The site of action of Ptychodiscus brevis toxin within the parasympathetic axonal sodium channel h gate in airway smooth muscle

The red tide toxin produced by Ptychodiscus brevis ( PBTX ) may cause cough, sneezing, and asthma. Previous in vitro studies with isolated canine tracheal smooth muscle demonstrated that PBTX stimulates sodium channels of parasympathetic nerve endings and thus causes a contractile response. The present study investigated the mechanism of the PBTX effect on canine tracheal smooth muscle. Repeated exposure of the muscle strip to PBTX (final concentration 46 micrograms/ml) followed by washout of the toxin resulted in reestablishment of baseline tension but a failure of contraction on further addition of PBTX . However, veratridine and scorpion toxin (SCT), which are voltage-sensitive sodium channel activators, still induced contraction. Furthermore, the contraction caused by veratridine was enhanced by a high dose of PBTX , whereas contraction caused by SCT was not. Responses to veratridine and SCT as well as PBTX (previously reported) were blocked by tetrodotoxin (a sodium channel blocker), while acetylcholine responsiveness remained intact. These results indicate that PBTX receptors in parasympathetic nerves influence Na+ flux at the h gate, that these receptors differ from the veratridine and SCT receptors, and that the conformational change in the receptors induced by PBTX affects the tissue response to veratridine.     

Effects of JTV-506, a new K+ channel activator, on airway smooth muscle contraction and systemic blood pressure

Background ATP-sensitive K⁺ (K_ATP) channel activators produce relaxation of smooth muscle in many tissues. However, this wide range of effects restricts their clinical usefulness in bronchial asthma because of a reduction in systemic blood pressure. Methods We have now examined the effects of JTV-506, a new benzopyran derivative, on airway smooth muscle contraction and systemic blood pressure and have compared this compound with cromakalim. We measured isometric tension records from guinea-pig isolated trachea, as well as the respiratory resistance (R_rs) and systemic blood pressure in anesthetized guinea-pigs. Results JTV-506 caused a concentration-dependent inhibition of histamine-induced contraction in guinea-pig isolated tracheal smooth muscle, and was antagonized by glibenclamide. JTV-506 was 7.6-fold more potent than cromakalim. In anesthetized animals the intravenous injection of JTV-506 reduced the increase in R_rs induced by intravenous application of 5 μg/kg of histamine in a dose-dependent manner, 10μ/kg of JTV-506 resulted in 57.0 17.9% inhibition of the increase in R_rs at 10 min. The inhibitory action on R_rs disappeared after 60 min. 10μg/kg of cromakalim caused 25.4 ± 5.8% inhibition of the increase in R_rs induced by histamine at 1 min. The ED₅₀ values for JTV-506 and cromakalim were 6.7 ± 3.5μg/kg and 60.1 ± 15.8μg/kg, respectively (P<0.05). Cromakalim was ± 9-fold less potent in inhibiting the increased R_rs by histamine. and the inhibitory action lasted less than 10 min. The reduction of systemic blood pressure by JTV-506 and cromakalim (each at a dose of 10μg/kg iv) was 11.3% and 21.5%, respectively Conclusion JTV-506 inhibits histamine-induced contraction of tracheal smooth muscle by activation of K_ATP channels. This compound is more potent and longer-lasting in the suppression of histamine-induced increases in R_rs, and is less hypotensive than cromakalim. Our results suggest that this compound merits further investigation for utility as a bronchodilator in the clinic.     

Coercion theory revisited: Toward a new theoretical perspective on the etiology of conduct disorders

This article examines the status of current behavioral theorizing regarding the etiology of conduct disorders in young children and proposes a new cognitive social learning model. A conduct disorder includes nonconformity to social rules, immaturity, and aggression, and predicts subsequent antisocial behavior. The existing model, coercive family process theory, has been of heuristic value, but the accumulated data fail to provide compelling evidence in support of its causal hypotheses. Coercion theory is, philosophically, an operant paradigm whose fundamental assumptions may constrict basic research by limiting investigation to the directly observable. It also precludes incorporation of recent advances in developmental and cognitive psychology. This paper outlines an alternate model in which a conduct disorder is conceptualized as a deviation from normal maturation determined by the interaction of person, behavior, and environment. Nonsynchronous parent-child interactions are hypothesized to establish a template for future disordered relationships, to impair abstract modeling of cultural values, and to detract from the impact of the adult's socialization efforts.     

Effects of spinal lesions on substance P levels in the rat sympathetic preganglionic cell column: evidence for local spinal regulation

Substance P has been localized to the neuropil of sympathetic preganglionic neurons in light and electron microscopic studies. Two recent reports have suggested that the majority of substance P in the rat intermediolateral cell column was contained in synaptic terminals of bulbospinal axons. However, previous investigations in our laboratory indicated the presence of major substance P spinal-sympathetic preganglionic neuron circuitry in pigeon. The present study used radioimmunoassay and immunohistochemistry to examine substance P levels in rat intermediolateral cell column following various spinal lesions in order to assess the relative contributions of bulbospinal and intraspinal substance P neurons to the substance P content of the intermediolateral cell column. The results from these experiments support the existence of both bulbospinal and intraspinal substance P-containing projections to the rat intermediolateral cell column. In addition, characterization of spinal cord substance P-like immunoreactivity by combined high performance liquid chromatography and radioimmunoassay, revealed that substance P in rat intermediolateral cell column was indistinguishable from synthetic substance P. Following transection of thoracic spinal cord, substance P-immunoreactive staining was still evident in the intermediolateral cell column caudal to the lesion. These substance P-positive fibers were studded with bouton-like swellings and appeared normal. Following high cervical hemisection, depletion of substance P (radioimmunoassay measurements) was bilateral and equal in the intermediolateral cell column: 25% depletion was observed after 7 days and 35% depletion after 14 days. However, rats which were hemisected at low cervical and/or mid-thoracic levels contained normal or elevated amounts of substance P in the intermediolateral cell column. Since substance P remains in the intermediolateral cell column following total transection, substance P spinal-sympathetic preganglionic neuron circuitry must exist. Additionally, depletion of substance P following high cervical hemisection suggests the existence of a substance P-containing, bilateral bulbospinal pathway to the intermediolateral cell column. The observation that substance P levels were normal or elevated following low cervical lesions raises the possibility that intraspinal substance P neurons can compensate for loss of substance P in the spinal cord. Sprouting or altered substance P metabolism and/or release by intraspinal substance P neurons could be responsible, suggesting an important homeostatic mechanism for maintaining substance P content within the intermediolateral cell column.     

Effects of adjuvants on the immune response to allergens in a murine model of allergen inhalation: cholera toxin induces a Th1-like response to Bet v 1, the major birch pollen allergen

Based on the fact that type I allergies are frequently elicited by inhalant allergens, we have established a model of aerosol inhalation leading to allergic sensitization in BALB/c mice. Using this model we studied the effects of aluminium hydroxide (Al(OH)₃), known to enhance IgE antibody responses, compared with cholera toxin (CT), a potent mucosal adjuvant, on the immune response to birch pollen (BP) and its major allergen Bet v 1. Two groups of BALB/c mice were either systemically immunized with recombinant Bet v 1 in Al(OH)₃ and subsequently aerosol exposed to BP allergen, or aerosolized with BP and CT. IgE-mediated skin reactions were only elicited in the mice which had received Bet v1/Al(OH)₃. Allergen-specific serum IgE and IgG1 antibodies dominated in the Al(OH)₃ group, IgG2a antibody levels to BP and rBet v 1 were markedly higher in the sera of mice exposed to CT with the allergen. IgA antibodies were only detected in the bronchial lavage of the CT-treated group. Moreover, the latter group displayed consistently higher T cell proliferative responses to BP and interferon-gamma production in vitro. Thus, the systemic immunization with rBet v 1 in Al(OH)₃ before inhalation of the BP extract promoted a Th2-like immune response, while CT mixed with the aerosolized BP extract rather induced a Th1-like immune response. In an attempt to reverse these ongoing immune responses we could achieve a shift towards a Th0 response. Immunization with BP extract without adjuvant treatment led to undetectable antibody or cellular immune responses. We conclude from the present study that the induction of an immune response to BP allergen after aerosol inhalation can be directed towards a Th1- or a Th2-like response. Once established, the immune response can be modulated.     

Physico-chemical and clinico-immunologic studies on the allergenic significance of Aspergillus tamarii, a common airborne fungus

Aspergillus-derived inhalant allergens play an important role in the etiology of allergic respiratory diseases. In the present study, we investigated the allergenic potential of Aspergillus tamarii, quantified its airborne content, identified its major/minor allergens, evaluated heterogeneity of patients’ IgE response to its allergens and cross-reactivity of its allergens with other Aspergillus allergens. Skin prick tests with A tamarii extract were performed on 300 patients of bronchial asthma/allergic rhinitis and 20 healthy volunteers. Sixty-six patients (22%) elicited positive cutaneous reactions to A tamarii extract. Only one of the 20 non-allergic healthy volunteer showed a mild positive cutaneous reaction. Allergen-specific IgE levels increased with increase in patients’ cutaneous response (0% in negative to 100% in 3+/4+). The skin positivity and allergen-specific IgE levels were significantly higher in patients compared to healthy volunteers (P > 0.05). However, no differences were found for these two parameters among patients of bronchial asthma, allergic rhinitis and bronchial asthma with allergic rhinitis. The airborne A tamarii allergen content was highest in February and October. A tamarii extract revealed at least 22 proteins (13.3-120 kDa). Seventeen of these proteins bound patients’ IgE with six being major allergens (13.3, 23, 25, 34, 39.5, 43 kDa). Three major allergens (13.3, 34, 43 kDa) were found to cross-react with A flavus and one (34 kDa) with A niger. Our results revealed that A tamarii allergen(s) are present in the air, which might serve as important inhalant allergens in IgE-mediated allergic respiratory diseases.