D. van Heuven-Nolsen

Delayed-type hypersensitivity-induced increase in vascular permeability in the mouse small intestine: inhibition by depletion of sensory neuropeptides and NK1 receptor blockade.

1 This study investigates the effects of capsaicin‐induced depletion of sensory neuropeptides and of neurokinin! (NK1) receptor blockade on delayed‐type hypersensitivity (DTH)‐induced changes of vascular permeability in the small intestine of the mouse.

The effects of dietary mackerel oil on the recovery of cardiac function after acute ischaemic events in the pig.

To investigate the effects of fish oil nutrition on cardiac haemodynamics and the biochemical response to ischaemia-reperfusion, young pigs (5 weeks old) were fed a 9% lard fat diet or a mixed diet of 4.5% mackerel oil and 4.5% lard fat for 16 weeks. In the mackerel oil fed pigs plasma cholesterol and triglyceride levels decreased by 22% and 58% (both p less than 0.05), respectively, while levels in the animals which received only lard fat did not change. The n-6 fatty acids present in cardiac and platelet membrane phospholipids underwent a partial replacement by n-3 fatty acids in the mackerel oil fed pigs. Under anaesthesia, multiple coronary artery occlusions (5 min) were interrupted by 10 min of reperfusion. The extent of recovery of cardiac function and reduction of adenine nucleotide levels were similar for both dietary groups. The incidence of reperfusion arrhythmias was significantly lower and the reactive hyperaemic responses were of longer duration in the mackerel oil fed animals. These effects cannot be explained by diet-induced alterations in thromboxane B2/6-keto-PGF1 alpha ratio, although a marked reduction in absolute levels of both prostaglandins was seen in the mackerel oil fed pigs (p less than 0.05). In conclusion, dietary fish oil caused changes in membrane fatty acid composition and plasma prostaglandin levels, although these did not affect alterations of cardiac performance during and after short periods of ischaemia.

The influence of Bordetella pertussis and its constituents on the beta-adrenergic receptor in the guinea pig respiratory system

In the present study, the effect of vaccination of guinea pigs with Bordetella pertussis was investigated, 4 days after treatment, on the cholinergic and beta-adrenergic receptor function in isolated tracheal spirals and the number of beta-adrenoceptor binding sites in guinea pig lung. It was found that B. pertussis caused an impairment in the beta-adrenoceptor function and a decrease in its number. Similar results were obtained with endotoxin. Leucocytosis promoting factor, however, was ineffective. These results indicate that endotoxin is the constituent responsible for the beta-adrenoceptor blocking effects of the bacterium. Also the combined whole cell diphtheria, B. pertussis and tetanus toxoid vaccine induced a beta-adrenoceptor blockade; the acellular vaccine was less effective. The results obtained with the B. pertussis vaccines are discussed in relation to the possible side-effects that sometimes occur after immunization of infants.

Oxytocin affects utilization of noradrenaline in distinct limbic-forebrain regions of the rat brain

The effects of oxytocin, administered intracerebroventricularly in doses of 1, 10, 100 and 1000 pmol, were studied on the disappearance of catecholamines induced by alpha-methyl-p-tyrosine in microdissected nuclei of the rat brain. Oxytocin dose-dependently decreased the utilization of noradrenaline in the lateral and medial septal nuclei and anterior hypothalamic area, whereas an enhanced utilization was observed in the nucleus supraopticus. Tendency towards a change in utilization of noradrenaline was found in the dorsal septal nucleus and the lateral amygdala. Utilization of dopamine was not significantly affected in any of the nuclei of the brain studied. Tendency towards a decrease in utilization of dopamine was observed in the nucleus caudatus, globus pallidus and medial septal nucleus. It thus appears that oxytocin elicited changes in only a restricted number of brain nuclei. Interestingly, these nuclei contain cell bodies (nucleus supraopticus) and terminals (other nuclei) of the oxytocin system in the brain. Though the effects of oxytocin were not as widespread as those previously seen after administration of vasopressin, it is worthy of note that, in general, the effects of oxytocin were opposite to those seen after vasopressin. The opposite effects of vasopressin and oxytocin on catecholamine metabolism could be related to the opposite effects of the two peptides on behaviour, neuroendocrine and autonomic regulation.

Role of platelet activating factor in the endotoxin induced tracheal hyperreactivity to histamine in the guinea pig

Bronchial as thma is characterized by a bronchial hyperreactivity. In t raper i toneal adminis t ra t ion of bacterial endotoxin to guinea pigs has been shown to exert a variety of actions which show similarities to those obtained in asthmatic patients like hyperreactivity in vivo and in vitro to histamine which coincides with a decreased function of the betaadrenoceptors in the isolated trachea and a decreased number of beta-adrenergic binding sites in peripheral lung tissue [1, 2]. The effects of platelet activating factor (PAF) show strong similarities with those obtained with endotoxin, i.e. an increase in non-specific hyperreactivity and a down regulat ion of beta-adrenergic binding sites [3]. In the present study we therefore investigated the effect of the selective PAF-antagonis t BN 52021 on the endotoxin induced changes in histamine reactivity in isolated guinea pig tracheal spirals.

Repeated challenge with dinitrobenzene sulphonic acid in dinitrofluorobenzene-sensitized mice results in vascular hyperpermeability in the trachea: a role for tachykinins.

This study investigates the role of tachykinins in a repeated challenge with dinitrobenzene sulphonic acid (DNS) on the tracheal vascular permeability in dinitrofluorobenzene (DNFB)‐sensitized mice. DNFB‐contact sensitization was followed by an intranasal (i.n.) challenge with DNS. A second challenge with DNS was administered 24 h after the first challenge. To assess changes in tracheal vascular permeability, Evans blue dye accumulation in tracheal tissue was measured. A repeated challenge with DNS in DNFB‐sensitized mice led to a 2.8 fold increase in tracheal vascular permeability when compared to DNFB‐sensitized and vehicle‐challenged mice or a 2.5 fold increase when compared to DNFB‐sensitized single DNS‐challenged mice (P<0.001, ANOVA). RP67580 (10−9 mol mouse−1 i.v.) reduced the increased tracheal vascular permeability induced by a second exposure to DNS in DNFB‐sensitized mice completely when injected 15 min before the second challenge (P<0.001, ANOVA). The increased tracheal vascular permeability response induced by the second exposure to DNS could be mimicked with i.n. application of capsaicin (10−10 mol mouse−1) or substance P (SP) (10−12 mol mouse−1) to DNFB‐sensitized and single DNS‐challenged mice. These results suggest that both tachykinin NK1 receptors and sensory nerves are involved in the development of vascular hyperpermeability changes found in the trachea of DNFB‐sensitized mice after a repeated DNS‐challenge.

Hypersensitivity reactions in mouse airways after a single and a repeated hapten challenge

Objective and designIn this study, we examined the effect of a single and a repeated hapten-challenge on inflammatory processes in the airways of mice undergoing a hapten-induced non-IgE mediated hypersensitivity reaction.MethodsBALB/c mice were skin-sensitized with the hapten dinitroflourobenzene (DNFB) and intra-airway challenged with dinitrobenzene sulphonic acid (DNS). Mucosal exudation, tracheal vascular permeability, cellular accumulation, and serum murine mast cell protease (MMCP) were investigated at different time points after the first DNS-challenge and 30 min after a repeated DNS-challenge.ResultsMMCP levels in serum were increased at all time points after single challenge and repeated challenge. Increased vascular permeability as determined by Monastral blue staining, was found in the trachea of DNFB-sensitized mice after single DNS-challenge. A second exposure to DNS profoundly enhanced the Monastral blue labeling of the tracheal blood vessels of DNFB-sensitized mice. Furthermore, increased mucosal exudation and polymorphonuclear cell (PMN) accumulation were present in DNFB-sensitized mice compared to vehicle-sensitized animals after the first DNS challenge.ConclusionsIncreased mucosal exudation, vascular permeability, and PMN accumulation are prominent inflammatory features of the DNFB-induced hypersensitivity reaction in the airways. Furthermore, mast cell activation is associated with this hapten-induced hypersensitivity reaction.

Bovine polymorphonuclear leukocytes increase sensitivity to noradrenaline in isolated mesenteric arteries.

1 The effects of polymorphonuclear leukocytes (PMN) on vascular function to (−)‐noradrenaline were examined in vitro. Purified bovine PMN were incubated in siliconized organ baths containing rings of bovine mesenteric arteries, after which a concentration‐effect curve in response to (−)‐noradrenaline was obtained. 2 PMN‐derived products induced a long lasting concentration‐dependent contraction of the blood vessels generating 24.4 ± 6.8% of the maximal tension to (−)‐noradrenaline at a cell concentration of 2.5 × 106 ml−1. The contractile response was also found in endothelium‐denuded vascular rings. 3 PMN present in the organ bath caused an increase in the sensitivity of vascular rings to (−)‐noradrenaline. At a cell number of 2.5 × 106 PMN ml−1 the pD2‐value for (−)‐noradrenaline was augmented 0.40 ± 0.05 (P < 0.001), while total contraction at the highest concentration (−)‐noradrenaline was not affected. This increase in sensitivity was dependent on an intact endothelium. 4 The increase in sensitivity to (−)‐noradrenaline by PMN was inhibited by superoxide dismutase, but not by catalase, dimethylthiourea, indomethacin or nordihydroguaiaretic acid. The non‐stimulated bovine PMN produced oxygen radicals as measured by chemiluminescence. 5 Simultaneous incubation of PMN and (−)‐noradrenaline with arterial rings induced an increase in the release of prostacyclin, measured by an elevated concentration of 6‐keto‐prostaglandin Fα in the supernatant. 6 It is concluded that PMN can increase vascular tone directly or indirectly probably via the interaction of PMN‐derived superoxide anions with endothelium‐derived relaxing factor.

Endotoxin-induced reduction of β-adrenergic binding sites on splenic lymphocytes in vivo and in vitro: Its modulation by anterior hypothalamic lesions

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.

Increased reactivity to histamine in the coronary vascular system of the guinea-pig after endotoxin.

Histamine produced a dose-dependent increase in heart rate, myocardial contractility and coronary flow in the isolated guinea-pig heart using a modified Langendorff procedure. Intraperitoneal treatment of the guinea pigs withE. coli endotoxin, 4 days prior to the experiment, enhanced the positive chronotropic and flow-increasing effect of histamine. The increased response to histamine appeared to be H1-receptor mediated, the positive chronotropic response is attributed to H2-receptors. These results indicate that bacterial endotoxin increases the reactivity of the coronary vascular system of the guinea-pig to histamine.