased the cAMP response to PACAP 1-38 (to 480% of control) only.

Release of calcitonin gene-related peptide in the pig nasal mucosa by antidromic nerve stimulation and capsaicin.

The overflow of calcitonin gene-related peptide like-immunoreactivity (CGRP-LI) in the nasal venous effluent upon antidromic stimulation of the maxillary division of the trigeminal nerve with 6.9 Hz for 3 min or upon capsaicin (0.3 mumol bolus injection) were analysed in the nasal mucosa of sympathectomized pentobarbital anaesthetized pigs. The overflow of CGRP-LI upon antidromic stimulation displayed a slower appearance in the venous effluent than the overflow upon bolus injection of capsaicin. The vascular effects as revealed by the arterial blood flow, the venous blood flow, the blood volume of the nasal mucosa, i.e., the filling of the capacitance vessels and the superficial mucosal blood flow as revealed by the laser-Doppler signal were also studied. Antidromic stimulation of the trigeminal nerve as well as capsaicin bolus injection induced a marked vasodilation which was parallel to the overflow of CGRP. However, capsaicin bolus injection also resulted in a marked increase in the mean arterial blood pressure which may be due to reflex activation of sympathetic fibers. In conclusion, we have demonstrated that chemical stimulation with capsaicin as well as antidromic stimulation of nasal sensory nerves in sympathectomized animals induces both vasodilation and overflow of CGRP-LI in vivo. This indicates that CGRP may contribute to the sensory regulation of the microcirculation in the nasal mucosa.

PACAP-induced plasma extravasation in rat skin.

The effects of pituitary adenylate cyclase activating peptide (PACAP) 38, PACAP 27 and vasoactive intestinal peptide (VIP) on plasma extravasation were investigated in vivo in rat skin. PACAP 38, PACAP 27 and VIP, caused concentration-dependent extravasation in rat skin. The order of potency was PACAP 38 > PACAP 27 = VIP, whereas the order of maximal induced extravasation was PACAP 38 = PACAP 27 > VIP, suggesting that PACAP 38 might be the most powerful inducer of plasma extravasation of the three tested members of the secretin-glucagon-VIP family. Substance P (SP) was about 5 times more potent than PACAP 38 and 15 times more potent than PACAP 27. These data indicate that PACAP 38 induced plasma extravasation in concentrations roughly equimolar to SP. Pyrilamine (H1 receptor antagonist) reduced the PACAP 38-induced plasma extravasation more than 50%; cimetidine (H2 receptor antagonist) was without effect. To investigate whether a cAMP-mediated process is involved in the induction of plasma extravasation, the synthetic adenosine 3',5'-cyclic monophosphate (cAMP), dibutyryl adenosine cyclic monophosphate (DBcAMP) and the cAMP-inducing drug, salbutamol, were each injected in the skin; neither of these drugs caused extravasation. We conclude that PACAP 38 and PACAP 27 cause potent plasma extravasation which, at least in part, involves histamine release.