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The aim of this study was to investigate the possible role of capsaicin-sensitive nerves in a pulmonary delayed-type hypersensitivity (DTH) reaction. Mice (Balb/c) were skin-sensitized with dinitrofluorobenzene (DNFB; 0.5%, 100 microliters) on two consecutive days and challenged intranasally 5 days later with dinitrobenzene sulphonic acid (0.6%, 50 microliters). Sensitized mice exhibited tracheal hyperreactivity to carbachol 24 and 48 h after challenge; however, no hyperreactivity was observed 2 h after challenge. At 24 h, but not at 48 h, hyperreactivity was associated with antigen-specific lymphocyte accumulation in bronchoalveolar lavage fluid (BALF). Capsaicin pretreatment, resulting in the depletion of sensory neuropeptides, virtually abolished hyperreactivity to carbachol 24 and 48 h after challenge in sensitized mice. Although at 24 h after challenge the lymphocyte population was elevated in the BALF collected from capsaicin-pretreated mice, this accumulation was not antigen-specific. Additionally, there was an increase in polymorphonuclear leukocyte accumulation (neutrophils and eosinophils) in the BALF collected from capsaicin-pretreated mice at this time point, but this increase was more profound in the sensitized group. In summary, tracheal hyperreactivity and cellular accumulation are prominent features of the lymphocyte-associated DTH reaction induced by DNFB in the mouse lung. Evidence presented in this report highlights the possible importance of sensory neuropeptides in pulmonary inflammation and airways hyperreactivity.

Chronic obstructive pulmonary disease (COPD) is characterized by chronic airway inflammation. Cigarette smoke has been considered a major player in the pathogenesis of COPD. The inflamed airways of COPD patients contain several inflammatory cells. Vitamin A metabolites have been implicated in the repair of lung damage. Exposure to cigarette smoke has been shown to depress levels of retinol in lungs of rats. The purpose of this study was to investigate if a low, but not deficient, vitamin A status potentiated susceptibility to the development of cigarette smoke-induced lung emphysema in mice. Mice were bred that were the offspring's of 3 generations of mice that were fed a purified diet containing low levels of vitamin A and exposed to cigarette smoke for 3 months, every weekday. Then, levels of 9-cis, 13-cis, and all-trans retinoic acid, retinol and retinyl palmitate were measured in plasma, liver and right lung lobe. The left lung lobe was used to assess mean linear intercept (Lm), as a measure of smoke-induced lung damage. Average feed intakes were not different between treatment groups. We show that both retinol and retinyl palmitate levels were dramatically decreased in the storage organs of mice on the low vitamin A diet (retinol 2-fold in both lung and liver, and retinyl palmitate 5- fold in lung) which shows that the depletion was successful. However, this treatment did not result in the development of lung emphysema. However, smoke exposure led to a significant increase in Lm in mice with a low vitamin A status compared to the room air-breathing controls. Lung levels of acid retinoids were similar in all mice, irrespective of diet or smoke exposure. Concluding, a low vitamin A status increases the susceptibility to the development of cigarette smoke-induced lung emphysema, possibly because of decreased anti-oxidant capacity in the lungs due to locally reduced retinol and retinyl palmitate levels. These observations indicate that human populations with a low vitamin A status and a high prevalence of smoking may be at increased risk of developing lung emphysema.

The prevalence of asthma has increased worldwide. The reasons for this rise remain unclear. Oxidative stress plays an important role in the pathogenesis of asthma. Glutathione (GSH) is the major representative of the class of nonprotein thiols and plays a pivotal role in a variety of enzymatic and nonenzymatic reactions that protect tissues against oxidative stress. In antioxidative reactions, GSH is converted into its oxidized form, glutathione disulfide (GSSG) that in its turn is enzymatically reduced into GSH to maintain a physiological redox balance. We used a guinea pig model of asthma to assess whether the early asthmatic reaction is associated with decreased lung levels of glutathione, and whether decreased glutathione is implicated in the increased airway smooth muscle reactivity that is associated with exposure of the lungs to allergen. Lung glutathione levels were decreased immediately after the onset of the early asthmatic reaction in vivo and associated with the release of 8-iso-PGF(2alpha), an indicator for oxidative stress. Glutathione ethylester, a glutathione precursor, blunted the airway obstruction during an early asthmatic reaction in a perfusion model and glutathione depletion rendered the airways hyperreactive. Glutathione ethyl ester in the buffer prevented this hyperreactivity. These results indicate that glutathione can modulate the early asthmatic reaction as well as the airway hyperresponsiveness.

Summary This paper describes the influence of stress, immediately before a massive inoculation of a logphase P. haemolytica A 1 culture in brain-heart-infusion broth by fiberoptic bronchoscopy in 5 months old conventional calves. Differences in phagocytic cell function and numbers, lung function and lung tissue damage between stressed and non-stressed, infected calves were studied. Compared with the non-stressed calves before infection, the superoxide generation by blood polymorphonuclear leucocytes of the stressed animals was markedly reduced immediately after a 2 hours stress period, but it recovered within 3 days. The total numbers of phagocytic cells, harvested from lung lavage fluid 3 days after inoculation were twice as high in the non-stressed calves than in the stressed calves. In contrast, no differences in pulmonary lesions and functions were found between stressed or non-stressed calves. The role of several stress factors on infiltration and metabolic response of polymorphonuclear leucocytes in P. haemolytica infections and the effects of bacterial endotoxin and leukotoxin on alveolar and vascular injury are discussed.

The hygiene hypothesis suggests that a lack of bacterial infections would favour the development of allergic disease. For this reason, bacteria or their components can be used as potential treatment for allergic asthma. We investigated whether heat-killed Mycobacterium vaccae is either able to suppress the induction of allergic asthma or able to suppress already established allergic asthma.Mice were sensitized with ovalbumin (OVA)/alum on days 0 and 14. Thereafter, mice were challenged on days 35, 39 and 42 by inhalation of either OVA or saline aerosols. M. vaccae-treated mice received an injection with 106, 107 or 108 CFU heat-killed M. vaccae on days 0 and 14 or 107 CFU on days 35 and 39. On day 43, the airway responsiveness of the mice to increasing concentrations of methacholine was assessed, blood was withdrawn to measure serum parameters, and lung lavage was performed to detect cytokines and inflammatory cell number.Treatment of OVA-sensitized mice with 107 CFU M. vaccae either during sensitization or challenge suppresses airway hyper-responsiveness, airway eosinophilia and IL-5 production after OVA challenge. The increases in OVA-specific serum IgE and in IL-4 by respiratory challenges with OVA were only diminished after M. vaccae treatment (107 CFU) during sensitization.Heat-killed M. vaccae prevents allergic and asthmatic manifestations in a mouse model and, more importantly, M. vaccae treatment during challenge suppresses features of asthma, which opens up possibilities for new therapeutic interventions.

IL-16 has been described as a natural soluble CD4-ligand with immunosuppressive effects in vitro. However, little is known about the effect of IL-16 on immune responses in vivo.In the present study, we examined the effect of IL-16 administration in a murine model of allergic asthma. Next, we determined whether these effects were mediated by modulation of CD4+ T lymphocytes.Intraperitoneal administration of IL-16 completely inhibits antigen-induced airway hyper-responsiveness and largely decreases the number of eosinophils in bronchoalveolar lavage fluid (90%) and airway tissue of ovalbumin-sensitized and challenged mice. Firstly, it appears that thoracic lymph node cells isolated from in vivo IL-16-treated ovalbumin-challenged animals produce less IL-4 (77%) and IL-5 (85%) upon antigenic re-stimulation, when compared to vehicle-treated mice. Secondly, pre-incubation of lymphocytes with IL-16 in vitro reduces antigen-induced proliferation (55%) and Th2-type cytokine production (IL-4; 56%, IL-5; 77%). Thirdly, the presence of IL-16 during priming cultures of TCR transgenic T cells (DO11.10), reduces IL-4 (33%) and IL-5 (35%), but not IL-10 and IFNgamma levels upon re-stimulation.It can be concluded that IL-16 has potent immunosuppressive effects on a Th2dominated allergic airway response.

We have previously demonstrated that the administration of nerve growth factor (NGF) to guinea-pigs results in airway hyper-responsiveness within 1 h.In the present study we document the involvement of NGF in the acute allergic airway response.Guinea-pigs that are sensitized to ovalbumin show an acute bronchoconstriction directly after challenge with ovalbumin.Intratracheal application of 10 microg of antibodies directed against NGF (anti-NGF) 1 h before the challenge reduces the acute severe bronchoconstriction to approximately 40% and the sustained bronchoconstriction to approximately 20% of the reaction in controls. This shows a high potency of anti-NGF in diminishing the direct bronchoconstriction. Inhibition of the tyrosine kinases of the tyrosine kinase receptor A, the high-affinity receptor for NGF, has no effect on the bronchoconstriction. Therefore, we postulate that the p75, the low-affinity receptor for neurotrophins, is responsible for the acute bronchoconstriction. Our findings suggest a role for NGF in the induction of the acute asthmatic reaction.These findings offer a new potential therapeutic strategy for the treatment of allergic asthma.

1. Nerve growth factor induces an airway hyperresponsiveness in vivo in guinea-pigs, as we have shown previously. Since antagonizing the neurokinin-1 (NK(1)) receptor can prevent this NGF-induced airway hyperresponsiveness and since sensory nerves release tachykinins, we investigated the role of sensory nerves in the NGF-induced airway hyperresponsiveness. 2. We used isolated tracheal rings from guinea-pigs to measure tracheal contractility. In these rings sensory nerve endings are present, but these endings lack any contact with their cell bodies. 3. In this in vitro system, NGF dose-dependently induced a tracheal hyperresponsiveness to histamine. The NK(1) receptor antagonist SR140333 could block the induction of tracheal hyperresponsiveness. 4. To further investigate the involvement of sensory nerve endings we used the cannabinoid receptor 1 (CB(1)) agonist R-methanandamide to inhibit excitatory events at the nerve terminal. The CB(1) receptor agonist was capable of blocking the tracheal hyperresponsiveness to NGF in the isolated system, as well as the airway hyperresponsiveness to NGF in vivo. 5. This indicates that NGF can induce an increase in airway responsiveness in the absence of sensory nerve cell bodies. NGF may act by increasing substance P release from sensory nerve endings, without upregulation of substance P in the neurons. Substance P in its turn is responsible for the induction of the NGF-induced airway hyperresponsiveness.

1. The contribution of reactive nitrogen species to the development of airway hyperresponsiveness in a mouse model of allergic inflammation was investigated by the use of selective inhibitors of nitric oxide and superoxide formation. 2. Sensitized mice, repeatedly challenged with ovalbumin showed a significant (P0.001, n=9) increase in airway responsiveness measured using whole body plethysmography. This hyperresponsiveness was accompanied by an influx of eosinophils into the airway lumen and increased levels of ovalbumin-specific serum IgE. 3. Treatment of mice with the iNOS inhibitor 1400 W or the NADPH-oxidase inhibitor apocynin did not significantly alter cellular influx into the airway lumen nor serum ovalbumin specific IgE. In contrast, apocynin as well as 1400 W inhibited ovalbumin-induced airway hyperresponsiveness (P0.001 and P0.05 respectively, n=9). Furthermore, the airways of allergen challenged animals showed clear 3-nitrotyrosine staining, which was mainly located in eosinophils. Remarkably, treatment with apocynin or 1400 W did not alter 3-nitrotyrosine staining. 4. These data suggest that the development of airway hyperresponsiveness during the airway inflammation upon ovalbumin challenge is dependent on the release of both superoxide and nitric oxide and is therefore likely to be dependent on reactive nitrogen species. This mechanism, however, is not reflected by 3-nitrotyrosine formation in the airways.

In this study the effect of betamethasone was investigated in guinea pigs that demonstrate airway inflammation and airway hyperresponsiveness after a viral respiratory tract infection with parainfluenza-3 (PI3) virus. Guinea pigs were pretreated with saline or betamethasone 8 mg/kg intraperitoneally twice a day for five consecutive days, starting on day 0 and ending on day 4. On day 1, the guinea pigs were inoculated with either control solution (medium) or PI3 virus. On day 5, airway responsiveness was measured. Furthermore, a blood sample was taken, lungs were lavaged, blood leucocytes were counted, and bronchoalveolar lavage (BAL) cells were counted and differentiated. Accordingly, the activity of the bronchoalveolar cells was measured by lucigenin-amplified chemiluminescence. In virus-infected guinea pigs the total bronchoalveolar cell number was increased by 44% compared with medium-treated guinea pigs. This was mainly due to the increase in macrophages (70%, P0.05) and eosinophils (344%, P0.001). The increase in both total and differential (macrophages and eosinophils) cell numbers in virus-infected guinea pigs was completely abolished in animals treated with betamethasone. Moreover, betamethasone prevented the decrease in number of blood leucocytes in virus-infected guinea pigs. In contrast, betamethasone did not prevent the increase in airway responsiveness to both histamine (200%) and methacholine (100%) after the virus infection. In conclusion, betamethasone treatment prevents virus-induced airway inflammation but not airway hyperresponsiveness in guinea pigs.

In previous studies we found that guinea pigs demonstrate an increase in airway reactivity and eosinophil numbers 4 days after a respiratory infection with parainfluenza-3 (PI3) virus. Clinical data support the possible involvement of eosinophils in virus-induced airway hyperresponsiveness. Eotaxin, a newly discovered chemokine, could be involved in eosinophil migration to the airways. In this study, eosinophil numbers were counted in blood and bronchoalveolar lavage (BAL) fluid and related with eotaxin concentrations in BAL fluid 1, 2, 3, and 4 days after intratracheal PI3 virus administration. On day 1, blood eosinophils increased by more than 200% (P0.01). The number of eosinophils were only slightly enhanced from day 2 to day 4 (40%-70%). BAL fluid eosinophils were not increased on day 1 but were significantly elevated on day 2 (180%) and remained high on days 3-4 (300%, P0. 05). This increase in lung eosinophils correlated well with eotaxin levels measured in BAL fluid. There was no significant increase in eotaxin on day 1 following PI3 infection; however, on days 2-4 eotaxin levels in BAL fluid were significantly elevated (four-sixfold increase) when compared with medium inoculated controls. Eotaxin appears to play an important role in eosinophil accumulation in guinea pig lung following PI3 infection.

There is increasing evidence that in allergic asthma the inflammatory process is regulated by T lymphocytes. In BALB/c mice the majority of ovalbumin responsive T lymphocytes express the Vbeta8.1+ and Vbeta8.2+ T-cell receptor.We analysed the contribution of Vbeta8+ T lymphocytes during the sensitization and challenge phase in the regulation of antigen-specific IgE, airway hyperresponsiveness and cellular infiltration in the airways in a murine model of allergic asthma.Mice strains genetically lacking (SJL/J and SJA/9) and expressing (BALB/c) the Vbeta8+ T cell receptor were used. In addition, prior to the sensitization and prior to the challenge BALB/c mice were treated with antibodies to Vbeta8. Mice were sensitized with ovalbumin, followed by repeated challenge with ovalbumin or saline aerosols.In ovalbumin challenged BALB/c mice treated with control antibody a significant increase in eosinophils in the bronchoalveolar lavage, airway hyperresponsiveness and increased serum levels of ovalbumin-specific IgE were observed compared to control mice. Treatment of BALB/c mice with antibodies to Vbeta8 prior to the sensitization or prior to the challenge period completely inhibited the ovalbumin induced infiltration of eosinophils and airway hyperresponsiveness, while ovalbumin-specific IgE was slightly decreased. In SJA/9 and SJL/J mice ovalbumin challenge did not induce eosinophilic infiltration and airway hyperresponsiveness. In SJL/J mice ovalbumin challenge induced an upregulation of ovalbumin-specific IgE, however, in SJA/9 mice no upregulation was observed.It is demonstrated that Vbeta8+ T lymphocytes are essential for infiltration of eosinophils in the airways and development of airway hyperresponsiveness in a murine model of allergic asthma. In contrast, although Vbeta8+ T lymphocytes seem to be important for the extent of IgE levels, no essential role for Vbeta8+ T lymphocytes in the induction of antigen-specific IgE was observed.

Allergic asthma is thought to be regulated by Th2 cells, and inhibiting this response is a promising mode of intervention. Many studies have focused on differentiation of Th cells to the Th1 or Th2 subset in vitro. IL-4 is essential for Th2 development, while IL-12 induces Th1 development, which can be enhanced by IL-18. In the present study, we investigated whether IL-12 and IL-18 were able to interfere in Th2 development and the associated airway symptoms in a mouse model of allergic asthma. Mice were sensitized with OVA using a protocol that induces IgE production. Repeated challenges by OVA inhalation induced elevated serum levels of IgE, airway hyperresponsiveness, and a predominantly eosinophilic infiltrate in the bronchoalveolar lavage concomitant with the appearance of Ag-specific Th2-like cells in lung tissue and lung-draining lymph nodes. Whereas treatments with neither IL-12 nor IL-18 during the challenge period were effective, combined treatment of IL-12 and IL-18 inhibited Ag-specific Th2-like cell development. This inhibition was associated with an absence of IgE up-regulation, airway hyperresponsiveness, and cellular infiltration in the lavage. These data show that, in vivo, the synergistic action of IL-12 and IL-18 is necessary to prevent Th2-like cell differentiation, and consequently inhibits the development of airway symptoms in a mouse model of allergic asthma.

1. Since both histamine and 5-hydroxytryptamine (5-HT) can be released by murine mast cells, we investigated the possible role of these autacoids on airway hyperresponsiveness (AHR), eosinophil infiltration and serum-IgE levels in a murine model of allergic asthma. 2. Ovalbumin-sensitized mice were exposed to either ovalbumin (2 mg ml(-1)) or saline aerosols on 8 consecutive days. Starting one day before the challenge, animals were injected i.p. twice a day with a 5-HT-type 1 (5-HT1) or type 2 (5-HT2) receptor antagonist (methiotepine, 1.25 or 2.0 mg kg(-1) and ketanserin, 12 mg kg(-1), respectively) or a histamine-type 1 (H1) or type 2 (H2) receptor antagonist (mepyramine, 12 or 20 mg kg(-1) and cimetidine, 10 or 25 mg kg(-1), respectively). Furthermore, animals were injected with a combination of cimetidine and ketanserin or with an alpha-adrenoceptor antagonist (phentolamine, 5 mg kg(-1)). 3. In vehicle-treated ovalbumin-challenged animals airway responsiveness to intravenous injections of methacholine in vivo was significantly (9 fold increase, P0.01) increased when compared to vehicle-treated saline-challenged animals. Furthermore, ovalbumin challenge of vehicle-treated animals induced a significant increase in both eosinophil numbers in bronchoalveolar lavage (BAL) fluid (0+/-0, vehicle/saline and 15.0+/-5.9 x 10(4) cells vehicle/ovalbumin, P0.05) and ovalbumin-specific IgE levels in serum (157+/-69 and 617+/-171 units ml(-1), respectively, P0.05) compared to saline-challenged mice. Virtually no eosinophils could be detected in saline-challenged animals after all different treatments. 4. Treatment with ketanserin or cimetidine resulted in a partial but significant decrease of the ovalbumin-induced AHR compared to ovalbumin-challenged controls (P0.05) and reduced eosinophil infiltration after ovalbumin challenge by 60% and 58%, respectively. The combination of cimetidine and ketanserin almost completely abolished AHR whereas eosinophilia was decreased by 49%. No effects of these antagonists were observed on IL-16 levels in BAL fluid or on serum antigen-specific IgE levels. Treatment with either the H1-receptor, the 5-HT1-receptor or the alpha-adrenoceptor antagonist, did not decrease the observed ovalbumin-induced airway responsiveness or eosinophilia in vehicle-treated animals. Higher doses of either methiotepine (2.0 mg kg(-1)) or mepyramine (20 mg kg(-1)) did decrease ovalbumin-induced eosinophil infiltration (by 67%, P0.05 and 73%, respectively), whereas no effects of these antagonists were observed on ovalbumin-specific IgE levels in serum. 5. From these data it can be concluded that both histamine and 5-HT play a role in antigen-induced AHR and eosinophilia in the mouse.

In this study, the role for sensory neuropeptides in the induction of pulmonary inflammation associated with a delayed-type hypersensitivity (DTH) reaction in the mouse lung was investigated. Dinitrofluorobenzene (DNFB) was used as the sensitizing hapten and dinitrobenzene sulfonic acid was used as the intranasal challenge. Two hours after the challenge, no hapten-specific differences were observed between vehicle- and DNFB-sensitized mice. However, mucosal exudation and leukocyte accumulation (mononuclear leukocytes and neutrophils) were enhanced in the DNFB group 24 h after the challenge. In additional experiments we investigated whether the sensory nerves and specific sensory neuropeptides play a role in this pulmonary DTH reaction. The selective NK1 antagonist (RP 67580; 5.10(-9) mol/mouse), administered 5 min before and 1 h after the challenge, suppressed mucosal exudation and leukocyte accumulation in the airways 24 h after the challenge. In contrast, the selective calcitonin gene-related peptide (CGRP) antagonist, CGRP8-37 (5.10(-9) mol/mouse) had no effect on the pulmonary DTH reaction. Surprisingly, the depletion of all sensory neuropeptides resulted in an enhancement of mucosal exudation in vehicle- and DNFB-sensitized mice 24 h after the challenge. In conclusion, these results demonstrate that the tachykinins are important in mediating mucosal exudation and leukocyte accumulation associated with the DTH reaction in mouse airways. However, the findings in neuropeptide-depleted mice suggest that the sensory nerves may also play a protective role in mouse airways.

Rabbit aorta contracting substance-releasing factor (RCS-RF) is found in perfusates from guinea pig lungs during anaphylaxis. It has been identified as a small peptide which releases arachidonic acid from lung tissue, thus generating prostaglandin endoperoxides and tbromboxanes and causing bronchocconstriction. Anti-inflammatory steroids block the release of arachidonate by RCS-RF. In this activity their relative potency is very similar to their relative anti-inflammatory potency, suggesting that the two actions may be related.

Bacterial endotoxin induced a 38% decrease in the number of beta-adrenergic binding sites (Bmax) on splenic lymphocytes, four days after intraperitoneal administration to guinea pigs. No change in the affinity (Kd) for [125-I]-cyanopindolol ([125-I]-CYP) binding was observed. Incubation of guinea pig splenocytes in vitro with different concentrations of bacterial endotoxin for 24 hours resulted in an increased incorporation of [3H]-thymidine, a parameter for lymphocyte activation. Activation of splenic lymphocytes with the optimal endotoxin concentration of 100 micrograms/ml for 24 hours induced a 27% decrease in the Bmax whereas the Kd for [125-I]-CYP binding was not changed. Based on these findings, we speculate that activation of lymphocytes with endotoxin in vitro and in vivo is associated with a reduction in the number of beta-adrenergic binding sites on these cells. Anterior hypothalamic (AHA) lesions protected against the endotoxin-induced reduction in the number of beta-adrenergic binding sites on lymphocytes. The protective effect of these lesions could not be related to alterations in the plasma levels of cortisol, triiodothyronine (T3), thyroxine (T4), adrenaline and noradrenaline or to splenic noradrenaline content. Since AHA lesions have been shown to inhibit several lymphocyte functions, it is suggested that these lesions prevent lymphocyte activation after in vivo endotoxin administration and through this abrogate the reduction of the beta-adrenergic binding sites.

Noradrenaline and alpha-methylnoradrenaline applied to the area of the nucleus tractus solitarii of the medulla oblongata decreased arterial blood pressure and heart rate of anesthetized normotensive rats. Alpha-Methylnoradrenaline was more effective than noradrenaline. Prior administration of the alpha-adrenergic blocking agent phentolamine at the same site prevented the central inhibitory action of the two catecholamines and even reversed the effect on blood pressure. The hypotensive responses evoked by electrical stimulation or alpha-methylnoradrenaline application were found to have a common distribution of the most effective site, comprising the middle-caudal part of the nucleus tractus solitarii at the obex level. Bilateral electrolytic lesions of this area caused an immediate and severe hypertension. The data suggest that the area of the nucleus tractus solitarii is a site of action of hypotensive drugs which may act by noradrenergic receptor stimulation in the brain. In addition brain serotonin may also play an inhibitory role as indicated by the association of elevated blood pressure and brainstem serotonin depletion during treatment with para-chorophenylalanine of normotensive and genetic hypertensive rats.

Application of a solid renal artery clip (0.25 mm i.d.) in rats with an undisturbed contralateral kidney (two-kidney one clip renal hypertension; 2KH ) causes a small increase in blood pressure within the first 3 hr. After pretreatment of the animals with aspirin the blood pressure response was enhanced. In contrast, in unilaterally nephrectomized rats after clipping(one-kidney one clip renal hypertension; 1KH ), the increase in blood pressure of the control and aspirin pretreated group was similar and at the level of the aspirin pretreated group of the 2KH -rats. One day after clipping in the 2KH -rats there was still a marked enhancement of the blood pressure increase induced by the prostaglandin-synthesis inhibitor. Plasma renin activity of the aspirin and control group 1 hr after clipping was significantly increased as compared to the sham operated animals in as well the 2KH - and 1KH -rats. The converting enzyme inhibitor captopril attenuates the acute increase in blood pressure in both control and aspirin treated 2KH - and 1KH -rats pointing to a major role for angiotensin II. It is suggested that the potentiation of blood pressure after prostaglandin synthesis inhibition is due to a diminished release of prostaglandins by the contralateral kidney. The data indicate that in intact rats prostaglandins may act as breaking mechanism against hypertensive influences such as a sudden increase in blood pressure by angiotensin II.

Renal hypertension (one-clip, two kidney) developed to a lower level in essential fatty acid (EFA)-deficient rats than in controls on a complete diet. Body weight gain was the same in both clipped groups. Hypertension in rats on an EFA-deficient diet supplemented with linoleic acid (corn oil) was comparable to that in rats on a complete diet. Plasma renin activity was significantly higher in both hypertensive groups. However, in the EFA-deficient groups the difference between hypertensive and sham-operated rats was 63% less than in the "control" groups. Indomethacin potentiated the development of renal hypertension of the control group. Addition of 3.5% linoleic acid (corn oil) to a complete diet blunted the development of hypertension. It is suggested that in the EFA-deficient rats, a lack of endogenous prostaglandin biosynthesis is not responsible for the attenuated development of renal hypertension.

The Gram-negative bacterium Haemophilus influenzae has been shown to cause a deterioration of the guinea pig pulmonary beta-adrenergic receptor system. In the present study we investigated further the mechanisms behind this effect. To this extent we evaluated the involvement of pulmonary macrophages (PM). Treatment of guinea pigs with killed H. influenzae bacteria resulted in the accumulation of a factor in the serum which could specifically stimulate PM. Thus stimulated, PM from nontreated animals caused a decrease of tracheal beta-adrenergic receptor function in vitro. This effect was evident by a decrease of the maximal response of the dose-response curves to isoprenaline, whereas the EC50 values did not change. Catalase and thiourea abolished the PM-induced effects, whereas superoxide dismutase did not, indicating that oxygen-centered radicals, in particular the highly reactive hydroxyl radical, may be responsible for the observed effects. In addition, dexamethasone also inhibited the decrease of tracheal beta-adrenergic receptor function. When activated PM, taken from animals that had been pretreated with killed H. influenzae bacteria 4 days beforehand, were stimulated with serum from a H. influenzae-treated animal, a potentiation of tracheal beta-adrenergic receptor function was observed.

At an ambient temperature of 21 °C α-methyldopa (25–200 mg kg−1) induces a dose-dependent decrease in body temperature in rats. A relationship between adrenergic and opioid neuronal systems has been reported. Therefore, in this study the hypothesis that α-methyldopa produces hypothermia through release of endogenous opioid peptides has been investigated using the opiate antagonist naltrexone. The hypothermic effect of α-methyldopa is potentiated by naltrexone pointing to antagonism of an hyperthermic acting opioid system. However, at an ambient temperature of 6 °C, pretreatment with naltrexone did not significantly alter the hypothermic effect of α-methyldopa. Although the hypothesis proved not to be correct, it is concluded that depending on ambient temperature opioid peptides are involved in the determination of the ultimate effect of α-methyldopa on body temperature in rats.

Haemophilus influenzae is a bacterium that can be isolated from the deeper airways of asthmatic patients. We investigated the effect of vaccination with H. influenzae on alpha and beta adrenoceptor function in guinea-pig tracheal spirals and lung parenchymal strips. The tracheal spirals from H. influenzae-vaccinated animals showed significantly less relaxation to isoproterenol as compared to controls, independent of whether the trachea was maximally contracted with carbachol or only exhibited an intrinsic tone. Furthermore, an increased contractile response to carbachol was observed in these spirals. To isoproterenol in the presence of a beta-2 adrenergic antagonist (H35/25), or to salbutamol alone, the tracheal preparations from H. influenzae-vaccinated animals also showed a decreased relaxation. These results suggest involvement of both beta-1 and beta-2 subtype adrenoceptors. On the other hand, lung parenchymal strips from vaccinated guinea-pigs relaxed significntly more to these drugs. This effect was not influenced by H35/25 but could be inhibited by phenoxybenzamine. Histamine-induced contraction did not differ between the groups. These results indicated that H. influenzae causes a partial blockade of the beta adrenoceptors in tracheal spirals and, therefore, may have important implications in asthmatic bronchitis. In contrast, parenchymal lung strips of the H. influenzae-pretreated group showed an increased relaxation.

The present study compares the cardiovascular activity of a newly introduced and possibly safer acellular pertussis vaccine with that of a conventional whole-cell pertussis vaccine. The vasodilation that occurs after beta-2 adrenoceptor stimulation with salbutamol, as well as the negative chronotropic action induced by the muscarinic receptor stimulant arecoline, were inhibited 4 days after vaccination with two combined diphtheria-pertussis-tetanus whole-cell vaccines and their plain pertussis product. Using doses equivalent to those given to humans, detoxified acellular pertussis component-combined vaccines (diphtheria-pertussis-tetanus) and the nonabsorbed (detoxified pertussis component) induced minimal or no reduction in vascular beta-2 adrenergic and cardiac cholinergic receptor responsiveness as compared to saline-treated animals. Moreover, basal blood pressure values were significantly lower in whole-cell vaccine-treated rats than in animals vaccinated 4 days previously with acellular vaccine (or its ground products). Assuming that the present model can be used to predict the toxicity of pertussis vaccines in infants, it is concluded that the absence of a strong autonomic impairment might point toward the use of a less toxic acellular component vaccine in clinical practice.